Chimeric antigen receptors with intracellular signaling domains tailored for use in macrophages/monocytes
Christian Brendel, PhD, Department of Hematology/Oncology

Despite tremendous efficacy of CAR-T cells for some liquid cancers, CAR-T cell therapy is less efficient in most solid tumors as penetration into tumors are limited and/or suppression of the CAR-T cell activity is suppressed by the tumor milieu leading. In contrast, macrophages are abundant in many solid tumors and are criticial in shaping the milieu and modulating immune responses. Thus, key factors wich limit CAR-T cell anti-tumor responses could be addressed by conferring anti-tumor activity to macrophages by introducing CARs into macrophages or their progenitors.
Previously, Dr. Brendel and his team evaluated intracellular signaling domains derived from cell surface receptors suggesting a TLR-derived ICD outperformed other established and novel configurations in phagocytosis assays. With support from Boston Children’s Technology Development Program, Dr. Brendel and his team are looking to gather data showcasing their modified CAR-structure to be compatible with a variety of different extracellular domains for the targeting of different solid tumor antigens in vivo and in vitro in mouse models.


  • Klichinsky, M., Ruella, M., Shestova, O., Lu, X. M., Best, A., Zeeman, M., Schmierer, M., Gabrusiewicz, K., Anderson, N. R., Petty, N. E., Cummins, K. D., Shen, F., Shan, X., Veliz, K., Blouch, K., Yashiro-Ohtani, Y., Kenderian, S. S., Kim, M. Y., O’Connor, R. S., Wallace, S. R., … Gill, S. (2020). Human chimeric antigen receptor macrophages for cancer immunotherapy. Nature biotechnology, 38(8), 947–953.
  • Morrissey, M. A., Williamson, A. P., Steinbach, A. M., Roberts, E. W., Kern, N., Headley, M. B., & Vale, R. D. (2018). Chimeric antigen receptors that trigger phagocytosis. eLife, 7, e36688.

Evaluating short term efficacy of novel cartilage implant in a large animal model
April M. Craft, PhD, Department of Orthopedic Surgery

Osteoarthritis (OA) and post-traumatic osteoarthritis (PTOA) are debilitating degenerative diseases caused by the inability of the joint-lining articular cartilage to repair itself as we age, or after injury. Instead, this tissue will progressively deteriorate, causing lifelong pain and interference with daily living activities. Current therapies for cartilage degeneration, primarily pain management and joint replacement surgery, are inadequate, particularly for younger patients who face repeat joint replacement surgeries throughout their lifetime. Successful repair of damaged articular cartilage would effectively prevent or delay the onset of joint degeneration, thus there has been much effort focused on developing cell and tissue based therapies, many of which use autologous cells.
The Craft lab is looking to establish a novel, low-risk, cost-effective, single-step treatment to replace damaged tissue from human embryonic stem cells. With support from Boston Children’s Technology Development Program, Dr. Craft and her team are planning to evaluate the efficacy of their hESC-derived cartilage implant in Yucatan miniature swine. This large animal pilot study will provide the crucial proof-of-concept data to acquire sponsored research support to fund a large-scale preclinical study and initiate manufacturing efforts, and they will be able to provide individuals with better treatment options that allow them to maintain a pain-free high quality of life.


Drug Development for Arteriovenous Malformation: Determining the Therapeutic Index for Subcutaneous Injection of MEK Inhibitor Microparticles
Arin K. Greene, MD, MMSc, Department of Plastic and Oral Surgery

Arteriovenous malformation (AVM) is a congenital vascular anomaly that enlarges over time to cause deformity, bleeding, pain, ulceration, and congestive heart failure. Patients are treated with embolization or excision, but almost all AVMs recur following these treatments; drugs have not been available for AVMs.
Previously, the Greene lab found the cause of AVM and was awarded IP for the treatment of AVMs with MAP2K1 inhibitors. Based on their discovery, AVM patients around the world have started to be treated with an FDA-approved MAP2K1 inhibitor from Novartis (trametinib). However, a major drawback to trametinib and other oral drugs available is their systemic toxicity. As such, patients require routine cardiac and ophthalmology screening and blood laboratory monitoring.
With support from Boston Children’s Technology Development Program, Dr. Greene and his team are looking to develop an injectable MEK inhibitor to treat AVMs and reduce systemic toxicity. Advantages of a subcutaneous delivery method compared to topical medications include: (1) the drug doesn’t need to penetrate the integument which can be difficult and injure the skin, (2) the drug can be incorporated into microparticles for slow release to allow long term therapeutic effect, and (3) patient compliance and quality of life is improved. For example, instead of placing a topical cream twice a day or wearing a patch over their skin, a patient may only need 1 injection every few weeks or months.


A novel compound for imaging and therapeutic targeting of liver cancer
Khashayar Vakili, MD, Department of Surgery

World-wide, liver cancer afflicts about 900,000 people annually and is the 3rd cause of mortality. Current treatments for liver cancer include surgery, liver transplantation, transarterial chemoembolization, and chemotherapy. The most effective treatment option has been surgical resection. However, many patients, particularly adolescents and young adults present with advanced metastatic disease which renders surgery ineffective in achieving cure and eventually succumb to their cancer given the lack of an effective chemotherapeutic agent.
Dr. Vakili and his team have already established a method of synthesizing a PET tracer compound expected to be preferentially retained by liver cancer cells for the detection of metastatic liver cancer. With support from Boston Children’s Technology Development Program, they are aiming to establish the kinetics of this compound in wild-type mice and demonastate its efficacy in a PDX model.


Prolonged Pain Relief with Aromatized Liposomes
Daniel S. Kohane, MD, PhD, Department of Anesthesiology, Critical Care & Pain Medicine

Millions of surgical cases are performed every year in the US. Perioperative analgesia is commonly (and sometimes inadequately) addressed with the use of opioids. Alternatively, prolonged pain relief can be achieved by the placement of indwelling catheters for continuous infusions of local anesthetics, which involve tethering the patients to devices and may cause infections, and which are resource-intensive, necessitating skilled personnel for administration.
Dr. Kohane and his team have developed liposomes in which the acyl chains of the constituent lipids are modified with aromatic groups (aromatized liposomes), thus increasing drug loading and sustained drug release compared to unmodified liposomes. They have demonstrated a proof-of-principle application of aromatized liposomes in local anesthesia, an area where liposomal products are used clinically. With support from Boston Children’s Technology Development Program, Dr. Kohane and his team aim to move the platform toward clinical translation by identifying the formulations with the best combination of the duration of effect and lack of systemic toxicity.

A portfolio of gene-up regulating oligonucleotides for neurogenetic diseases
Timothy Yu, MD, PhD, Department of Genetics & Genomics

Recent years have seen great inroads into discovering the genetic basis of pediatric neurologic diseases, with hundreds of single gene disorders being discovered, but treatments remain scarce. Advances in genomic technologies are beginning to point not only to critical disease genes but also methods for intervening upon them. Viral gene replacement strategies are showing promise for some conditions, but are also appreciated to have significant challenges.
Previously, the Yu lab successfully developed antisense oligonucleotides (ASOs) capable of boosting levels of progranulin (GRN), a genetic cause of a childhood neurodegenerative disorder (Batten disease) as well as adult onset fronto-temporal dementia (FTD), leveraging the ability of ASOs to relieve naturally occurring inefficiencies in GRN RNA splicing. A similar ASO boosting SCN1A expression in epileptic children with Dravet Syndrome is already in Phase 1/2 clinical trial.
With support from Boston Children’s Technology Development Program, they are aiming to (1) identify at least 10 potential gene targets for ASO intervention for a variety of pediatric neurogenetic disorders, and (2) generate a genome-wide catalog of therapeutic ASOs designs targeting their specific inefficiencies. By targeting existing gene loci, ASO-enhanced expression remains under the control of endogenous gene regulatory elements, allowing one to avoid potential toxicity caused by over-or misexpression.


  • Kim, J., Hu, C., Moufawad El Achkar, C., Black, L. E., Douville, J., Larson, A., Pendergast, M. K., Goldkind, S. F., Lee, E. A., Kuniholm, A., Soucy, A., Vaze, J., Belur, N. R., Fredriksen, K., Stojkovska, I., Tsytsykova, A., Armant, M., DiDonato, R. L., Choi, J., Cornelissen, L., … Yu, T. W. (2019). Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease. The New England journal of medicine, 381(17), 1644–1652.

Medical Equipment Adaptable Travel Restraint (MEATR), Supporting Mobilization of Individuals with Complex Medical Needs
Michele DeGrazia, PhD, RN, NNP-BC and Kathryn Gustafson BSN, RN, CCRN, Department of Nursing Research

Durable Medical Equipment (DME) includes items such as oxygen and feeding pumps necessary to deliver life-sustaining support for children and adults with complex medical needs. They can become a projectile in a motor vehicle and cause passengers’ significant bodily injury or death. With support from a 2015 Boston Children’s Hospital Innovation Grant, we developed the first of its kind Medical Equipment Adaptable Travel Restraint (MEATR). Every child and adult that utilizes life-sustaining DME can benefit from the MEATR. Currently, there are no commercial products like it available.
With support from Boston Children’s Technology Development Program, Dr. DeGrazia and her team are looking to bring the MEATR to market by conducting a crashworthiness test to demonstrate its performance as outlined in Federal Motor Vehicle Safety Standard (FMVSS) No. 208, which may encourage the development of a federal safety standard for DME securement, and gather information on the voice of the customer population.

Proning Device
Heung Bae Kim, MD, Department of Surgical Research

Evidence has shown that proning patients during early stages of Acute Respiratory Distress Syndrome (ARDS) where there is significant fluid buildup in lung alveoli leads to better distribution of this fluid and thereby decreases patient morbidity, and mortality while increasing extubation rates. Given that the COVID-19 pulmonary disease progression is similar to ARDS, there has been an initiative to prone COVID positive patients both in the early disease stages (self-proning prior to intubation), and once intubated. There are proning beds that exist to prone patients mechanically, however these beds are expensive and often not readily available as they require onsite delivery to the hospital which can take an extended period of time. The device proposed by Dr. Kim’s research team is designed to address the ease of patient turning, safety, and organization during proning.
With support from Boston Children’s Technology Development Program, the team is looking to design and manufacter prototype devices with CROs. Following prototyping, the team will perform user testing in-house with ICU caregivers before returning to the CRO for design and/or material changes. The goal will be to demonstrate the device’s ease of use, efficacy, and safety and lower the barrier to prone positioning, allow providers to prone patients more readily and earlier in their clinical course.

Prolonged Pain Relief with Aromatized Liposomes
Daniel S. Kohane, MD, PhD, Department of Anesthesiology, Critical Care & Pain Medicine

Millions of surgical cases are performed every year in the US. Perioperative analgesia is commonly (and sometimes inadequately) addressed with the use of opioids. Alternatively, prolonged pain relief can be achieved by the placement of indwelling catheters for continuous infusions of local anesthetics, which involve tethering the patients to devices and may cause infections, and which are resource-intensive, necessitating skilled personnel for administration.
Dr. Kohane and his team have developed liposomes in which the acyl chains of the constituent lipids are modified with aromatic groups (aromatized liposomes), thus increasing drug loading and sustained drug release compared to unmodified liposomes. They have demonstrated a proof-of-principle application of aromatized liposomes in local anesthesia, an area where liposomal products are used clinically. With support from Boston Children’s Technology Development Program, Dr. Kohane and his team aim to move the platform toward clinical translation by identifying the formulations with the best combination of the duration of effect and lack of systemic toxicity.

Self-Expanding Shunts for Treatment of Fetal Lower Urinary Tract Obstruction
Michael P. Kurtz, MD, MPH, Department of Urology

Fetal lower urinary tract obstruction (LUTO) is a life-threatening condition in which the bladder outlet is blocked during prenatal development. It has been shown in a randomized trial treatment the placement of a shunt in utero to drain the bladder into the amniotic space results in approximately triple the odds of neonatal survival as it restores the amniotic fluid. While shunts are effective, device-related complications of the current shunts are common and severe. All shunts currently on the US market are extruded plastic tubes, unchanged in design since the 1980s.
Dr. Kurtz and his team have shown that in fetal lambs a self-expanding nitinol shunt delivered though a system designed in-house has significantly less design, usage, and use issues than the shunt currently on the market. This could allow for a one-step fetal treatment of LUTO, providing improved pregnancy outcomes.
With support from Boston Children’s Technology Development Program, they are aiming to refine the shunt and deployment system in preparation for a human trial. A handful of prototype designs will be evaluated and few will be brought all the way through production to animal testing at BCH’s ARCH animal testing facility.
Publications | Kurtz, M. P., Koh, C. J., Jamail, G. A., Sangi-Haghpeykar, H., Shamshirsaz, A. A., Espinoza, J., Cass, D. L., Olutoye, O. O., Olutoye, O. A., Braun, M. C., Roth, D. R., Belfort, M. A., & Ruano, R. (2016). Factors associated with fetal shunt dislodgement in lower urinary tract obstruction. In Prenatal Diagnosis (Vol. 36, Issue 8, pp. 720–725). Wiley.

A New Lipid Emulsion for Premature Neonates
Mark Puder, MD, PhD and Scott Fligor, Department of Surgical Research, Vascular Biology Program

Parenteral nutrition (PN) is a life-saving treatment for patients who cannot eat. PN has improved the survival of premature infants, but long-term use of the standard lipid emulsions (the fat source in PN) results in severe liver disease and increases the risk of retinopathy of prematurity and bronchopulmonary dysplasia. These lipid emulsions are also very low in critical fatty acids for brain development: docosahexanoic acid (DHA) and arachidonic acid (ARA). DHA and ARA accumulate rapidly in the brain in the third trimester and first year of life.
With support from Boston Children’s Technology Development Program, they are aiming to generate a new pharmaceutical grade lipid emulsion specifically formulated to support neurodevelopment with sufficient DHA and ARA, prevent liver toxicity, and minimize fluid requirements for administration. Following formulation, the emulsion will be tested for safety in mice and then evaluated in two mouse models of liver disease that mimic the premature infant.

Targeting of the YAP-TEAD protein-protein interaction as a novel therapeutic approach in cancer
Fernando Camargo, PhD and Sophia Shalhout, PhD, Division of Hematology/Oncology

The Hippo signaling pathway is a critical transcriptional pathway that regulates cell growth, proliferation, and organ development. This pathway is widely viewed as a novel and highly promising target for the development of therapeutics, with the potential to impact several malignancies. Despite enthusiasm from multiple sectors, chemical probe and drug discovery for this pathway has been particularly challenging given the lack of traditional ‘druggable’ proteins within the pathway. There are currently no specific therapeutics able to antagonize this pathway.

Through a large-scale screen using DNA barcoded chemical libraries, Dr. Camargo and his team have discovered novel small molecule scaffolds able to interfere with of the YAP-TEAD pathway responsible for oncogenic properties with high specificity and with cell-based activity in the nanomolar range for the treatment of liver cancer and many other solid cancers. These molecules bind the transcription factor TEAD and inhibit its interaction with the Hippo transducer YAP.

With support from Boston Children’s Technology Development Program, they are aiming to determine the exact binding site and structural mechanism of action for the development of pre-clinical candidates to inhibit the YAP-TEAD interaction, potentially leading to new clinical trials using effective drugs aimed at increasing survival for those suffering from liver malignancies.


  • Yimlamai, D, Christodoulou, C, Galli, GG, Yanger, K, Pepe-Mooney, B, Gurung, B, Shrestha, K, Cahan, P, Stanger, BZ, Camargo, F (2014). Hippo pathway activity influences liver cell fate. Cell, 157(6), 1324-38.
  • Tremblay, AM, Missiaglia, E, Galli, GG, Hettmer, S, Urcia, R, Carrara, M, Judson, RN, Thway, K, Nadal, G, Selfe, JL, Murray, G, Calogero, RA, De Bari, C, Zammit, PS, Delorenzi, M, Wagers, AJ, Shipley, J, Wackerhage, H, Camargo, F (2014). The Hippo transducer YAP1 transforms activated satellite. Cell, 26(2), 273-87.

Targeted delivery of therapeutic antibodies into motor neurons for treating botulism
Min Dong, PhD, Department of Urology

Botulinum neurotoxins (BoNTs) are one of the six most dangerous potential bioterrorism agents (Category A and Tier 1 classified by the CDC). They are a family of bacterial toxins that cause the disease botulism in humans and animals. There are approximately 200 human botulism cases per year in the United States, with >70% of them occurring in infants less than 1-2 years old. These toxins target motor neurons with extreme specificity, enter the cytosol of neurons, and block neuronal activity, thus causing paralysis of muscles. There is currently no available treatment against BoNTs once the toxins enter motor neurons.

With support from Boston Children’s Technology Development Program, Dr. Dong and his team are looking to create a novel protein-based delivery platform that can deliver small single-domain antibody (nanobody) into the cytosol of motor neurons to neutralize botulinum neurotoxins. Their studies will provide a first-in-class post-exposure treatment for a top-priority toxin, and also establish a modular delivery tool for targeting motor neurons and delivering biologics into the cytosol of neurons for treating devastating motor neuron degenerative diseases.

Publications | Zhang, S., Masuyer, G., Zhang, J., Shen, Y., Lundin, D., Henriksson, L., Miyashita, S. I., Martínez-Carranza, M., Dong, M., & Stenmark, P. (2017). Identification and characterization of a novel botulinum neurotoxin. Nature communications, 8, 14130.

Transcatheter Mitral Edge-to-edge Repair
Pierre E. Dupont, PhD, Department of Cardiac Surgery

In the US, there are over 1.5 million patients with severe mitral regurgitation and its annual incidence is 250,000. For those with severe regurgitation, the standard of care is repair (not replacement) of the valve by open-heart surgery, but only a small fraction opt for surgery owing to its risks and long recovery period. This means that there is a large untapped market for a repair technology that does not involve the risks and trauma of surgery. Catheter-delivered valve repairs provide this alternative solution and is intended to treat adult patients with degenerative mitral regurgitation – a condition in which the mitral valve fails to close properly.

Dr. DuPont and his team previously developed a transcatheter beating-heart chordae implantation system for repairing mitral valve regurgitation. Their current system is transapical – it is inserted into the heart through its apex. With support from Boston Children’s Technology Development Program, they are aiming to prototype a system converting their current instrument into one that can reach the mitral valve via insertion into the femoral vein in the groin and demonstrate its capabilities through in vivo swine experiments.


Development and Evaluation of a Truncated Recombinant ADAMTS13 (mrADAMTS13) micro-particle with Extended Release
Juan C. Ibla, MD, Department of Anesthesiology, Critical Care & Pain Medicine

Human recombinant ADAMTS13 has been developed commercially for the treatment of thrombotic thrombocytopenic purpura (TTP), a rare disease affecting 1-10 people/million in the US. The commercial preparation has been tested in adult patients with TTP under a Phase I research study sponsored by Takeda. This intravenous formulation has limited half-life (48 hours) and repeated intravenous administration is required for long term-replacement.

Dr. Ibla and his team have engineered a genetically modified truncation of ADAMTS13 for extended release by incorporating a PLGA (poly (lactic-co-glycolic acid) micro-particle for subcutaneous administration. Their preparation offers the potential advantage of less frequent administration (30 days) while extending the use and indications to exceedingly common clinical conditions. Increased mortality after myocardial infarction (MI) and stoke have been associated with low ADAMTS13 in adults and children.

With support from Boston Children’s Technology Development Program, Dr. Ibla and his team are looking to deomonstrate the pharmacokinetic properties of their PLGA-encapsulated ADAMTS13 on an in vivo model for subcutaenous injection. The Ibla lab‘s formulation would allow self-administration at home or on a ambulatory basis for patients at high risk of death from vascular disease in whom ADAMTS13 is persistently low after a MI or stroke.

Safe sensory-selective local anesthetics
Daniel S. Kohane, MD, PhD, Department of Anesthesiology, Critical Care & Pain Medicine

Pain, whether acute or chronic, is generally treated with opioids and/or local anesthetics. Opioids are associated with the clouding of the sensorium, urinary retention, pruritius, and addiction, potential lethal overdose, and diversion. Local anesthetics are very effective, but they all cause motor nerve block in addition to senseory nerve block, which can be problematic. They currently play a relatively little role in the treatment of chronic pain, in part because the unavoidable motor block would entail prolonged paralysis, perhaps of significant portions of the body. Safe senseory-selective local anesethetics have been a much sought-after, but elusive, goal for decades.
Dr. Kohane and his team has developed a family of small-molecule quaternary derivatives of local anesthetics (QDLAs), some of which are sensory selective. These compounds would find use across a broad range of conditions and could possibly replace all local anesethetics.
With support from Boston Children’s Technology Development Program, Dr. Kohane and his team are planning to produce at least 40 more such QDLAs by systematic modification of the R group, identify a few compounds with the best sensory selectivity and/or duration effect with good biocompatibility in vivo and show no signs of systemic toxicity.

AAV gene therapy for CPVT, an inherited arrhythmia
Vassilios Bezzerides, MD, PhD and William Pu, MD, Department of Cardiology

CPVT (catecholaminergic polymorphic ventricular tachycardia) is an inherited arrhythmia in which potentially fatal ventricular arrhythmias are precipitated by exercise and stress. Current therapies do not adequately treat many cases of CPVT, and there are significant therapy-associated complications.

Dr. Bezzerides and his team have discovered that inhibition of a key signaling pathway prevents arrhythmia in CPVT mice and in hiPSC-CMs derived from patients with a variety of CPVT mutations. These findings provide the foundaton for the development of AAV-based gene therapy to prevent arrhythmia in CPVT.

With support from Boston Children’s Technology Development Program, Dr. Bezzerides and his team are planning to demonstrate safety and efficacy of their therapeutic strategy in a rabbit model of CPVT, a larger animal model whose cardiac physiology is more similar to humans than mouse.

Publications | Bezzerides et al., Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia by Inhibition of Ca2+/Calmodulin-Dependent Kinase II. Circulation. 2019 Jul 30;140(5):405-419.

Lead adjuvant optimization via Structure-activity relationship studies
David Dowling, PhD and Ofer Levy, MD, PhD, Division of Infectious Diseases

Over the past 200 years, vaccination has been the most effective medical intervention to reduce death and morbidity caused by infectious diseases, especially in childhood. New adjuvants are critical for optimizing current vaccines and developing new ones. Adjuvants enhance responses to vaccine antigens (Ags) by a variety of mechanisms.

The Precision Vaccine Program (PVP) in the Division of Infectious Diseases at Boston Children’s Hospital (BCH), is a platform to enhance collaboration between academia, government and industry to develop adjuvanted vaccines for vulnerable populations. The Program has used distinct capabilities in modeling age-specific human immunity in vitro, systems vaccinology as well as adjuvant discovery/development and formulation, to discover and develop several novel small molecule adjuvants. With support from Boston Children’s Technology Development Program, Dr. Dowling and his team plan to develop structure-activity-relationship of lead adjuvant hits.


Neonatal chest approximator device
David Hoganson, MD and Peter Hammer, PhD, Department of Cardiac Surgery

The current clinical practice for neonates who are unstable after complex heart surgery is to leave the sternum separated with a small spacer and temporarily close the skin with a protective patch. After 2-7 days post-surgery, the chest is completely closed. However, about 11% of patients do not tolerate the sudden closure and must have their chests reopened, which carries a mortality rate of up to 50%.

Dr. Hoganson and his team propose the development of a chest approximator, an external user-controlled device that gradually closes the chest through multiple daily adjustments depending on the child’s tolerance. With support from the Boston Children’s Technology Development Program, Dr. Hoganson and his team plan to optimize the chest approximator design with early prototyping and minimal viable product testing with the end user and to verify the performance of the design.


Therapeutic targeting of RIG-I-like receptors
Sun Hur, PhD, Program in Cellular and Molecular Medicine

RIG-I-like receptors (RLRs) are key viral RNA sensors in the vertebrate innate immune system. They are cytosolic receptors that detect viral RNAs during infection and elicit the type I interferon (IFN) response. Recent studies suggest these receptors play an important role not only during viral infection, but also during cancer therapies and in the pathogenesis of auto-inflammatory diseases. Currently, there are no small molecular modulators that can activate or inhibit the RLR pathways.

Dr. Hur and her team have already identified several potential hits that can modulate these pathways via a pilot small molecule screen. With support from Boston Children’s Technology Development Program, they plan to follow up on these hits and perform structure-activity relation analysis to identify molecules with highly specific and potent stimulatory activities against RLRs.


Metabolic mapping of the optic nerve head for early disease detection
Lois Smith, MD, PhD, Department of Ophthalmology and Bertan Cakir, MD, Department of Ophthalmology

All eye diseases are currently diagnosed late in disease progression by visualizing structural changes in the eye. The very metabolically active retina has high mitochondrial energy needs. Impaired mitochondrial function (seen with aging and metabolic disease) initiates age-related macular degeneration, diabetic retinopathy and glaucoma. To date, there has been no way to assess mitochondrial dysfunction non-invasively in vivo (metabolic mapping) to detect diseases early to prevent permanent structural changes.

Dr. Smith and her team are working to establish a non-invasive method, light-based resonance Raman spectroscopy, to assess mitochondrial function in the eye in real time to map the metabolic health of eye tissue. Combined with optical coherence tomography, which defines structural changes, this technique can potentially revolutionize diagnostics (and preventative treatment) in ophthalmology and become standard of care for the management of eye diseases. With support from Boston Children’s Technology Development Program, Dr. Smith will use the funds to characterize mitochondrial redox state in healthy and chronic glaucoma in vivo models.

Publications | Perry et al. Responsive monitoring of mitochondrial redox states in heart muscle predicts impending cardiac arrest. Sci. Transl. Med. 2017 Sep 20;9(408).

Genetically engineered, safely applicable, food grade bacteria for the long-term, cost effective, side effect free treatment of inflammatory bowel disease
Zoltan Zsallasi, MD, Computational Health Informatics Program

Inflammatory bowel disease (IBD) is a potentially severe inflammation of the digestive tract, which affects both humans and animals. Dr. Zsallasi and his team are developing a method to directly target one of the common mediators of this inflammatory process by delivering gene silencing to the gut epithelium by safely applicable, food grade engineered bacteria with the ability to invade the gut wall. They have already created a prototype bacteria that successfully treated the most commonly used animal model of IBD. With support from Boston Children’s Technology Development Program, Dr. Zsallasi will be standardizing the delivery methods, the quality control assays and finalize the first version of biosafety and bio containment methods.

Development of a potential ALS treatment via Kv2.1 Inhibition
Clifford J. Woolf, MB, BCh, PhD and Laurel Heckman, PhD, Neurobiology Program

Dr. Woolf and his team have identified an ion channel as a completely new target for preventing cell death in motor neurons derived from induced pluripotent stem cells (iPSCs) from patients with ALS. This discovery converged with an ongoing collaborative project developing small-molecule inhibitors of this channel as investigational tools with Bruce Bean at Harvard Medical School. They find that these inhibitors mitigate cell death of ALS patient iPSC-derived motor neurons. Through funding of this collaboration from HMS Q-FASTR, they will validate this channel as a drug target for multiple familial and sporadic forms of ALS and investigate its ability to promote cell survival in neurodegenerative diseases such as Parkinson’s and Alzheimer’s Disease. Additionally, they will conduct a high throughput primary screen with HMS ICCB-L to identify novel small molecule scaffolds capable of inhibiting the channel.

With support from the Boston Children’s Technology Development Program, Dr. Woolf will expand the screen to include 50,000 compounds, increase the numbers of sodium channel subtypes studied, conduct an electrophysiological characterization of the hits, run a medicinal chemistry program to optimize the most promising drug-like hits, identify potential development candidates and evaluate their analgesic effectiveness and selectivity.


Novel small molecule therapeutics for telomere diseases
Suneet Agarwal, MD, PhD, Division of Hematology and Oncology

Telomere diseases encompass a spectrum of rare and fatal syndromes that are caused by mutations in genes regulating telomere biology. These include a severe childhood hematologic disorder dyskeratosis congenita (DC) and several later-onset diseases including idiopathic pulmonary fibrosis (IPF), myelodysplastic syndrome, and cirrhosis/non-alcoholic steatohepatitis.

Dr. Agarwal and his lab have discovered components of the post-transcriptional machinery that regulate accumulation of the non-coding telomerase RNA (TERC), which is critical for telomerase function and is disrupted in several genetic forms of telomere diseases. Components of this pathway, regulating telomere maintenance could be targeted for the treatment of DC, IPF and other degenerative disorders.

With support from TDF, Dr. Agarwal is planning to identify and test a set of small molecules that could be developed as therapeutic modifiers of telomere function for treatment of DC and other diseases with similar underlying pathology.

In the news/References:

Targeting lysine demethylases as a novel chemotherapy for cancers
George Daley, MD, PhD and Deepak Jha, PhD, Stem Cell Program, Division of Hematology and Oncology

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma (NHL). This and several other cancer types show widespread epigenetic dysregulation, in part due to over activation of lysine demethylases. Recently, using cellular and animal models, the Daley lab has discovered that targeting a specific family of lysine demethylases is a viable therapeutic strategy for treating DLBCL. TDF funds will help Dr. Daley and his team engage with medicinal chemistry consultants, conduct additional high throughput screening and identify promising lead compounds with strong anti-cancer effects.

Targeting of the YAP-TEAD protein-protein interaction as a novel therapeutic approach in cancer
Fernando Camargo, PhD and Sophia Shalhout, PhD, Stem Cell Program

There are currently no effective therapeutic strategies for patients with advanced liver and pancreatic cancers. These tumors often rely on activated Hippo-Yap pathway for proliferation and evasion of immune system. Dr. Camargo’s lab is developing novel small molecules inhibitors of interactions between transcription factor TEAD and the Hippo transducer YAP with the goal of developing therapeutics for treatment of liver, pancreatic and other malignancies. With TDF 2018 funds, the Camargo lab will utilize medicinal chemistry and structure-based insights to enhance the potency, specificity, and pharmacological properties of small molecule inhibitors of TEAD activity.

In the news/References:

Therapeutic development of Sphingosine-1-Phosphate (S1P) Chaperone Apolipoprotein M (ApoM)
Timothy Hla, PhD, Vascular Biology Program, Steven Swendeman, PhD, Vascular Biology Program and
Mark Puder, MD, PhD, Department of Surgery

A bioactive sphingolipid, Sphingosine-1-Phosphate (S1P) is an important regulator of many physiological processes. When chaperoned by Apolipoprotein M (ApoM), S1P suppresses endothelial cell inflammation in different pathologies, including cardiovascular diseases. Dr. Hla has engineered a novel fusion protein of ApoM with the Fc-region of immunoglobulin (ApoM-Fc) that is stable and pharmacologically active as a chaperone for S1P. Together with BCH clinician Dr. Mark Puder, Professor Hla is now testing whether the stable ApoM-Fc/S1P complexes and/or their mutant variants could be used to treat respiratory conditions, including bronchopulmonary dysplasia (BPD). TDF funds be used to generate additional data using clinically relevant animal models of BPD and advance this work towards the clinic.

In the news/References:

Fibroblast growth factor 21 protects against cone loss in all forms of retinal degeneration
Lois Smith, MD, PhD and Zhongjie (Kira) Fu, PhD, Department of Ophthalmology

Dr. Smith and her laboratory have discovered that metabolic modulation in the retina toward lipid catabolism can rescue cone loss resulting from over 60 Retinitis pigentosa (RP) gene defects. They found that fibroblast growth factor 21 (FGF-21), a liver derived metabolic regulator, increases lipid use to meet the high energy demands of photoreceptor cells. Furthermore, they show that pharmacologically improved long-acting FGF21 analogs developed as leads for diabetes drugs can prevent cone loss in RP mice models and importantly preserve vision. Extensive data collected to date, indicate that metabolic cone rescue mediated by FGF21 could save central vision and significantly improve the quality of life of RP patients. With TDF 2018 funds, Dr. Smith will perform IND-enabling pre-clinical efficacy studies in the appropriate animal models if deemed necessary prior to starting first in humans studies.

In the news/References:

Heart valve coaptation mapping device
David Hoganson, MD and Peter Hammer, PhD, Department of Cardiac Surgery

Dr. Hoganson and his team developed a heart valve coaptation mapping device. This is a hand held instrument or catheter that measures the coaptation height (distance over which valve leaflets meet), a well-recognized measure of the robustness of the valve repair during surgery or during interventional procedures. The proposed device would provide real-time quantitative information regarding the severity and mechanism of the valve disease and efficacy of the repair or catheter intervention. With TDF funds, Dr. Hoganson will be developing a prototype device and testing it in clinically relevant animal models.

In the news/References:

Intratumoral oxygen delivery to enhance the efficacy of cancer radiotherapy
Brian Polizzotti, PhD, Department of Cardiology

Oxygen is a natural and potent radio-sensitizer that increases the effectiveness of radiation therapy by forming DNA-damaging free radicals. One of the most well recognized phenomena that diminishes the efficacy of radiotherapy is intra-tumoral hypoxia frequently found in solid tumors. Brian Polizzotti and colleagues have developed injectable hollow microparticles, which contain and release large quantities of oxygen gas. The team will use TDF funds to investigate whether the oxygen loaded microbubbles could reverse tumor hypoxia in a mouse model of carcinoma and if the microbubbles can increase efficacy of radiotherapy in a syngeneic orthotopic mouse model.

In the news/References:

A novel method to treat the systemic inflammatory response syndrome (SIRS)
Brian McAlvin, MD, Department of Medicine and Daniel Kohane MD, PhD, Department of Anesthesiology

Brian McAlvin, Daniel Kohane and colleagues have developed blood-filtering devices for selective removal of harmful proteins from the blood of patients. The surfaces of these silicone-based devices are modified with antibodies (Antibody-Modified Conduits – or AMCs) to specific circulating proteins. To date, the team has targeted the systemic inflammatory response syndrome (SIRS) and built AMCs to eliminate specific circulating cytokines.

With support from TDF 2014 award, the investigators showed selective cytokine filtration in a rat model of SIRS. TDF 2017 funds willbe used to expand the work to a large animal model to demonstrate that the technology is scalable.

In the news/References:

Automated tests to assess rodents’ behavior from their footwork
Clifford Woolf, MB, Bch, PhD and David Roberson, PhD, MBA, F.M. Kirby Neurobiology Center

Rodent behavioral assays are an indispensable tool for advancing the understanding of human biology; however, identifying clinically relevant outcomes in rodent models of neurological dysfunction has been difficult, particularly the prediction of drug efficacy and side effects.

To address this unmet need, David Roberson and Clifford Woolf invented a novel technology that can infer neurological function and disease states through analysis of the footprints and somatic behaviors of freely behaving rodents in the dark (and ideal state for nocturnal animals). With support from a TDF 2015 award, the team developed a user-friendly software package that permits automated detection and scoring of spontaneous rodent behaviors. TDF 2017 funds will be used to apply machine learning approaches to robustly identify behavioral patterns indicative of specific neurological activity.

In the news/References:

A microphysiologic tissue construct for age-specific vaccine development
Ofer Levy, MD, PhD and Guzman Sanchez-Schmitz, PhD, Precision Vaccines Program; Department of Medicine/Division Infectious Diseases

Infections claim millions of lives every year, especially among neonates and infants less than 6 months of age, whose distinct immune system renders them particularly susceptible. Vaccines are a highly cost-effective measure to reduce global morbidity and mortality; however, development of new vaccines is empiric, costly and slow. To accelerate and de-risk vaccine development, the Ofer Levy and Guzman Sanchez-Schmitz created an in vitro microphysiologic screening platform (Tissue Constructs – TCs) that accurately model age-specific human vaccine responses. TDF funds will help the team continue in vivo validation of the TC technology with the Pneumococcal conjugate vaccine.

In the news/References:

A self-assembling, self-adjuvanting whole cell vaccine targeting diarrheal disease
Paula Watnick, MD, PhD and Julie Liao, PhD, Department of Medicine/Division of Infectious Diseases

Diarrhea caused by intestinal pathogens is the primary cause of morbidity and second most common cause of mortality for children in resource-poor countries. In the absence of improved sanitation, vaccination is the best means of disease prevention. Recently, enterotoxigenic Escherichia coli (ETEC) and Shigella have been identified as the two most common causes of bacterial diarrhea in children under 5, yet no vaccines targeting these pathogens are available.

With support from a TDF 2013 award, Paula Watnick and Julie Liao developed and tested a novel antigen presentation platform derived from live, attenuated V. cholerae. The team has tested this platform with ETEC antigens and has demonstrated a robust immune response. TDF 2017 funds will extend this approach to Shigella.

In the news/References:

DNA nanoswitches for high-sensitivity, low-cost biomarker detection
Wesley Wong, PhD, Department of Medicine/Program in Cellular and Molecular Medicine

Wesley Wong and his team have developed a technology for ultra-sensitive detection of a wide array of analytes. The system uses DNA-based molecular probes that change their topological state when they bind to ligands of interest. The two-state structures (bound/unbound) are called DNA nanoswitches. This DNA nanoswitch detection method can be deployed for rapid, low-cost detection of analytes, to achieve single-molecule mechanical detection.

To date, the team has demonstrated high-sensitivity detection of prostate-specific antigen in complex biological fluids, and high-specificity detection of different dengue virus nonstructural proteins. Now, the team will use TDF funds to optimize nanoswitch-based detection in biological fluids and validate the utility of nanoswitch detection for cancer and/or infectious diseases.

In the news/References:

  • Vector
  • H. Hansen, D. Yang, M.A. Koussa, W.P. Wong, Nanoswitch-linked immunosorbent assay (NLISA) for fast, sensitive, and specific protein detection, Proc. Natl. Acad. Sci. USA(2017). [link]
  • A. Koussa, K. Halvorsen, A. Ward, W.P. Wong, DNA Nanoswitches: A quantitative platform for gel-based biomolecular interaction analysis, Nature Methods(2015). [link]

Wearable device for pelvic floor muscle therapy to treat urinary incontinence
Carlos Estrada, MD, Urology, and Jeanne Chow, MD, Radiology

Urinary incontinence affects 25 million American adults and is best treated with pelvic floor muscle training (PFMT), also known as biofeedback. PMFT is highly effective but underutilized because it is time and resource-consuming when performed in specialized centers while in-home solutions are invasive.
Drs. Estrada and Chow are developing a novel non-invasive PMFT product consisting of an undergarment with electrodes and sensors that communicates with a smartphone app to provide personalized feedback. TDF funds will be used to develop a device prototype providing PFMT, quantify incontinence and track treatment progress for user testing.

In the news/References:

Treating otitis media with single-dose antibiotic ear drops
Daniel S. Kohane, MD, and Rong Yang, PhD, Pediatric Critical Care

Over 95% of US children have had otitis media (OM) by age 5. Acute OM is the most common reason for prescribing antimicrobial to US children. Current treatment for OM with oral antibiotics) is difficult to administer to young children, causes side effects and selects antibiotic-resistant bacteria– a significant public health issue.
Drs. Kohane and Yang are developing a novel delivery system for the treatment of OM. The proposed approach uses ear drops that flow easily onto the ear drum then gel firmly to treat pain and deliver antibiotics into the middle ear for 1-2 weeks. The TDF funds will be used to conduct a study to simplify and optimize the formulation, and show efficacy of the simpler formulation in relevant animal models.

In the news/References:

Novel dental device to non-surgically correct cleft lip and palate
James MacLaine, BDS, and Elizabeth Ross, DDS, Craniofacial Orthodontics

Cleft lip and palate, one of the most common birth defects, is often accompanied by challenges with feeding, hearing, and speech. Current treatments include three sequential surgical interventions: lip repair at 3 months, palate repair at 9 months, alveolus repair at 8-10 years. Then lip repair takes weeks of physical manipulation to align the cleft upper jaw using oral appliances.

Drs. MacLaine and Ross are developing a removable device that repositions and closes the gap between the cleft jaw before the lip repair surgery. This device aims to simplify the treatment, reduce the number of clinic visits, and limit exposure of these infants to general anesthesia. The TDF funds will be used to create a FDA compliant prototype device to use in first-in-human studies.

Crisis Care: A smartphone app for suicidal adolescents
Elizabeth Wharff, PhD, and Kimberly O’Brien, PhD, Psychiatry

Suicide is at its highest rate in 30 years and is the second leading cause of death among 10-24 year olds. Adolescents treated in the clinic after a suicide attempt are at high risk for future suicide attempts. Yet, few intervention techniques exist for these kids.

To address this gap, Drs. Wharff and O’Brien have designed a smartphone app, named Crisis Care, for adolescents and parents to use following discharge from an emergency visit for suicide. Crisis Care provides immediate access to: 1) coping skills; 2) listening and safety planning for parents; 3) connection and support between adolescents and parents; and 4) immediate help from emergency services. The TDF will turn the web-based prototype into fully functioning iPhone and Android apps, which will be tested in the clinic by suicidal adolescents and their parents.

In the news/References:

Optimization of Pseudomonas aeruginosa vaccines
Gregory Priebe, MD, Infectious Diseases

The Gram-negative bacterial pathogen Pseudomonas aeruginosa can cause a wide range of infections in hospitalized and immunocompromised patients, burn or combat wound patients, and cystic fibrosis patients. The increasing antibiotic resistance of P. aeruginosa has creates an urgent need for vaccines. To date, there are no P. aeruginosa vaccines approved for human use. The most advanced vaccine -an OprF/I hybrid fusion protein developed by Valneva- induces opsonic antibodies as well as antibodies that inhibit IFN-g binding to P. aeruginosa and IFN-g+ Th1 T cell responses.

Dr. Priebe’s team discovered that a P. aeruginosa protein -PopB- stimulates helper T cells, called Th17 cells, to protect against pneumonia and wound infection in mouse models of infection. The team expects that combination of the PopB properties with the OprF/I vaccine will result in a broadly protective vaccine in murine models of pneumonia and wound infection and, ultimately, in humans. TDF funds will be used to optimize the production and formulation of a PopB/PcrH and OprF/I vaccine to test the immune response and protective efficacy in mouse models of infection.

In the news/References:

Control of chronic viral infection by targeted activation of TMEM16F
Florian Winau, MD, PhD, Program of Cellular and Molecular Biology

In chronic infection and cancer, T cells become exhausted due to the persistence of antigen and inflammation. Reversal of T cell exhaustion by immune checkpoint blockade with monoclonal antibodies against CTLA4 or PD-1 is actively used in the clinic for the treatment of certain cancers. Unfortunately, while immune checkpoint blockade shows substantial clinical benefit, not all patients respond to anti-PD1 or anti-CTLA4 treatment.

Dr. Winau’s team has identified a lipid scramblase, TMEM16F, as an immune checkpoint that protects T cells, especially cytotoxic T lymphocytes, from severe exhaustion. The team demonstrated that mice lacking TMEM16F fail to clear viral infections due to compromised T cell responses. Therefore, targeting the activation of TMEM16F may prevent T cell exhaustion and improve viral control. TDF funds will be used to establish a novel mouse model to evaluate TMEM16F as a therapeutic target for viral infections and tumors.

In the news/References:

  • Scramblase TMEM16F terminates T cell receptor signaling to restrict T cell exhaustion. Yu Hu, Hyung Kim, Kangmin He, Qi Wan, Jessica Kim, Melanie Flach, Tom Kirchhausen, Andrea Vortkamp, Florian Winau. The Journal of Experimental Medicine Oct 2016. DOI: 10.1084/jem.20160612
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Targeting the Lin28 protein–RNA interface to inhibit human cancer
George Q. Daley, MD, PhD, Hematology/Oncology and Dean of Harvard Medical School

Dr. George Daley, in collaboration with Dr. Piotr Sliz from Harvard Medical School, is developing a novel therapeutic strategy to treat a variety of cancers. The strategy is based on Daley’s and Sliz’s discovery that the Lin28 transcription factors bind to the let-7 family of miRNAs and inhibit their tumor suppressor function. Indeed, LIN28 overexpression has been associated with a variety of human tumors including lung, breast, colon, ovarian and in several rare pediatric tumor types such as neuroblastoma and Wilms tumor.Drs. Daley and Sliz’s work aims to identify small molecule inhibitors that disrupt the association of the LIN28 proteins with let-7 microRNA precursors. TDF funds will be used toward medicinal chemistry to optimize hits from initial high throughput screens into promising lead compounds.

In the news:

Myocardial perfusion imaging with F-18-labeled rhodamine 6G: First-in-human studies
Alan B. Packard, PhD, Radiology, and S. Ted Treves, MD, Brigham and Women’s Hospital

Cardiovascular disease (CVD) is the leading cause of death in the US and other developed countries. Myocardial perfusion imaging (MPI) is a safe and effective way to assess CVD, but currently available imaging agents have significant limitations. Drs. Packard and Treves have developed a promising positron emission tomography (PET) MPI agent, 18F-labeled rhodamine 6G (18F-Rho6G). 18F-Rho6G shows high and persistent uptake in the heart in a preclinical model of CVD and presented no evidence of toxicity in a microdose toxicology study in rats. TDF funding will be used to carry out first-in-human studies with 18F-Rho6G to translate the promising pre-clinical results into the clinic.

Specific glycoceramides as a novel platform for drug delivery (and mucosal vaccines)
Wayne I. Lencer, MD, and Daniel Chinnapen, PhD, Gastroenterology, Hepatology and Nutrition

Delivering therapeutically active proteins across tight epithelial and endothelial barriers has been a goal and challenge for decades. Drs. Lencer and Chinnapen are advancing a novel drug delivery platform that is inspired from the cholera toxin’s tactic for entry into intestinal epithelial cells, through binding to the GM1 ganglioside receptor on the cell surface. In the course of their studies, Dr. Lencer’s team discovered that the structure of the ceramide (lipid) domain of the GM1 receptor dictates its trafficking in epithelial cells. The team further hypothesized that these lipid structures could be engineered to transport therapeutic peptides and proteins across the epithelial monolayer. To date, the group has used reporter peptides and therapeutic proteins (GLP1) fused to GM1 variants to show transport in epithelial cells in vitro.

The team is using TDF funds to validate the delivery platform and assess bio-distribution, pharmacokinetics and pharmacodynamics of a known therapeutic agent in mouse models.

Novel natural products avtive against carbapenem-resistant Enterobacteriacae
Paula Watnick, MD, PhD, and Julie Liao, PhD, Infectious Diseases

There is an urgent need for new antibiotics that are active against infections caused by bacteria of the Enterobacteriaceae family such as Klebsiella pneumoniae (Kp). Many of these Gram-negative bacteria are resistant to a broad spectrum of antimicrobial due to the production of carbapenemase which hydrolyses many antibiotics including, the therapy of last resort, the carbapenem. These carbapenem-resistant Enterobacteriaceae (CRE) can only be treated with the highly nephrotoxic aminoglycosides and CRE infections are associated with extremely high rates of mortality.

The team recently developed an extremely sensitive, reproducible high-throughput, whole cell assay for products with antimicrobial activity against CRE. TDF funds will be used for screening of chemical libraries to identify new active compounds.

DNA nanoswitches: A diagnostic platform
Wesley P. Wong, PhD, Program in Cellular and Molecular Medicine

Dr. Wong’s team has developed a technology for robust detection of a wide array of protein analytes. This novel platform technology would provide an affordable, easy-to-use, and ultra-sensitive approach for point-of-care and home diagnostic testing. The system relies on the ability of a gel to separate DNA based on topology. When a large DNA scaffold binds to ligands, antigens, receptors, antibodies or nucleic acids, the resulting molecular interactions lead to a change in the DNA topological state. The two-state structure, called DNA nano switches, can be resolved via simple gel electrophoresis.

In conjunction with funds from the Harvard Blavatnik Biomedical Accelerator and the Wyss Institute, TDF funds will be used to further optimize the platform and compare sensitivity and specificity of this novel assay to those of well-established biomarkers.

In the news:

Automated apparatus to detect and quantify rodent behavioral signs of injury, disease, and drug effects
Clifford Woolf, MB, BCh, PhD, and David Roberson, PhD, MBA, FM Kirby Neurobiology Program

Rodent behavior studies have provided invaluable insights into our understanding of the human nervous system. However, currently available animal behavior assessment technologies are unable to objectively assess many key aspects of CNS function, and as a result the CNS drug development field is plagued by extremely high clinical trial failure rates. To address this need, the team has developed a device that permits unprecedented detection of CNS activity through prolonged observation of voluntary rodent behavior, without intervention or presence of an observer.
TDF funds will support software development to optimize the device, as well as animal studies, to validate the technology with previously developed therapeutic compounds.

In the news:

A rapid, efficient, high-throughput mouse model for optimizing therapeautic antibodies
Frederick W. Alt, PhD, and Ming Tian, PhD, Program in Cellular and Molecular Medicine

Humanized antibody approaches are among the most successful therapeutic drugs for a broad set of diseases ranging from autoimmunity to cancer. However, many of the current therapeutic humanized antibodies do not achieve maximum potential in terms of affinity and specificity, which can lead to failed drug trials. Dr. Alt’s team developed a “high throughput” antibody producing mouse model to generate a broad range of variant therapeutic antibodies with higher affinities or greater specificity for the target antigen. The TDF funds will be used to validate the platform technology. Dr. Alt’s team will use the novel method to generate new antibodies to well-known targets and compare affinity and specificity of these new antibodies to their commercial counterparts.

Publication: Highly sensitive and unbiased approach for elucidating antibody repertoires. Lin SG, Ba Z, Du Z, Zhang Y, Hu J, Alt FW. Proc Natl Acad Sci U S A. 2016 Jul 12;113(28):7846-51.

Therapeutic to reduce inflammation following severe burn injury
Michael C. Carroll, PhD, Program in Cellular and Molecular Medicine

Second degree burns often result in significant scarring, and may require skin grafts. Current treatments typically involve anesthetics and ointments. Much of tissue loss following burn injury is not from the burn itself, but from the acute inflammatory reaction which occurs at the site of the injury and the surrounding tissue. Dr. Carroll and his colleagues discovered a novel pathway of inflammation following scald burn that is initiated by specific recognition of a self-antigen at the site of injury by natural IgM. The team further designed a peptide mimetope(N2) to mitigate the damage caused by IgM. The TDF award will be used to optimize the therapeutic peptide and develop a pre-clinical package to support its development as a drug candidate for topical delivery.

Validation and enhancement of a microphysiologic tissue construct to accelerate age-specific human vaccine development microphysiologic tissue construct to quickly and accurately develop age-specific human vaccines
Ofer Levy MD, PhD, and Guzman Sanchez-Schmitz, MS, PhD, Infectious Diseases

Infections claim millions of lives every year, especially among neonates and infants under 6 months of age, whose distinct immune system renders them particularly susceptible. Vaccines are a highly cost-effective measure to reduce global morbidity and mortality, however development of new vaccines is empiric, costly and slow. A key contributor to vaccine development failure is the pre-clinical selection of leading candidate vaccines through biologically irrelevant cells and animal models.

To accelerate and de-risk costly vaccine development, the investigators created an in vitro microphysiologic screening platform (tissue constructs) that accurately model age-specific human vaccine responses. TDF funds will be used to validate the system with both vaccines that successfully elicited early-life immunogenicity and those that failed to do so.

In the news:

EpCAMAptamer-siRNAs, a platform to treat common epithelial cancers
Judy Lieberman, MD, PhD, Program in Cellular and Molecular Medicine

RNA interference (RNAi) was discovered over a decade ago and chemically synthesized small interfering RNAs (siRNAs) are emerging as a new class of pharmaceutical drugs. However the early promise of the siRNA field has been hampered by multiple challenges most notably cell delivery, which to date remains limited to the liver. Dr. Lieberman is proposing a new approach for targeted delivery of siRNAs and is developing aptamer-siRNA chimeras (AsiCs) which are taken up efficiently by cells expressing a receptor recognized by the aptamer.

Dr. Lieberman will apply her platform technology to the development of a targeted therapeutic for basal-like triple negative breast cancer (TNBC). She will use TDF funds to develop and optimize AsiCs that bind to the tumor antigen EpCAM that is highly expressed on cancerous epithelial cells.

Publication: Gene Knockdown by EpCAM Aptamer-siRNA Chimeras Suppresses Epithelial Breast Cancers and Their Tumor-Initiating Cells. Gilboa-Geffen A, Hamar P, Le MT, Wheeler LA, Trifonova R, Petrocca F, Wittrup A, Lieberman J. Mol Cancer Ther. 2015 Oct;14(10):2279-91.

Development of extremely short magnetic needle for laparoscopic surgery
Kaifeng Liu, MD, and Gary Visner, DO, Pulmonary

Drs Liu and Visner are proposing a new suturing system that is designed for working in small spaces, where current suturing solutions can sometimes be difficult to maneuver. In some scenarios, having a smaller needle may be highly advantageous, particularly in preventing accidental injury to neighboring tissue. The new system consists of a hollow needle containing a magnet, which pairs with suture thread connected to a small magnet at its end. The team has already shown proof of concept ex vivo in animal tissue. The TDF funds will be used to generate needle prototypes for use in laparoscopic procedures.

In the news:

Rapid visualization of epileptogenic networks in epilepsy surgery planning
Joseph R. Madsen, MD, Eun-Hyoung Park, PhD, and Tomer Anor, PhD, Neurosurgery

Epilepsy is a prevalent condition, usually treated with medicines, but only cured when surgery can be performed to remove the region of the brain which causes seizures. The challenge of epilepsy surgery is therefore to locate and safely remove the epileptic foci. Many kinds of data can be used to accomplish this, with the gold standard being intracranial EEG monitoring. In those cases, epileptologists wait to observe seizures, then analyze the recorded ictal intracranial EEG by eye. This procedure requires two craniotomies and prolonged, expensive and somewhat risky hospitalization of patients.

To address this problem, the team has developed a Matlab code to identify the pathological network based on Granger causality analyses. If successful, this approach has the potential to identify the seizure foci during the initial surgery, and thus eliminate the need for a second surgical procedure. The TDF award will be used to 1) improve the software by reducing the computation time and 2) validate the method by acquiring and analyzing additional patient data

In the news:

Use of the multiple antigen presentation system (MAPS) for the development of a tuberculosis vaccine
Richard Malley, MD, Joanne O’Hara, PhD, and Fan Zhang, PhD, Infectious Diseases

Mycobacterium tuberculosis is a major cause of morbidity and mortality worldwide, with approximately nine million new cases per year resulting in 1.5 million deaths. The current Bacille Calmette-Guerin (BCG) vaccine is safe and reasonably effective in children, but does not generate herd immunity as it does not offer protection for adults. BCG -like other current vaccine approaches-aims to elicit antibodies to a small number of antigens. However, it is becoming clear that a specific T-cell response will be critical for protection against M. tuberculosis.

Dr. Malley’s team has developed a novel multiple antigen presentation system (MAPS) vaccination platform that can elicit both strong antibody and T-cell responses to a large number of antigens. The TDF funds will be used to design a TB vaccine using the MAPS platform and evaluate its protective potential in a mouse model of TB inhalation and pulmonary disease.

In the news:

Highly selective blood filtration with a novel circuit device to treat sepsis
Daniel Kohane, MD, PhD, Anesthesia and Critical Care and Brian McAlvin, MD, Critical Care Medicine

Systemic inflammatory response (SIRS) is an underlying disease for a number of conditions, including sepsis, pancreatitis, burns and trauma. A number of cytokine pathways are activated by SIRS. These pathways transition from an initial pro-inflammatory response to an anti-inflammatory response, and can leave the patient in an immuno-compromised state.

Dr. Mc Alvin and Kohane have developed blood-filtering devices that selectively remove harmful proteins, such as inflammatory cytokines, from the blood of patients rendered critically ill by SIRS. The TDF award is being used to optimize the hemofiltration device and validate the technology in small and large animal models of SIRS and other inflammatory conditions.

In the news:

Children’s Research Integration System (ChRIS) – a web-based medical image data and workflow platform
Rudolph Pienaar, PhD, Radiology

Current image analysis software requires advanced computing expertise, is often non-collaborative and does not have real-time sharing capabilities. Dr. Pienaar’s team developed a web-based software named Children’s Research Integration System (ChRIS), which allows real-time collaboration. The system has a news feed view of the processing pipeline and allows for the integration of various plug-ins for data processing. The TDF award will support development of a user interface for ChRIS.

In the news:

Optimization of Pseudomonas aeruginosa vaccines
Gregory Priebe, MD, Infectious Diseases

Infections claim millions of lives every year, especially among neonates and infants under 6 months of age, whose distinct immune system renders them particularly susceptible. Vaccines are a highly cost-effective measure to reduce global morbidity and mortality, however development of new vaccines is empiric, costly and slow. A key contributor to vaccine development failure is the pre-clinical selection of leading candidate vaccines through biologically irrelevant cells and animal models.

To accelerate and de-risk costly vaccine development, the investigators created an in vitro microphysiologic screening platform (tissue constructs) that accurately model age-specific human vaccine responses. TDF funds will be used to validate the system with both vaccines that successfully elicited early-life immunogenicity and those that failed to do so.

In the news:

Small molecules for ex vivo maintenance and expansion of hematopoietic stem cells (HSCs)
Derrick Rossi, PhD, Program in Cellular and Molecular Medicine

Over 50,000 allogeneic and autologous bone marrow transplants are performed annually usinghematopoietic stem cells (HSCs)to treat patients with a variety of life-threatening disorders. However, current and future therapeutic uses of HSCs are limited by the inability to maintain or expand HSCsex vivo. Dr. Rossi’s team discovered a cocktail of small molecules that allows for both substantial expansion of HSC numbers and preservation of functional transplantation potential. The TDF awardis being used to optimize the cocktail for human HSCs and validate it in in vitro and in vivo in animal models.

In the news:

Neosaxitoxin for Prolonged Duration Local Anesthesia
Charles Berde, MD, PhD, Anesthesia and Daniel S. Kohane, MD, PhD, Anesthesia and Critical Care

Currently available local anesthetics have toxicities and generally provide pain relief lasting no longer than10 hours after surgery. A 3-day local anesthetic for wound infiltration and peripheral nerve blockade could revolutionize postoperative care. Neosaxitoxin (NeoSTX) is a site 1 sodium channel blocker that provides prolonged nerve blockade in animal models, and appears safe and more effective than the leading competitor, bupivacaine, in Phase 1 and Phase 2 trials. The 2013 TDF award will help advancement of the asset for a commercial partner.

In the news:

OPENPediatrics™: Virtual Dialysis Simulator
Jeffrey Burns, MD, MPH, and Traci Wolbrink, MD, Critical Care

OPENPediatrics™ ( is a peer-reviewed, academically rigorous web-based education platform designed to promote knowledge exchange between clinicians caring for critically ill children around the world. Dialysis is needed in children with renal disease, acute kidney injury, and kidney failure. Worldwide, about 1.6 million patients receive hemodialysis and 200,000 receive peritoneal dialysis. These numbers don’t include patients who would benefit from dialysis, but whose clinicians are not familiar with how to use a dialysis machine. The 2013 TDF award will be used to develop a dialysis simulator to serve as an educational tool for physicians and nurses within critical care, nephrology, and general pediatrics.

In the news:

Transapical Mitral Valve Leaflet Plication Clip
Pedro del Nido, MD, and Nikolay Vasilyev, MD, Cardiac Surgery

The mitral valve Leaflet Plication Clip (LPC) is a device being developed for repair of the mitral valve prolapse-one of the most common heart valves abnormalities- through leaflet plication using a deployable metal clip. The clip creates a fold in the diseased leaflet to reduce prolapse and restore function. The 2013 TDF award will support development of an optimized prototype device and delivery tool for testing in a large animal model.

In the news:

Pediatric Nutrition Assessment
Christopher Duggan, MD, MPH, Gastroenterology and Medicine and Karen Warman, MS, RD, LDN, Gastroenterology and Nutrition

The TDF 2013 award will allow development of the Pediatric Nutrition assessment software. This application is intended to be a cross-platform, integrated computer application that streamlines the acquisition, analysis, documentation and communication of clinical nutrition assessment data for children. This technology will allow data to be compiled quickly, allow longitudinal comparisons, and formulate nutritional therapy plans that define dietary intake recommendations based on age, health-related micronutrient recommendations and body composition calculations. Data will be displayed in a consitent format for patients and providers to improve medical and nutritional care.

Optimization and Testing of Oxygenated Microparticles as Adjunctive Therapy for Cardiac Arrest
John Kheir, MD, and Brian Polizzotti, PhD, Cardiology

Tissue hypoxia is a pathway leading to cellular injury and dysfunction in a number of critical illness states. For example, cardiac arrest confers an 80-90 percent mortality rate and a high incidence of organ injury in survivors. Cardiac arrest relies on chest compressions, administration of inspired oxygen, and administration of intravenous inotropic agents to augment oxygen delivery. Dr. Kheir’s group has developed a platform technology that enables the administration of oxygen gas intravenously. Gas is partitioned into hollow microparticles which circulate through the bloodstream, raising the oxygen content of the blood and delivery to the brain. The 2013 TDF award will be used to further develop the microparticle materials and manufacturing methods, and to test the ability of optimized microparticles to improve oxygen delivery and survival in a model of cardiac arrest.

In the news:

Multi-layer Silk Biomaterial for Augmentation Cystoplasty
Carlos R. Estrada, MD, and Joshua Mauney, PhD, Urology

Our novel technology uses acellular bi-layer scaffolds composed of Bombyx mori silk fibroin for functional tissue repair of urinary tract defects. This technology consists of a biodegradable matrix – and a water-tight surgical seal and encourages host tissue integration and regeneration. Drs. Mauney and Estrada seek to provide an alternative for bladder augmentation with autologous gastrointestinal segments in patients with urinary tract pathologies at risk for renal damage due to low capacity, poorly compliant bladders. The 2013 TDF award will be used to validate the efficacy of this matrix in large animal models of bladder exstrophy and bladder outlet obstruction to demonstrate clinical viability.

In the news:

The bacterial biofilm matrix as a platform for vaccine development
Paula Watnick, MD, PhD, Infectious Diseases

In the developing world, diarrheal disease, including cholera, is the second leading cause of death in children under 5 years old. Two cholera vaccines, Shanchol and Dukoral, are currently produced and while Dukoral is more expensive, it provides protection against enterotoxigenic Escherichia coli (ETEC), the third most common cause of childhood diarrhea. Dr. Watnick’s goal is to expand the coverage of the more affordable cholera vaccine, Shanchol, first to ETEC then to other common diarrheal pathogens. Her lab has identified a protein, RbmA, that spontaneously associates with the biofilm exopolysaccharide and conceived of using RbmA to associate antigens with the bacterial surface. The 2013 TDF award will be used to test this technology through development of a V. cholerae strain that secretes CtxB fused to RbmA and to develop an inexpensive vaccine that rivals Dukoral in its spectrum of protection.

In the news:

Communicating audiological results: A new and improved tool
Howard Shane, PhD, Brian J. Fligor, AuD, ScD, and Joseph Resendes, Communication Enhancement

Hearing loss causes a delay in developing communicating skills and may affect a child’s academic accomplishments and social functioning. On the other end of the age spectrum, there is an increasing need for audiology services for the aging population. The growing demand for services calls for greater efficiency in audiology practices, yet the hearing tests are still recorded largely via pen and paper. The 2012 TDF award will support development of a next generation electronic audiogram software that offers unique point-of-contact clinical documentation and a counseling system for audiologists.

In the news:

Contact lens drug delivery
Daniel Kohane, MD, PhD, Anesthesia and Critical Care and Joseph B. Ciolino, MD, Massachusetts Eye and Ear

Glaucoma is the leading cause of irreversible blindness worldwide. Drug treatment delivered by eye drops is the mainstays of treatment. However, the drugs need to be administered frequently and are often associated with burning, stinging, and ocular surface toxicity. The result is poor patient compliance (50% at 6 months of treatment), which leads to vision loss. A drug-eluting therapeutic contact lens (TCL) has been developed to overcome these challenges. The TLC delivers drugs in large quantity for a long period at a relatively constant rate for over one month. The 2012 TDF award will be used to to test the ability of the drug-eluting lens to reduce intra-ocular pressure in a primate model of glaucoma in anticipation of a phase I clinical trial.

In the news:

Development of a multiple antigen presenting (MAPS) vaccine
Richard Malley, MD, Yingjie Lu, PhD, and Fan Zhang, PhD, Infectious Diseases

Current pneumococcal vaccines are based on conjugation of capsular polysaccharides (CPS) with a protein carrier. Broad distribution and use of these vaccines is limited by high cost of manufacture, limited serotype coverage, and inadequate functional antibody production to some CPS.

Dr. Malley’s team developed a novel vaccine platform, called Multiple Antigen Presenting System (MAPS), allowing coupling of CPS and protein carriers with extremely high efficiency (>90%) while preserving the immunological properties of the antigens. In addition to using CPS to elicit an immune response, this technology uses conserved protective pneumococcal antigens as protein carriers resulting in greater antibody production than that of conventional conjugates, as well as potent T cell (Th17) response to the proteins conferring serotype-independent protection against carriage. The 2012 award will be used to construct vaccine conjugates and to evaluate these against pneumococcal colonization and disease in a pilot study in rabbits.

In the news:

Bioenhanced repair of ACL injuries for skeletally immature patients
Martha Murray, MD, Orthopedic Surgery

Today, ACL tears are one of the most common knee injuries, especially among basketball and soccer players. The current technique for treating ACL tears is surgical reconstruction, which involves removing the torn ligament and replacing it with a graft of a tendon from elsewhere in the body or from a cadaver. While this allows patients to return to sports in the short term, many will develop early arthritis of the knee.

Dr. Murray is developing a procedure to stimulate the healing of a patient’s own ACL. She and her team have developed a scaffold made of collagen and other extracellular matrix proteins. When placed in the site of an ACL tear, not only does it enhance healing of the ligament, it also eliminates the post-traumatic osteoarthritis seen in animals and patients undergoing ACL reconstruction. The 2012 TDF award will support the transition of the scaffold production process to a GMP facility and certify the terminal sterilization process required by the FDA.

In the news:

Developing sepiapterin reductase inhibitors for treating neuropathic pain
Clifford Woolf, MB, BCh, PhD, Neurobiology Program, Nick Andrews, PhD, Neurobiology, Michael Costigan, PhD, Anesthesia and Neurobiology, Alexandra Latini, PhD, Universidad Federal de Santa Catarina, Alban Latremoliere, PhD, Neurobiology

New therapeutic strategies for neuropathic pain are urgently required because of the poor efficacy, abuse liability, and high side effect burden of currently available treatments. The Woolf laboratory has shown that the tetrahydrobiopterin (BH4) pathway is linked to neuropathic and inflammatory pain and found that peripheral nerve injury results in increased expression -in injured sensory neurons- of several key members of the BH4 synthetic pathway, including the terminal synthetic enzyme, sepiapterin reductase (SPR). They found that an elevation in BH4 levels after nerve injury is a key contributor to the production of, and susceptibility for, neuropathic pain. The 2012 award will be used to further understand the role of BH4 in the mediation of chronic pain through the use of a unique tool compound and development of biomarker assays relating to the target pathway.

In the news:

Prominin-1: Topical treatment for chronic wounds
Avner Adini, PhD and Robert D’Amato, MD, PhD, Vascular Biology Program

A short peptide, derived from Prominin-1, dramatically improves vessel formation by potentiating endogenous VEGF binding to its receptor. Drs. Adini and D’Amato showed an acceleration of diabetic wound healing over the control in mouse models. The 2011 Technology Development grant will fund formulation and pharmacokinetic work.

Lodamin: An oral anti-angiogenic therapeutic
Ofra Benny-Ratsaby, PhD and Robert D’Amato, MD, PhD, Vascular Biology Program

Lodamin is a polymer-conjugated TNP-470 – one of the most potent anti-angiogenic agents ever discovered – rationally designed by Drs. Benny-Ratsaby and M. Judah Folkman to overcome the obstacles that prohibited the success of TNP-470: poor pharmacokinetics and reversible neurotoxicity. Lodamin is orally available and demonstrated broad spectrum anti-angiogenic activity in a range of in vitro assays and murine primary cancer models. Compared to anti-VEGF, Lodamin was able to repress lesions in a mouse model of AMD. Also awarded a TDF grant in 2009 to devise a reproducible and scalable synthesis protocol, the 2011 grant will support pharmacokinetic work to support an IND package.

ABCB5: Monoclonal antibody therapy for metastatic melanoma
Markus Frank, MD, Nephrology

ABCB5 is expressed selectively on cancer stem cells that are resistant to conventional forms of therapy, but are critical drivers of tumor initiation and metastatic disease progression. Dr. Frank has shown that targeted killing of cancer stem cells in melanoma through ABCB5 monoclonal antibody (mAb)-dependent cell-mediated cytotoxicity (ADCC) significantly inhibits human xenograft tumor growth in immunodeficient mice established either with patient tumor cells or established melanoma cell lines. The 2011 TDF grant will be used to generate a panel of fully human ABCB5 antibodies.

Neosaxitoxin: Prolonged-duration local analgesic
Charles Berde, MD, PhD, Anesthesiology

Neosaxitoxin (NeoSTX) is a member of the chemical family of site 1 sodium channel toxins which was shown by Dr. Berde and colleagues in both preclinical and clinical studies to be active for up to twice as long as current analgesics. NeoSTX also shows a lack of neurotoxicity and cardiotoxicity and other side effects of traditional anesthetics and analgesics. Also the recipient of a 2010 TDF grant, the 2011 grant will fund remaining preclinical studies as recommended by FDA at a pre-IND meeting in November 2010.

Cardioport for trans-apical cardiac interventions
Pedro J. del Nido, MD, and Nikolay Vasilyev, MD, Cardiac Surgery

Dr. del Nido and his team have designed a cardiac port with an air purging system and a one-way valve that prevents air emboli and minimizes blood loss during trans-cardiac interventions. The port has the added functionality of an optical window that allows continuous visualization inside the beating heart. The TDF grant will support functional prototype optimization of the visualization system as well as reducing the diameter of the cardioport.

Heart valve leaflet utilizing a novel fiber arrangement
Peter Hammer, PhD, Cardiac Surgery

Dr. Hammer has created a novel heart valve leaflet using polymer and reinforcement fibers that promises to achieve the durability of mechanical valves without their risk of thrombogenicity. Dr. Hammer’s valve mitigates this risk through the fiber pattern’s unique control of valve function and stress distribution. The 2011 TDF grant will fund design, manufacturing and testing of a series of valve prototypes.

Intravenous oxygen delivery via microbubble technology
John Kheir, MD, Cardiology

Dr. Kheir has shown that intravenous delivery of oxygen via microbubbles can nearly instantly increase plasma oxygen concentration to rapidly reverse acute hypoxia. Notably, one study maintained near-normal levels of oxygen in a rabbit during a 15 minute period of asphyxia. The microbubble technology has been shown to have several clinical advantages over CPR, intubation, and mechanical ventilation with respect to survival and tissue damage. Also the recipient of 2009 and 2010 TDF grants, this year’s grant will fund formulation and stability work on the microbubbles.

Diagnostic for Kawasaki disease
Susan Kim, MD, MMSc, Rheumatology

Kawasaki Disease (KD) is a pediatric autoimmune disease which causes inflammation of blood vessels and which, if left untreated, can lead to coronary artery aneurysms in up to 25% of affected children. There is currently no diagnostic test for KD, however Dr. Kim has identified several novel protein markers in the urine of KD patients, two of which have been validated. The 2011 TDF grant will be used to further assess the specificity and predictive utility of these proteins in diagnosing KD.

Cystatin B: Novel prognostic biomarker for bladder cancer
Bruce Zetter, PhD, Vascular Biology Program

Dr. Zetter and his team, in collaboration with investigators at Massachusetts General Hospital, have discovered a novel cancer urinary biomarker. Called cystatin B, the marker has been found to be a powerful, non-invasive and predictive marker of transitional cell carcinoma in the bladder. Dr. Zetter has shown that cystatin B correlates with tumor grade and stage, and is predictive of future disease recurrence and progression. The 2011 grant will support validation of cystatin B in a larger patient cohort using a quantitative assay.

eDMC: Web-based disease management system
Eric Fleegler, MD, MPH, Emergency Medicine and Eugenia Chan, MD, MPH, Developmental Medicine

eDMC is a multi-modal patient management system for children with ADHD. eDMC systematically monitors patient symptoms, functioning and learning, medication use and side effects as well as family and patient quality of life. The central gathering of this data will allow practitioners treating ADHD access to a robust set of clinical data to significantly increase efficacy and efficiency of ADHD care. The 2011 TDF grant will fund expansion of the proof of concept software to enhance accessibility and user experience.

MedWatcher: Crowdsourcing for drug safety surveillance
John Brownstein, PhD, Computational Health Informatics Program and IDHA

Nearly half of all Americans currently take a prescription drug, yet the public remains largely unaware of medication safety concerns. Dr. Brownstein and colleagues are developing MedWatcher to engage users (both the public and healthcare practitioners) in issues of drug safety, providing up-to-date safety advisories and a reporting tool for direct submission of adverse drug events by the user. The 2011 TDF grant will fund development of the user interface and back-end data interoperability.

Glyco-Trap: Novel glycoprotein capture and analysis device
Richard S. Lee, MD and Hui Zhou, PhD, Urology

Glyco-Trap, developed by Dr. Lee and colleagues, is a novel device technology that has the capability to sequentially release, capture and purify both glycans and protein fractions of a sample to facilitate subsequent structural characterizations of both fractions – a critical tool for quality control analysis of biopharmaceutical product production, amongst other research and development applications. The 2011 TDF grant will fund development and optimization of a Glyco-Trap device prototype to evaluate commercial potential.

Site 1 sodium channel blocker as a prolonged-duration local anesthetic
Charles Berde, MD, PhD, Anesthesiology

Dr. Berde and his colleagues have shown that a class of site 1 sodium channel blockers has prolonged action as local anesthetics and has some very desirable safety features, including no toxicity to the heart and no entry into the brain. The goal of the project is to perform animal toxicology studies as part of the final package of data for an investigator-initiated investigational new drug (IND) submission to the FDA and for clinical trials for use as a prolonged-duration local anesthetic.

Optical device to monitor capillary refill
Vassilios J. Bezzerides, MD, PhD, Cardiology

Currently, the diagnosis of dehydration is based on a combination of clinical signs and symptoms that have limited sensitivity and specificity. Dr. Bezzerides developed a hand-held prototype that accurately measures capillary refill time (CRT) and conducted a pilot study in Children’s Emergency Department to determine the device’s effectiveness. The purposes of this project are to improve the device and perform clinical studies to diagnose patients with various degrees of dehydration.

Early autism diagnosis and risk assessment using complex systems analysis of EEG signals
William Bosl, PhD, Medicine/Informatics Program

The primary goal for this technology is to enable early detection of autism and routine monitoring of infants’ cognitive development through EEG measurements. Dr. Bosl envisions a diagnostic service based on novel analysis of EEG data recorded during a pediatric well-visit. A risk profile and cognitive assessment based on Dr. Bosl’s analysis will be sent to the health care provider for use and follow up.

A GDNF receptor agonist for topical treatment of peripheral neuropathies
Gabriel Corfas, PhD, Neurology and Otolaryngology

The goal of this project is to develop a new therapy to treat peripheral neuropathies (PN) by targeting the underlying physical and/ or functional defects in peripheral nerves to stop (and potentially reverse) nerve damage. Using two mouse models of small fiber PN, Dr. Corfas’ team showed that topical application of a non-peptidyl GDNF receptor agonist to the skin of affected mice has dramatic therapeutic effects. They used last year’s TDF grant to perform chemical manufacturing control studies on their compound, and pharmacokinetic and pharmacodynamic studies are underway. The 2010 award will be used to perform studies to move the compound towards IND submission to the FDA.

Novel transillumination PICC line catheter
Farhad Imam, MD, PhD, Newborn Medicine/Surgery

Dr. Imam has developed a novel transillumination method and device to improve the safety and efficiency of peripherally inserted central catheter (PICC) line insertion. The device allows the external observer to see light emission from the internal catheter through the skin. A functional prototype has been constructed and tested successfully in cadaver tissue and live animals. The goal of this project is to construct and optimize a functional transilluminating PICC catheter that can be used in cadaver, animal and, ultimately, human testing.

Intravenous oxygen using injectable microbubbles
John Kheir, MD, Cardiology

When systemic oxygen levels are low, irreversible and severe injury occurs to the brain, heart and other organs. The goal of this project is to develop a platform technology allowing therapeutic gas to be injected intravenously. Dr. Kheir has demonstrated that oxygenated microbubbles can be manufactured and stored in bulk for weeks. Oxygenated microbubbles have been successfully tested in a rabbit model of hypoxic ventilation. The purpose of this project is to expedite further optimization of the lipid formulation and examine the possibility of using well-established processes for drug manufacturers to make size-limited, gas-filled microparticles.

Platform to deliver vaccines and drugs across the intestinal wall
Wayne I. Lencer, MD, Gastroenterology/Nutrition

Dr. Lencer will test his recent discovery that “short” or “unsaturated” ceramide-based lipids may act as molecular carriers to deliver therapeutic peptides across mucosal epithelial barriers and extend drug half-life. The goal of this project is to provide proof-of-principle for this novel nanotechnology designed to transport peptides and proteins across the epithelial membrane. If successful, this technology could become a platform for oral or nasal administration of therapeutic proteins and/or vaccine adjuvants.

Novel myocardial imaging agent
Alan Packard, PhD, and S. Ted Treves, MD, Nuclear Medicine and Molecular Imaging

This project proposes the development of an 18F-labeled rhodamine B for myocardial perfusion imaging in patients with known or suspected coronary artery disease using positron emission tomography. In preliminary studies, the investigators have demonstrated that 18F-labeled rhodamine B accumulates in the heart. The goal for this project is to optimize the synthesis of the compound and obtain sufficient toxicology data to support a physician-sponsored IND.

Development of Saposin A derivatives as a cancer therapeutic
Randolph Watnick, PhD, Vascular Biology Program

Dr. Watnick has identified a peptide that retains the in vivo activity of the full-length prosaposin protein. He has shown that prosaposin is secreted by weakly aggressive human breast and prostate cancer cells, and that it inhibits metastasis in a prostate cancer model in vivo. Dr. Watnick is currently working with TD2 (a CRO) to perform pharmacokinetic stability studies on the peptide as part of the initial funding he received from TDF last year. For this next phase of the project, he will continue to work with TD2 to perform pre-clinical efficacy studies using multiple xenograft models including breast, colon and pancreatic cancer.

Ion channel blockers to manage neurogenic inflammation
Clifford Woolf, MD, PhD, Neurobiology Program

The goal of the project is to use certain large-pore cation channels, located on sensory neurons that are activated in allergic conditions, as drug entry ports to introduce charged calcium channel blockers into bronchial sensory fibers. This will disrupt the neurogenic inflammation produced by the calcium-dependent release of pro-inflammatory mediators from the targeted nerves, for treatment of conditions such as asthma, rhinitis, conjunctivitis and Crohn’s disease. This project will study respiratory diseases because the evidence for a neurogenic component is very compelling, there is an unmet need and preclinical models are available.

Novel therapeutic approach for metastatic prostate cancer
Bruce Zetter, PhD, Vascular Biology Program

Dr. Zetter and colleagues developed a screen that relies on differential cytotoxicity of drugs for highly metastatic cells to select novel therapeutic agents for late-stage cancer. From a library of 1,120 non-toxic FDA-approved drugs, they identified benzimidazoles as a class of compounds that are preferentially active against highly metastatic prostate tumor cells and exhibit minimal cell killing in normal cells. They aim to bring forward a member of this class of compounds as a potential treatment for androgen-resistant metastatic prostate cancer and develop a novel formulation suitable for cancer patients. They will also conduct efficacy and pharmacokinetic studies.

A topical, slow-release anti-angiogenic drug for treating eye diseases
Ofra Benny, PhD and Robert D’Amato, MD, PhD, Vascular Biology Program

Lodamin is a novel oral anti-angiogenic drug and a non-toxic derivative of TNP-470 with preclinical activity in oncology. Angiogenesis-related eye diseases, such as diabetic retinopathy and macular degeneration are common. Effective anti-angiogenic therapies aim to delay the progression of these ophthalmic diseases and prevent vision loss. Currently there are no antiangiogenic drugs approved for corneal neovascularization but only indirect angiogenesis inhibitors such as steroids and immunosuppressants. For retinal angiogenesis-related diseases, such as Age-Related Macular Degeneration (AMD), the only antiangiogenic therapies available are based on targeting a single growth factor: Vascular Endothelial Growth Factor (VEGF). Contrary to these available treatments, Lodamin inhibits both vessel growth and leakage of fluid. In addition, targeting a single growth factor can lead to either a resistance to the treatment over time or reduced efficacy over time, as other growth factors other than VEGF start playing a significant role in the progression of the disease.

TDF 2009 supported studies to show enhanced activity of Lodamin when compared to VEGF trap technologies in a mouse model of AMD, and to further characterize and optimize Lodamin synthesis. Pharmacokinetic studies of Lodamin and its metabolites are currently underway.

A topical treatment for peripheral neuropathies
Gabriel Corfas, PhD, Neurobiology Program

The goal for this project is to develop new therapies to treat and prevent further progression of peripheral neuropathies. Dr. Corfas’ team has found that topical application of a small molecule acting on neurotrophic receptors is an effective therapeutic strategy, as demonstrated in two mouse models of small fiber peripheral neuropathy.

The 2009 award supported studies performed by Particle Sciences Inc. that defined key physical properties and biodistribution of the lead compound. In 2010, the Children’s TDF committed additional funding to this technology for the development and testing of analogues to the lead compound.

In parallel, the Corfas laboratory has received external funding that is allowing him to test the molecule in additional animal models.

Dr. Corfas believes that these studies will significantly clarify, and likely substantiate the commercial viability of this type of compound. The work is expected to enhance its potential for licensing and expedite its subsequent development as a therapeutic.

Fetal tissue engineering to repair congenital diaphragmatic hernia
Dario Fauza, MD, Surgery

Congenital diaphragmatic hernia (CDH) is among the most common major structural congenital anomalies, occurring in approximately 1:2,200 births. It encompasses a defect in the diaphragm, allowing for herniation of abdominal organs into the chest. This project is aimed at the eventual approval of the first human trial of neonatal diaphragmatic repair with a mesenchymal amniocyte-based, autologous engineered graft. The team hopes to fulfill definite pending requirements, as specified by the FDA authorities governing such processes, and eventually bring this concept to clinical fruition. The precise strategy and experiments to be performed will depend on the FDA’s review of the latest data. Two project scenarios can be foreseen. In the first, the FDA is satisfied with the current pre-clinical data and approves the first clinical trial. In that case, this award would be used to fund such a trial. In the second, the FDA requires additional pre-clinical large animal and cell manufacturing data before allowing the first clinical trial. In this case, this award would be used to accomplish such new demands. This project is currently on hold pending the FDA review anticipated for early summer 2011.

Semaphorin 3F as a treatment for brain cancer
Michael Klagsbrun, PhD, Vascular Biology Program

Class-3 semaphorins were originally described in the neuronal system as axon guidance molecules; however their contribution to vascular/tumor biology is becoming evident. The overall goal for this project is to develop SEMA3F as a novel cancer therapeutic. SEMA3F is a strong candidate as a new therapeutic because there is evidence that it is a robust inhibitor of both angiogenesis and, importantly, metastasis. Moreover, SEMA3F is lost in metastatic tumor cells.

TDF 2009 funding supported the production of recombinant SEMA3F and pharmacokinetic studies on the protein. Efficacy studies in the glioma tumor mouse model are in progress. Gliomas are tumors that arise from glial cells in the brain or spinal cord. They are rarely curable and affect ~10,000 new patients per year in the U.S.

Pediatric Vision Scanner
David Hunter, MD, PhD, Ophthalmology

Amblyopia (“lazy eye”) and strabismus are two eye conditions that can blind an eye if left untreated. When a child has strabismus, the eyes are misaligned, and to prevent double vision, the child’s brain suppresses the weaker one, eventually blinding it. Physicians have struggled to consistently detect and diagnose strabismus and amblyopia because the signs cannot always be detected by a competent primary care doctor. Dr. Hunter has developed the Pediatric Vision Scanner (PVS), a device that in a quick 2.5 second scan of the eyes can automatically detect strabismus, amblyopia, and other serious eye conditions in children as young as 2 years of age. In 2008, a pilot study of the PVS prototype involving over 200 subjects (article submitted for publication) showed unprecedented accuracy, with a sensitivity and specificity both exceeding 97 percent.

Originally, there was only one existing current version of the PVS prototype, and that device contains extra components and circuitry that were required for initial development. The TDF 2009 award, as well as additional external funding, allowed Dr. Hunter to work with Continuum LLC to develop several lighter, easier-to-use prototypes. The next step for this project is to pursue independent IRB-approved clinical trials at other institutions to assess its feasibility in the field and generate widespread acceptance of its effectiveness. Four sites have been identified and the clinical trials are scheduled to begin in the next few months.

Urine diagnostic markers of acute appendicitis
Alex Kentsis, MD, Division of Hematology/Oncology, Richard G. Bachur, MD, Emergency Medicine, and Hanno Steen, PhD, Proteomics

Acute appendicitis is the most common surgical emergency, with the life time personal risk of nearly one in ten. Even with modern ultrasound and computed tomography imaging, accurate diagnosis of appendicitis is challenging, with as many as 10-30 percent of patients undergoing unnecessary surgeries, and as many as 30-45 percent of patients having delayed diagnosis, with associated increased mortality, morbidity, and cost. This team recently completed a study of discovery and validation of urine markers of acute pediatric appendicitis by using high accuracy mass spectrometry. They discovered several novel urine markers of acute appendicitis, with improved diagnostic performance as compared to ultrasound and CT imaging, as well as to known laboratory markers of acute appendicitis. Among these markers is the leucine-rich alpha-2-glycoprotein (LRG) that is enriched by several orders of magnitude in diseased appendices and in the urine of patients with appendicitis, and exhibits superior diagnostic performance, as assessed using receiver operating characteristic (ROC) area under the curve value of 0.97. The TDF 2009 award is supporting the translation of the LRG test to an antibody based platform, and is helping validate this biomarker for appendicitis.

Intravenous oxygen using injectable microbubbles
John Kheir, MD, Cardiology

The goal of this project is to package oxygen in such a way that it can be administered intravenously. Low oxygen levels are a final common pathway which causes death or severe disability in a variety of diseases affecting both adults and children. To address this, Dr. Kheir has developed a liquid suspension containing very high concentrations of oxygen gas packaged into microbubbles designed for intravenous injection. In this project, his team will expand the body of evidence in support of I.V. oxygen as a therapy. Specifically, they will test the efficacy of I.V. oxygen to improve outcomes during airway obstruction and during cardiac arrest.

A novel pneumococcal vaccine
Ying-Jie Lu, PhD, and Richard Malley, MD, Infectious Diseases

Dr. Malley and Dr. Lu have developed a new technology platform to create new vaccines that elicit potent immunity to pneumococcus and other targets. Unlike current pneumococcal vaccines, a vaccine based on this technology will be effective in both developing and developed countries because it will include the coverage of all strains, induce both antibody and T cell responses to the organism, generate immunity to protect against invasive disease and mucosal carriage, and carry with it a lower cost and ease of manufacture. Because the vaccine elicits not only antibody, but also T cell immunity, which is quite different between mice and primates, this study is designed to confirm vaccine immunogenicity and safety in nonhuman primates.

The main goal of this project is to evaluate the novel vaccine against pneumococcal colonization and disease in nonhuman primates and to further characterize ideal antigenic combinations. The 2009 award has been used to further this technology, evaluate novel pneumococcal antigens that provide protection against colonization and invasive disease, and optimize the formulation of the vaccine.

Additionally, Drs. Lu and Malley were awarded a grant from the Bill and Melinda Gates Foundation to create and test a vaccine that may protect against pneumococcus and the causative agent of typhoid fever, Salmonella typhi, which is another major cause of morbidity and mortality in the developing world.

Development of chemical chaperones to treat obesity and Type 2 diabetes
Umut Ozcan, MD, Endocrinology

The discovery of leptin more than a decade ago heralded a potential therapeutic for the treatment of obesity; however, the enthusiasm surrounding leptin as a therapeutic agent diminished rapidly with the findings that both diet-induced rodent models of obesity and obese humans are minimally responsive to leptin due to development of leptin resistance in the brain. Dr. Ozcan’s team has shown that drugs that alleviate ER stress can re-sensitize the brains of the obese mice to leptin and act as leptin sensitizers.

Dr. Ozcan and collaborators have discovered several new chemical chaperones, which have the ability to decrease ER stress at very low doses compared to previous agents. These have shown promising results in in vivo mouse models of obesity. With TDF 2009 funding and in partnership with Shanghai Chem Partners, they performed PK studies on the four most powerful compounds and are currently performing short term efficacy studies in animal models.

Development of Saposin A as a cancer therapeutic
Randolph Watnick, PhD, Vascular Biology Program

Dr. Watnick identified an endogenous protein, saposin A, which is secreted by weakly aggressive human breast and prostate cancer cells, and has demonstrated that it inhibits metastasis in a prostate cancer model in vivo. One major advantage that saposin A, and its derivatives, would have over traditional therapies is the fact that its mode of action is directed toward the normal cells that make up the stroma of primary tumors and the parenchyma of normal organs. These cells are genetically stable and unlikely to develop mutations that would confer resistance to saposin A treatment. The goal for this project is to confirm the efficacy of saposin A, and derivatives thereof, against tumor growth and further characterize the product candidates.

In the past year with TDF 2009 funding Dr. Watnick identified a small peptide, derived from prosaposin (psaptide) that retains the in vivo activity of the full-length protein. Further studies indicate that it is stable and specific. He is performing pharmacokinetic stability studies on psaptide. With TDF 2010 funding, he will perform pre-clinical efficacy studies using multiple human xenograft models and plans to carry out pharmacodynamic studies to continue to compile a package for IND filing.

Hand-held solution to improve communication, coordinate emergency department care
Debra Weiner, MD, PhD, Emergency Medicine

Emergency care in this country and throughout the world is in crisis. Increasing patient volume and decreasing Emergency Department (ED) resources threaten patient care and safety, as well the survival of EDs themselves. Solutions to improve patient services, as well as to maximize efficiency and lower costs, are desperately needed. Efficient and timely communication is critical for meeting these challenges, however, at present, communication is part of the problem. The goal of this project is to develop a workflow integrated communication network that coordinates ED patient care between the multitude of providers, services and systems within the ED and throughout the hospital to impact patient care and the health of the ED healthcare system. The project was put on hold pending matching funds, and is scheduled to begin soon.