Integrated in silico, in vitro, and in vivo studies towards the design of molecules with therapeutic potential for Retinitis Pigmentosa

Retinal degenerations are the major cause of incurable blindness caused by loss of the cells responding to light in the retina. The molecular mechanism causing cell death of photoreceptors in the retina is still not well known despite the identification of many genes mutated in these diseases. A high percentage of patients affected by retinal degeneration bears mutation in the RHO gene. So far, ~140 point mutations have been discovered in the RHO gene and although some of them cause Autosomal Recessive Retinitis Pigmentosa (ARRP), the vast majority cause the Autosomal Dominant form of the pathology (i.e. ADRP). A majority of ADRP RHO mutations cause misfolding and mislocalization of the protein. Yet, the molecular mechanisms by which single amino acid changes lead to disease phenotypes are largely unknown, which hampers the development of therapeutic interventions. Understanding the changes in the RHO structure caused by the mutations and the basic processes activated by these mutations and leading to cell death are fundamental questions for the development of therapeutic approaches able to prevent photoreceptor demise and loss of vision. Our studies are aimed at in silico screening of compound libraries, at a computational analysis of wild type and mutant RHO, and at the identification of the molecules triggering cell death in mutant photoreceptors. Based on this knowledge we will develop small therapeutic molecules able to prevent RHO misfolding to be tested in murine models of the disease. We will also test genetic tools to interfere with cell death pathways activated in the retina affected by RP, taking advantage of in vitro and in vivo models of rod degeneration.