Autologous TGFB1 Modified CD34+ Stem Cells for Repair of Diabetic Macular Edema and Macular Ischemia Retinal vascular diseases, such as diabetic macular edema and macular ischemia remain a common cause of vision loss and blindness. Diabetes can damage the small blood vessels in the retina causing them to leak and occlude resulting in vision loss. Although treatments are available for aspects of diabetic ocular disease no therapy is available to treat the damaged retinal vasculature and ischemic retina. Vision loss from retinal ischemia can be irreversible. A subgroup of DR patients suffers from macular ischemia and currently there is also no effective therapy. Research over the last decade has identified a class of bone marrow?derived circulating cells, CD34+ stem cells, which are capable of homing to vascular lesions and facilitating vascular repair. However, many diabetic patients have dysfunctional CD34+ stem cells with no reparative potential. In this SBIR Fast Track phase l/ll proposal we use a novel strategy to correct dysfunctional diabetic CD34+ cells by transiently modifying CD34+ stem cells derived from patient blood that both restores perfusion to the ischemic retina and correct vessel leaking. Experiments from our NIH funded studies show that this CD34+ dysfunction can be corrected by transiently inhibiting endogenous transforming growth factor?? 1 (TGF??1) within the patient's own dysfunctional CD34+ stem cells using antisense phosphorodiamidate morpholino oligomers (TGF?1 PMO) to TGF?1. Our proposed studies are focused according to guidance of the FDA. In 2012 we completed a pre?IND meeting with the FDA. A major goal is to complete an IND in order to begin a first?in?man clinical trial. Our concern in developing this autologous stem cell approach is the safety of the patient and the efficacy of the therapy. We have proposed 5 in vitro phase l CD34+ studies and 5 phase ll in vivo studies (including Akimba mice and diabetic baboons), testing safety and efficacy of our therapy. The investigators of this application include a very experienced CEO, a well?known practicing/research ophthalmologist, an international known PMO expert and a CD34+ stem cell biologist.
Public Health Relevance Statement: Project Narrative BetaStem's goal is to develop an efficient, safe clinical treatment for diabetic retinopathy (DR) using stem cells from the patient's blood, that we activate outside of the patient, then are returned to the patient's eye where they repair damaged capillary vessels. Currently, no effective treatment exists that will reverse DR, which is marked by vision loss as a result of damaged retinal blood vessels and reduction of blood/oxygen supply to the retina.
Project Terms: Adult; Adverse effects; American; Animal Model; Australia; Autologous; base; Blindness; Blood; Blood capillaries; Blood Vessels; Bone Marrow; Canada; capillary; CD34 gene; Cell Differentiation process; Cell Proliferation; Cells; Chromosome Positioning; Clinical; Clinical Treatment; Clinical Trials; CXCR4 gene; Development; Diabetes Mellitus; diabetic; diabetic patient; Diabetic Retinopathy; Disease; Disease Progression; Dose; Drug Kinetics; economic impact; effective therapy; Endothelium; Europe; experience; experimental study; Extravasation; Eye; Functional disorder; Funding; Generations; Goals; Healthcare Systems; Heterochromatin; Homing; Human; immunosuppressed; In Vitro; in vivo; Individual; Injectable; International; Intravenous; Investigational Drugs; Ischemia; Legal patent; Lesion; macula; macular edema; man; Measures; meetings; migration; Mission; mouse model; Mus; Natural regeneration; Newborn Infant; non-diabetic; Non-Insulin-Dependent Diabetes Mellitus; novel strategies; Ophthalmologist; Oxygen; Papio; patient safety; Patients; Perfusion; peripheral blood; Phase; phosphorodiamidate morpholino oligomer; pre-clinical; PTPRC gene; Quality of life; repaired; Reperfusion Injury; Research; Research Personnel; response; restoration; Retina; retina blood vessel structure; Retinal; retinal damage; Retinal Degeneration; retinal ischemia; Safety; safety study; safety testing; Small Business Innovation Research Grant; stem cell population; Stem cells; Stromal Cell-Derived Factor 1; Subgroup; Surface Antigens; TGFB1 gene; Therapeutic; Time; Toxicology; Transforming Growth Factors; Treatment Efficacy; United States Food and Drug Administration; United States National Institutes of Health; Vascular Diseases; Vascular Endothelium
