?Diabetes mellitus affects >380 million individuals worldwide and its incidence is increasing at alarming rates. Diabetic retinopathy (DR), the most common complication of diabetes, is the leading cause of new blindness in working-aged persons in the United States. Unfortunately, existing therapies are limited to advanced forms of DR. While therapeutic approaches such as laser photocoagulation, surgical vitrectomy and anti-angiogenic (anti-VEGF) agents treat some of the sight threatening complications, efficacy is inadequate as the disease has already progressed. There is a critical need for therapeutic approaches that act earlier in progression of DR, which would enable the physician to initiate treatment before the onset of visual deterioration. Zietchick Research Institute (ZRI) is investigating a potentially transformative therapeutic approach to addressing early stage DR. Based on work by our group and by others, there is strong support for the role of gonadotropins in upregulating vascular endothelial growth factor (VEGF) levels. High levels of VEGF are strongly associated with the retinal neovascularization that is characteristic of advanced DR. High intraocular VEGF levels have been mainly attributed to retinal ischemia; however, ZRI may have identified another mechanism for retinal VEGF upregulation (independent of hypoxia) via activation of a gonadotropin signaling pathway, that occurs upstream of VEGF production. Thus, targeting gonadotropin receptors may represent a new therapeutic approach for initiating treatment at early stage DR. In this Phase I SBIR proposal, we will assess the feasibility of targeting gonadotropin receptors to provide a DR therapeutic that could be implemented at early DR stage to prevent progression. In particular, we will determine the correlation between intraocular gonadotropin and VEGF levels in vitreous samples (extracted during vitrectomy surgery from diabetic and non-diabetic patients). We will also evaluate whether gonadotropins induces VEGF expression in a human retinal cell line, and furthermore, whether gonadotropin antagonists will inhibit this effect. Upon completion of this Phase I project, we will have demonstrated the feasibility of targeting a hormonal signaling pathway as a new therapeutic approach to addressing DR. In Phase II, ZRI will develop a (non-antibody-based) therapeutic of moderate molecular weight which will allow intraocular penetration. Thus, ZRI's therapeutic would be amenable to convenient and safe modes of administration (e.g., topical eye drop delivery). ZRI's approach has the potential to address the high unmet need for DR therapeutics that act earlier in the disease process before DR has reached its more advanced, vision-threatening form.
Public Health Relevance Statement: Public Health Relevance: Diabetic retinopathy (DR), the most common complication of diabetes, is the leading cause of new blindness in working-aged persons in the United States. Worldwide, nearly 25 million diabetics suffer from severe visual impairment or blindness from DR. Unfortunately, existing therapies are focus on the treatment of advanced forms of DR. While these therapeutic approaches, which include laser photocoagulation, surgical vitrectomy and anti-angiogenic (anti-VEGF) agents, treat some of the sight threatening complications, their effectiveness is limited as the disease has already progressed. There is a critical need to develop therapeutic approaches that act earlier in progression of DR before the onset of visual deterioration. Zietchick Research Institute is investigating a potentially transformative therapeutic approach which is centered on the role of hormones in upregulating vascular endothelial growth factor (VEGF) levels during early stages of DR. In this proposal, we will assess the feasibility of targeting retinal hormonal receptors which would lead to the development of novel DR therapeutics that can be implemented during early stage DR to slow or prevent vision impairment.
Project Terms: Address; Affect; aged; Anterior; Antibodies; base; Blindness; Cell Line; Characteristics; Complications of Diabetes Mellitus; Deterioration; Development; Diabetes Mellitus; diabetic; diabetic patient; Diabetic Retinopathy; Disease; Effectiveness; Eye; Eyedrops; glycosylated HCG; Gonadotropin Receptors; Gonadotropins; Hormonal; Hormone Antagonists; Hormones; Human; Human Chorionic Gonadotropin; Hypoxia; Impairment; Incidence; Individual; intravitreal injection; laser photocoagulation; Lead; LH Receptors; Liquid substance; Luteinizing Hormone; molecular size; Molecular Weight; non-diabetic; novel; novel strategies; novel therapeutic intervention; novel therapeutics; Onset of illness; Operative Surgical Procedures; Pathologic; Patients; Penetration; Persons; Phase; Physicians; Posterior eyeball segment structure; Prevalence; prevent; Procedures; Process; Production; public health relevance; receptor; research clinical testing; Research Institute; Retina; retina blood vessel structure; Retinal; Retinal Detachment; Retinal Diseases; retinal ischemia; Retinal Neovascularization; Risk; Role; Sampling; Signal Pathway; Small Business Innovation Research Grant; Staging; targeted treatment; Therapeutic; United States; Up-Regulation (Physiology); Vascular Endothelial Growth Factors; Vision; Visual; Visual impairment; Vitrectomy; Vitreous Hemorrhage; Work
