SBIR-STTR Award

Retinal vascular diseases, such as diabetic retinopathy (DR) 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 permanent and irreversible. A subgroup of DR patients suffer 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, endothelial progenitor cells (EPCs), which are capable of homing to vascular lesions and facilitating vascular repair. However, many diabetic patients have dysfunctional EPCs with no reparative potential. In this Challenge Grant using a novel strategy, we propose to correct dysfunctional EPCs of diabetic patients with maculopathy and use these EPC to both restore perfusion to the ischemic retina and correct vessel leaking. To address key gaps in knowledge, we propose to study 50 patients with diabetic maculopathy to define the critical 'window of opportunity' for stem cell treatment success. Thus, we propose the hypothesis that patients with diabetic macular ischemia (DMI) and diabetic macular edema (DME) have defective EPCs and this dysfunction can be corrected by transiently inhibiting endogenous transforming growth factor-¿ 1 (TGF-¿1) in the EPCs. Our specific aims will determine the best time in the natural history of the disease to treat the patient, identify the ideal EPC population to use for therapy, and determine the best method of delivery to the eye. In this proposal, we are using a combination of clinical studies, studies in animal models and the highly novel approach of transient (2-4 days) blockade of endogenous TGF-¿1 in diabetic EPCs using antisense phosphorodiamidate morpholino oligomers (PMO) to TGF-¿1. This treatment restores the reparative ability of the dysfunctional diabetic cells. The investigators of this application represent scientists from industry, from the private sector and from academia. With this unique mix, each investigator brings specific expertise including stem cell biology, clinical retina expertise and animal models of human disease. The results of this Challenge Grant will pave the way for clinical trials of stem cell therapy in patients with diabetic retinopathy.

Public Health Relevance:
Our goal is to develop an efficient, safe clinical treatment for diabetic retinopathy using stem cells from the patient's blood that have been activated outside of the patient then returned to repair damaged vessels in the eye. Currently, no effective treatment exists to reverse diabetic retinopathy marked by vision loss following retinal blood vessel damage caused by a lack of blood/oxygen supply to the retina.

Public Health Relevance Statement:
Project Narrative Our goal is to develop an efficient, safe clinical treatment for diabetic retinopathy using stem cells from the patient's blood that have been activated outside of the patient then returned to repair damaged vessels in the eye. Currently, no effective treatment exists to reverse diabetic retinopathy marked by vision loss following retinal blood vessel damage caused by a lack of blood/oxygen supply to the retina.

NIH Spending Category:
Clinical Research; Diabetes; Eye Disease and Disorders of Vision; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Stem Cell Research - Nonembryonic - Non-Human

Project Terms:
0-6 weeks old; 21+ years old; Academia; Address; Adoptive Transfer; Adult; adult human (21+); Age; Animal growth regulators, transforming growth factors; Animal Model; Animal Models and Related Studies; Area; Autologous; Blindness; Blood; Blood capillaries; Blood Cells; blood vessel disorder; Blood Vessels; Bone Marrow; Capillaries; capillary; Capillary; Capillary, Unspecified; CD34; CD34 gene; Cell Count; Cell Function; Cell Number; Cell physiology; Cell Process; Cell Therapy; cell-based therapy; Cells; Cellular Function; Cellular Physiology; Cellular Process; Characteristics; Clinical; clinical investigation; Clinical Research; Clinical Study; Clinical Treatment; Clinical Trials; Clinical Trials, Unspecified; Cohort Studies; Concurrent Studies; CXC-R4; CXCR-4; CXCR4; CXCR4 gene; cytokine; D2S201E; degenerative condition; degenerative disease; Degenerative Disorder; Development; diabetes; Diabetes Mellitus; diabetic; Diabetic mouse; diabetic patient; Diabetic Retinopathy; Disease; disease natural history; disease/disorder; Disorder; disorder of macula of retina; Dropsy; Dysfunction; Edema; effective therapy; Endothelial Cells; Ensure; Expression Profiling; Expression Signature; Eye; Eyeball; FB22; Functional disorder; Generalized Growth; Generations; Goals; Grant; Growth; HM89; Homing; HPCA1; HSY3RR; Human; human disease; Human, Adult; Human, General; Hydrops; in vivo; Industry; Infant, Newborn; Investigators; Ischemia; Ischemia-Reperfusion Injury; Knowledge; LAP3; LCR1; Lesion; LESTR; long-term study; Longitudinal Studies; macula; macular; macular edema; Mammals, Mice; Man (Taxonomy); Man, Modern; Methods; Methods and Techniques; Methods, Other; Mice; model organism; Modeling; molecuar profile; Molecular Fingerprinting; Molecular Profiling; molecular signature; Mother Cells; mouse model of diabetes; Murine; Mus; neovascularization; new approaches; newborn human (0-6 weeks); Newborn Infant; Newborns; non-diabetic; nondiabetic; novel approaches; novel strategies; novel strategy; NPY3R; NPYR; NPYRL; NPYY3R; O element; O2 element; ontogeny; Oxygen; paracrine; Pathologic; Pathology; pathophysiology; patient population; Patients; Perfusion; Peripheral; Peripheral Blood Cell; Phenotype; phosphorodiamidate morpholino oligomer; Physiologic; Physiological; Physiopathology; PMO oligomer; Population; Prevalence; Private Sector; Progenitor Cells; prospective; public health relevance; receptor; Receptor Protein; repair; repaired; reperfusion; Reperfusion Damage; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Researchers; restoration; Reticuloendothelial System, Blood; Reticuloendothelial System, Bone Marrow; Retina; retina blood vessel structure; retina degeneration; retina disease; retina disorder; retina ischemia; Retinal; Retinal Blood Vessels; retinal damage; Retinal Degeneration; retinal degenerative; Retinal Diseases; Retinal Disorder; retinal ischemia; Retinal Vessels; retinopathy; Role; SCID; SCID Mice; Scientist; severe combined immune deficiency; Severe Combined Immunodeficient Mice; Sight; social role; stem cell biology; Stem Cell Development; stem cell therapy; Stem cells; Structure of blood vessel of retina; Subcellular Process; SUBGP; Subgroup; success; Techniques; Testing; Therapeutic; Therapy, Cell; Time; Tissue Growth; Toxic effect; Toxicities; Transforming Growth Factors; trial regimen; trial treatment; Tube; Tumor Growth Factors; vascular; Vascular Diseases; Vascular Disorder; Vis