Understanding the pathogenesis of and identifying treatments for albinism

National Eye Institute

Investigators

Linked publications & trials

Abstract

1. High-throughput drug screening to identify compounds that regulate Tyr activity We used purified, truncated Tyr protein (previously tested and validated to have equivalent enzymatic activity to full length protein) in a high-throughput drug screening. In collaboration with NCATS, we screened 34,000 compounds from the Genesis Drug Collection, the Natural Products Library, and the NCATS Pharmaceutical Collection. We identified >100 new inhibitors and a few activators of tyrosinase. We performed in depth enzymology in vitro with WT and OCA1b purified proteins. Molecular modeling/docking experiments suggest potential mechanisms of action. We have extended these studies in collaboration with Dr. Jonathan Zippin at Cornell, who has used HPLC to measure flux in melanin synthesis as a result of drug treatment in WT and OCA1B melanocytes. We have validated findings in an 3D cell culture model of human epidermis. Findings have been written into a manuscript. 3. In vitro disease-in-a-dish modeling of OCA We previously developed a disease-in-a-dish model of oculocutaneous albinism type 1A (OCA1A) and type 2 (OCA2) using induced pluripotent stem cell (iPSC) technology and patient-derived fibroblasts. We have replicated these analyses using gene targeted CRISPR-based lines. We have explored potential drug treatments for OCA2 using our iRPE model. 4. Suprachoroidal gene replacement therapy We are currently conducting pilot studies of suprachoroidal delivery of an AAV-tyrosinase gene therapy construct in a rat model of oculocutaneous albinism, type 1.