By Ben Shaberman
Senior Director, Scientific Outreach
Foundation Fighting Blindness
With the launch in 2007 of the first gene augmentation therapy clinical trials for people with Leber congenital amaurosis (LCA) caused by RPE65 mutations, clinical and commercial development of gene therapies and gene-targeted treatments for inherited retinal diseases expanded dramatically. The subsequent U.S. Food & Drug Administration’s approval of voretigene neparvovec for RPE65-associated retinal disease in 2017 provided further affirmation to researchers and biotech companies that genetic treatments had strong clinical and commercial potential. Voretigene neparvovec, which has restored significant vision for recipients with severe vision loss, was the first gene therapy to receive FDA approval for the eye or an inherited disease.
Currently, there are approximately 2 dozen gene-targeted treatments in human studies, many of which were highlighted during “Retinal Frontiers: Updates in Retinal Gene Therapy,” a recorded session of the virtual 2020 annual conference of the American Academy of Ophthalmology.
For example, Paul Yang, MD, PhD, Oregon Health & Science University, reviewed 4 gene therapy clinical development efforts underway for X-linked retinitis pigmentosa (XLRP) caused by mutations in the gene RPGR. XLRP, which initially causes visual field loss and progresses to impact macular vision, accounts for about 10 percent of all RP cases. Applied Genetic Technologies Corporation, Biogen, and MeiraGTx/Janssen have all reported vision improvements in their Phase 1/2 RPGR gene therapy clinical trials and all are moving toward Phase 2/3 or Phase 3 studies. All 3 emerging treatments are administered through subretinal injections of gene copies contained in adeno-associated virus (AAV) capsids. In addition, 4D Molecular Therapeutics recently initiated a Phase 1/2 clinical trial of its intravitreally administered AAV-based RPGR gene therapy.
Isabelle Audo, MD, PhD, Institut de la Vision, presented a promising clinical development summary for antisense oligonucleotides (AONs), which are tiny pieces of genetic material designed to mask or silence mutations in RNA – an approach that can be beneficial when the therapeutic gene is too large for the AAV capsids. ProQR Therapeutics showed significant efficacy in a Phase 1/2 clinical trial for sepofarsen, its AON for LCA 10 caused by the CEP290 c.2991+1655A>G mutation. The company has advanced the LCA 10 AON into a Phase 2/3 trial and also has AON Phase 1/2 clinical trials underway for USH2A (exon 13 mutations), which can cause non-syndromic RP or Usher syndrome type 2A, and RP caused by RHO-P23H mutations.
Dr Audo also presented ongoing clinical trials for choroideremia (CHM) gene therapies, including the global Phase 3 study sponsored by Biogen.
While gene augmentation is targeted for people with remaining photoreceptors, optogenetics is a gene therapy approach that bestows light sensitivity to ganglion cells that often survive in people with advanced RP and other retinal diseases after all photoreceptors are lost. The hope is that the light-sensitive ganglion cells will provide meaningful vision to patients. Dr Audo discussed the early clinical trials for optogenetic treatments being developed by GenSight Biologics and Allergan.
Karmen Trzupek, a genetic counselor with InformedDNA, underscored the need for patients with inherited retinal diseases to get genetically screened to clarify their clinical diagnoses and help them understand which emerging genetic therapies and clinical trials may be relevant to them. She noted that the Foundation Fighting Blindness now provides no-cost genetic testing and counseling, which can be ordered by eye care professionals throughout the United States.
The session also included presentations on genetics, surgical techniques, imaging and functional testing, and other gene therapy clinical trials for inherited retinal diseases.