Project 2

Preclinical Study

Heads of Project: David Antonetti, Ph.D. and Steve Abcouwer, Ph.D.

Specific Aims:

The overarching goal for center project is to identify effective medical interventions to treat diabetic retinopathy (DR) and preserve vision. The Project 2, the Preclinical Interventions Study (PCIS) portion of the center represents a translational component providing initial evaluation of potential therapeutic treatments and delivery regimens. The goal of Project 2 is to develop a process for efficient preclinical evaluation of drugs in order to identify candidates for proof of concept clinical testing.

 

Accomplishments:

In its second year, Project 2 has made substantial progress in 3 areas. First, we have developed and are utilizing the infrastructure and expertise to systematically model the pathologies experienced in DR using both a short-term high throughput animal model of retinal ischemia-reperfusion (IR) and a long-term animal model of type-1 diabetes. Second, with the Biomarker Core, we have developed and validated sets of mRNA biomarkers that reflect the retinal responses to IR and diabetes. Third, we have overcome substantial challenges presented by the DR model and devised a rational and efficient means of screening potential drugs for their abilities to affect pathological alterations that occur in DR.

 

Who benefits from this research?:

Diabetic retinopathy remains a leading cause of blindness in the United States without approved medical therapeutic options. Developing new medical therapies that prevent the vascular dysfunction and neurodegeneration would provide important new treatment options for patients with diabetic retinopathy. Our overarching goal is to develop new therapies to treat or prevent diabetic retinopathy. The process of preclinical screening of drugs for the potential to prevent the pathologies in diabetic retinopathy is now done on an ad hoc basis. The present research project will establish the infrastructure for comprehensive preclinical analysis of potential therapeutic compounds by developing standardized methods to evaluate and compare drugs in a systematic and timely fashion. The screening system we have devised will provide a rational decision process for identifying promising drug candidates. This comprehensive approach of preclinical analysis will provide an improved ability to directly compare therapeutic compounds and is highly cost-effective compared to efforts of individual laboratories. It also provides the center with the ability to effectively test and compare both drugs and drug delivery regimens in order to evaluate and rank candidates prior to proof of concept clinical testing.

 

Future Plans:

We will employ a rat retinal pathology model, retinal ischemia-reperfusion (a model that shares common pathologies with the diabetic retinopathy model) to prescreen proposed drugs. These experiments will be used to test dosages and delivery modes for the drugs in order to find optimal therapeutic strategies amenable for preclinical evaluation. Once we are satisfied with drug dosages and delivery modes, and have a complete ischemia-reperfusion data set to evaluate and rank drug efficacies, we will progress drugs into the rat diabetes model. Evaluation of drugs in both ischemia-reperfusion and diabetes models will test the ability of the short-term model to predict efficacy in the long-term diabetes model. Drug efficacy data from both ischemia-reperfusion and diabetes models will be used to assess and further develop mRNA and protein biomarkers. The goal of biomarker development is both to understand the molecular changes occurring in these retinal pathologies and to validate biomarkers that can serve as accurate endpoints to assess drug efficacy. If successful, the outcome of this research will be not only the preclinical evaluation of drugs and identification of drugs with potential efficacy for proof of concept testing, but also the development of more efficient and effective means of preclinical testing of treatments for diabetic retinopathy.