Neuroprotective agents for retinal diseases

DESCRIPTION (provided by applicant): Retinal degeneration can be triggered by environmental insults as well as genetic mutations. The role for most disease genes is unclear and pathological processes are influenced environment making it difficult to identify one central cause. Indeed, the genetics of age-related macular degeneration (AMD) and other forms of retinal degeneration point to multiple causes, each of which may be involved in a subset of patients. As current therapies for AMD are limited, andsuccessful therapies for retinitis pigmentosa (RP) have yet to be identified, there remains a significant unmet need for novel therapeutic approaches to treating retinal degeneration.. Mitochondrial function and hence ATP production are very sensitive to environmental challenges and aging; tissues from elderly patients show a general decrease in ATP production capacity. We used the 661W photoreceptor cell line to show that stressor such as reactive oxygen species (ROS) cause significant changes in mitochondrial respiratory capacity in the absence of any cell death. We hypothesize that loss in metabolic capacity may be a major factor in retinal disease pathogenesis and that preservation of mitochondrial function may provide novel and promising therapeutic approaches. To identify novel pharmacological agents to treat retinal degeneration we screened a library consisting of over 50,000 compounds from the DIVERSet chemical library. We used a survival assay of 661W cells exposed to the calcium ionophore A23187 (amodel for RP) to identify 12 cytoprotective compounds. We then used the Seahorse Biosciences respirometer to screen the 12 compounds for those that protect mitochondrial function. Two mito-protective agents viewed as potential neuroprotectants (compounds CB11 and CB12) tested positive on intact retinas from rd1 mice to demonstrating that they can improve photoreceptor viability in diseased retinas. Finally, CB11 was tested and it exhibited significant in vivo protection in a mouse model of photoreceptor cell stress (light damage). These results demonstrate that agents that protect from loss of mitochondrial capacity can be used to slow down or prevent photoreceptor degeneration. Our short-term objective is to validate the effectiveness of CB11 in animal models of retinal degenerationvia two aims: (1) we will develop methods to determine the concentration of CB11 delivered to the retina. And (2) we will determine the efficacy of the CB11 in reducing the progression of photoreceptor degeneration in rodent models. PUBLIC HEALTH RELEVANCE: Mitochondrial dysfunction is a major contributor to retinal diseases. At this time, there are no effective therapies that can restore mitochondrial function to promote photoreceptor repair/regeneration. Thus, researchis needed to develop new drugs that promote mitochondrial function in the retina.