2011 TDF-Awarded Projects

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 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 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.

2010 TDF-Awarded Projects

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 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 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.

2009 TDF-Awarded Projects

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

This project’s aim is to develop Lodamin as a drug for ophthalmology uses. 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 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.