2017 TDF-Awarded Projects

Brian Polizzotti, PhD, Department of Cardiology

Project Summary:

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:

Brian McAlvin, MD Department of Medicine and Daniel Kohane MD, PhD Department of Anesthesiology

Project summary:

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 will be used to expand the work to a large animal model to demonstrate that the technology is scalable.

In the news/References:

Clifford Woolf, MB, Bch, PhD and David Roberson, PhD, MBA

F.M. Kirby Neurobiology Center

Project summary:

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:

Ofer Levy, MD, PhD and Guzman Sanchez-Schmitz, PhD

Precision Vaccines Program; Department of Medicine/Division Infectious Diseases

Project summary:

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:

Paula Watnick, MD, PhD and Julie Liao, PhD

Department of Medicine/Division of Infectious Diseases

Project summary:

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:

Wesley Wong, PhD

Department of Medicine/Program in Cellular and Molecular Medicine

Project summary:

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]

2016 TDF-Awarded Projects

Carlos Estrada, MD, Urology, and Jeanne Chow, MD, Radiology

Project summary:

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:

Daniel S. Kohane, MD, and Rong Yang, PhD, Pediatric Critical Care

Project summary:

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:

  • Formulations for Trans-Tympanic Antibiotic Delivery. Khoo X, Simons EJ, Chiang HH, Hickey JM, Sabharwal V, Pelton SI, Rosowski JJ, Langer R, Kohane DS. Biomaterials. 2013; 34(4): 1281–1288
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James MacLaine, BDS, and Elizabeth Ross, DDS, Craniofacial Orthodontics

Project summary:

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.

Elizabeth Wharff, PhD, and Kimberly O’Brien, PhD, Psychiatry

Project summary:

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

  • A Pilot Study of the Acceptability and Usability of a Smartphone Application Intervention for Suicidal Adolescents and Their Parents. McManama O’Brien KH, LeCloux M, Ross A, Gironda C, Wharff EA. Arch Suicide Res. 2016 May 2:1-11.

Gregory Priebe, MD, Infectious Diseases

Project summary:

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:

  • Th17-stimulating Protein Vaccines Confer Protection against Pseudomonas aeruginosa Weihui Wu, Jin Huang, Biyan Duan, David C. Traficante, Haeyeon Hong, Martina Risech, Stephen Lory, Gregory P. Priebe. Am J. Respir Care Med. 2o12 Sep 1; 186(5):420-427.

Florian Winau, MD, PhD, Program of Cellular and Molecular Biology

Project summary:

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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2015 TDF-Awarded Projects

George Q. Daley, MD, PhD, Hematology/Oncology and Dean of Harvard Medical SchoolDr. 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:

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.

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.

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.

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:

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:

2014 TDF-Awarded Projects

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.

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.

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:

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.

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:

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:

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:

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:

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:

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:

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:

2013 TDF-Awarded Projects

Charles Berde, MD, PhD, Anesthesia and Daniel 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:

Jeffrey Burns, MD, MPH, and Traci Wolbrink, MD, Critical Care

OPENPediatrics™ (http://openpediatrics.org/) 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:

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:

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.

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:

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:

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:

2012 TDF-Awarded Projects

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:

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:

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:

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:

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.

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