Pamela Silver, PhD., Elliot T and Onie H Adams Professor of Biochemistry and Systems Biology, Harvard Medical School, and a founding member of the Wyss Institute was awarded a DRIVE grant for continued development of a targeted erythropoietin-based therapeutic. EPO plays multiple biological roles by binding to EPO receptors (EPO-R) on diverse cell types, including erythroid progenitors, macrophages, pro-megakaryocytes, cancer cells, and neurons. The therapeutic goal of this work is to minimize the side effects of EPO by targeting this protein to red blood cell (RBC) precursors and away from other cell types. Recombinant EPO has been used for two decades to treat forms of anemia associated with end-stage renal failure, AIDS, chemotherapy, or hemoglobinopathies. Clinical use of EPO has recently decreased due to concerns over the drug’s off-target effects: EPO treatment has been linked to tumor recurrence and platelet formation or activation, which may lead to coronary disease or thrombosis. Targeting EPO to RBC precursors should allow higher doses to fully restore RBC levels without increasing the risk of cardiovascular events or cancer progression. In addition, the targeted EPO developed here should have an extended serum half-life and reduced immunogenicity relative to existing EPO drugs.
Jonghan Kim, PhD, Assistant Professor of Pharmaceutical Sciences at Northeastern University was awarded a Pilot grant for development of the pharmacokinetics of multifunctional nanochelators in iron overload disorders. Increased iron stores are associated with well-established risk factors of heart and liver failure, arthritis, dyslipidemia and diabetes. Iron overload occurs in several anemias and in addition, hereditary hemochromatosis, a genetic iron overload disorder, affects 7-32% of North American populations with genetic variants. Several neurodegenerative diseases (e.g. Alzheimer’s and Parkinson’s diseases) are also associated with high iron stores in the brain. Although chelation therapy has been widely used to improve disease conditions in patients with iron overload, iron chelators have serious adverse effects, including hypotension, tachycardia, agranulocytosis, neutropenia, neurotoxicity, musculoskeletal-joint pains, gastrointestinal disturbances and even death. This work will develop ultrasmall nanoprobes that covalently bind iron chelators (“nanochelators”) and thus limit drug distribution into non-target tissues, while efficiently capturing plasma iron and being exclusively cleared via urine, thereby decreasing iron burden and reducing the risk of iron-induced tissue damage, including heart diseases and dyslipidemia.
Eric Gale, PhD, Massachusetts General Hospital Martinos Center for Biomedical Engineering received a DRIVE grant to develop a manganese alternative to gadolinium for MRI contrast. Gadolinium based contrast agents (GBCAs) are routinely administered to visualize vascular and tissue irregularities using MRI but concerns over GBCA toxicity in patients suffering kidney disease have emerged over the last decade. In 2007 the FDA labeled all GBCAs with a black box warning. GBCA sales dropped by 1 million vials (~10%) in the year following the FDA issued warnings. This decrease reflects contrast withheld from patients suffering moderate-to-advanced chronic kidney disease which is 8% of the US population. No replacement technology has emerged and CKD patients are continuously denied contrast enhanced examinations. This non-gadolinium containing contrast agent is designed to be compatible with renally insufficient patients and operates analogously to the standard of care but with an improved toxicity and clearance profile. The primary indication for the product will be MR angiography, but it is amenable to any applications requiring GBCAs.
Elazer Edelman, MD, Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology, Massachusetts Institute of Technology, Professor of Medicine, Harvard Medical School, and Senior Attending Physician, Brigham and Women’s Hospital receives a DRIVE award to develop minimally invasive tissue engineering therapies for acute airway injuries. Airway inhalation injury produces severe lung damage and respiratory failure, and is the most common cause of death in burn centers. By embedding healthy bronchial epithelial and endothelial cells within porous matrices, the team has created stable cell constructs which can be implanted into peri-tracheal soft tissue surrounding injury sites. The matrix micro-environment allows for cell preservation with significant shelf-life, ready transport, and an effective therapeutic unit with no demonstrable immune response. Acellularized gelatin particle formulation also has been developed which can be deployed as an injectable, expandable gel around sites of injury. With the DRIVE award, the team will optimize the technology and begin large animal pilot studies on injectable formulations. Ultimately, Dr Edelman envisions two minimally invasive clinical formulations in treating inhalation injuries; an implantable cellularized matrix and injectable matrix particles in an expandable gel. The latter can be injected around the site of injury by first responders while the former can be deployed at designated medical centers as definitive therapy for inhalation injury.
Bruce Bean, PhD, Professor of Neurobiology, Harvard Medical School receives a DRIVE award for silencing airway nociceptors for treatment of cough and airway inflammation. Cough is the most common reason patients see their primary care physician and the sixth most common reason for hospital-based outpatient care. Cough is poorly treated by currently available therapeutics, including opioids, dextromethorphan and benzonatate. The team has developed a novel treatment based on selective delivery of permanently charged cationic sodium channel blockers into activated airway nociceptors through activated TRPV1 and TRPA1 ion channels, which are selectively expressed by nociceptors. Using the tool compound delivered as an inhaled aerosol, the team has shown that this approach can inhibit cough and dramatically reducing airway inflammation in small animal models. They have now synthesized novel compounds that block neuronal sodium channels more potently and propose to test these and initiate pharmacokinetic studies.