NIH Research Festival
Retinoschisis is an X-linked recessive genetic disease that leads to vision loss in young males. Discovered in 1898, the underlying biology of XLRS became apparent in the last 20 years with advances in human genetics leading to identification of the gene (RS1), causative mutations, and development of a model. The condition has characteristic intraretinal schisis cavities, in a “spokewheel” pattern, which compromises structural integrity and interrupts normal visual neurosignaling. Retinoschisin, a secreted protein that forms an octomer, is present throughout the neural retina. The clinical pathology of XLRS is consistent with loss of cell-cell adhesion RS1function, and the Rs1-KO mouse has cavities and depressed ERG b-waves as in the human disease. We developed a gene transfer therapy that delivers the normal human retinoschisin cDNA into the eye using an adeno-associated virus (AAV) vector. This produces RS1 expression in the Rs1-KO mouse and results in significant improvement in retinal structure (reduced cavities) and function (increased ERG amplitude), providing proof-of-concept for RS1 gene replacement therapy. We initiated a Phase I/IIa clinical study in participants with XLRS (NCT02317887) that involves a single intravitreal administration of AAV-RS1 in a standard dose-escalation design. The primary outcome is the safety of ocular AAV-RS1 vector assessed by ophthalmological and laboratory tests.
Scientific Focus Area: Cell Biology
This page was last updated on Friday, March 26, 2021