Optic atrophy 1 dependent signals in retinal ganglion cells: from identification to a therapy for autosomal dominant optic atrophy

Dominant optic atrophy (ADOA) is a genetic disease characterized by progressive loss of sight, starting during early childhood. This is caused by the death of the retinal ganglion cells, transmitting the images from the eye to the brain. This death is painless and occurs at a steady pace over the years, ultimately leading to blindness. If we want to generate new drugs that block this degeneration, we need to understand the processes that lead to the loss of these cells. Mitochondria, the “powerhouse” of the cells, are not only responsible for generating the energy that our cells need to live but are also key players in the intricate networks of cellular signals. Some proteins, called dynamins, control the shape of mitochondria and when they are damaged serious diseases ensue. One of these proteins, called Opa1, is affected in dominant optic atrophy. While our knowledge on the basic function of Opa1 grew considerably, we still lack a treatment to arrest the progressive ADOA visual loss. Our proposal bridges the study of the pathogenesis of ADOA with a proof of principle preclinical study of drugs that can interfere with the loss of vision in ADOA. To identify drugs that can interfere with the loss of sight in ADOA, we will take two approaches: in the first approach we will test inhibitors of a process, called autophagy (the self-digestion of pieces of the cell) that we found hyperactivated in ADOA. In the second, we will embark in a screening of several thousands of drugs to test if they can ameliorate the function of a model of ADOA constructed in our laboratory. We will test if these drugs can curtail visual loss in ADOA mouse model. Our proposal will provide preclinical proof of principle for pharmacological approaches that can curtail visual loss in vivo in an ADOA model. By exploiting multiple pharmacological approaches, we expand our potential to succeed in offering a drug to halt ADOA progression. We therefore envision that shortly the best preclinically validated leads will be ready to enter the exploratory phase as first in-kind treatments for ADOA patients.