Jayagopal, Ashwath , MS, PhD
Targeted nanocarriers for therapy of diabetic retinopathy
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Complications, Complications\Ocular
Type of Grant: Junior Faculty
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
Diabetic retinopathy is a leading cause of blindness in the working age. Blindness is often caused in this disease by abnormal growth of blood vessels in the eye, through a process called angiogenesis. Therapies designed to control or regress this blood vessel growth often involve laser treatments, which are not curative and can damage healthy retina along with pathologic blood vessels. To improve upon current treatment strategies, targeted therapies capable of preventing or regressing abnormal blood vessel growth without off-target effects on healthy tissues are needed. Targeted therapies have the potential to minimize dosage, frequency of intraocular injections, reduced side effects, and more effective resolution of disease in more patients.
This proposal is focused upon the development of molecularly targeted therapeutic strategies for improving clinical outcomes of patients in these disease. This proposal will facilitate the clinical translation of a new set of therapies called siRNAs for treatment of diabetic retinopathy. The applicant has developed a nanotechnology based polymeric carrier for siRNAs which recognize diseased blood vessels and only deliver therapy within them, and do not release therapy in healthy cells. The efficacy of this strategy will be tested in an animal model which exhibits abnormal vessel growth in the eye. If successful, the nanotechnology based strategy will be poised for transition to clinical testing to improve upon targeted treatment of blood vessel growth while sparing healthy retinal tissue.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
My research is focused on the development of targeted therapies for treatment of diabetic retinopathy, a complication of diabetes which can lead to vision loss. For improved clinical management of this disease, it is important that strategies are developed to deliver therapies such as drugs or gene therapies directly to the diseased cells, sparing healthy cells from off-target effects, minimizing dosage, and reducing the frequency of dosing. In this project, a biocompatible polymer-based carrier will be developed which is capable of delivering therapies exclusively within diseased cells in diabetic retinopathy. Specifically, these cells are the endothelial cells which line the blood vessels. In diabetic retinopathy, these endothelial cells are dysfunctional and contribute to vision loss in this disease. By targeting therapies to these cells using our system, we will improve the efficacy of treatments for this major cause of vision loss in the working age.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Diabetic retinopathy is a major complication of diabetes, and is a leading cause of vision loss. We have identified molecular signatures of diseased cells in eyes with diabetic retinopathy which distinguish them from healthy cells. In this project, we will exploit these differences in molecular signatures to target drugs and gene therapies directly within diseased cells. If our work is successful, a clinically-relevant framework will be established for targeting a multitude of drugs and gene therapies directly to the diseased cells in the eye, which will improve efficacy and specificity of treatments, and reduce off-target, adverse effects caused by the activity of drugs on healthy cells. This technology may also reduce or eliminate the need for laser treatment which is the standard of care in this disease. Furthermore, molecular targets within diseased cells which are currently "undruggable" will be accessible by our technology, allowing for the clinical translation of new therapeutic interventions in this disease.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Current treatments for diabetic retinopathy, such as laser therapies, are not curative and can ablate healthy tissue adjacent to the diseased tissue. Therefore, more effective treatments are needed that are selective for diseased cells in the eye. My laboratory’s expertise is in the application of nanotechnology for targeted therapy of vascular diseases. Nanotechnology involves the manipulation of matter on the nanoscale, which is the same scale on which many biological interactions and processes occur. By engineering drugs and gene therapies on the nanoscale, we can enhance homing of therapy toward diseased cells in the diabetic eye. We will apply our knowledge of nanoscale engineering of therapeutics toward developing targeted treatments for diabetic retinopathy, a disease for which targeted therapies have not been applied. This award will be instrumental in conducting this research and will help to establish nanotechnology as a powerful approach for improving the clinical management of diabetic retinopathy.
In what direction do you see the future of diabetes research going?
Every day, researchers identify new molecular biomarkers underlying disease initiation and progression in diabetes and its complications, contributing toward the development of "personalized medicine," or treatment customized toward the molecular signatures of the patient. The next challenge is to exploit expression of these biomarkers in the body to target therapies toward diseased cells for site-specific treatment. In other words, drugs must be "trained" to recognize diseased cells in the body, while avoiding healthy cells. In the near future, I expect to see these types of targeted therapies in preclinical studies, with many candidate therapies progressing to clinical trials within the next decade. These studies will translate into improved treatment of patients with diabetes and its complications.
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