Opus Genetics (Nasdaq: IRD) have announced that the U.S. Food and Drug Administration (FDA) has accepted its Investigational New Drug (IND) application for OPGx-BEST1, a gene therapy for the treatment of bestrophin-1 (BEST1)-related IRD. The experimental treatment is being developed for bestrophin-1 (BEST1)-related inherited retinal diseases, a form of macular degeneration found primarily in adults, estimated to affect approximately 9,000 people in the U.S. Bestrophinopathy is characterized by retinal lesions, with symptoms including dimness of vision, metamorphopsia or scotoma. The gene therapy treatment will use an adeno-associated virus (AAV) vector to deliver a functional copy of the BEST1 gene to the retina to allow bestrophin-1 protein to be produced in retinal pigment epithelial (RPE) cells. The approach aims to restore normal function of the RPE cells such that they may provide proper support to photoreceptors.
Opus Genetics is a public company, supported by the Retinal Degeneration Fund (RD Fund), the venture arm of the Foundation Fighting Blindness, aimed at rapidly driving research toward preventions, treatments and cures for the entire spectrum of retinal degenerative diseases. The Company’s pipeline features AAV-based gene therapies targeting inherited retinal diseases including Leber congenital amaurosis (LCA), bestrophinopathy, and retinitis pigmentosa. The company is also advancing Phentolamine Ophthalmic Solution 0.75%, a partnered therapy currently approved in one indication and being studied in two Phase 3 programs for presbyopia and reduced low light vision and nighttime visual disturbances. The Company is based in Research Triangle Park, North Carolina.
Best disease, also known as vitelliform macular dystrophy, is caused by mutations in the BEST1 (VMD2) gene, inherited in an autosomal dominant fashion although there is variable penetrance in the pathology. The prevalence of the disease is estimated at between 1 and 9/100,000 and the gene product (bestrophin-1)is a transmembrane protein expressed on the basolateral aspect of the RPE cells. The protein functions to facilitate chloride conductance across the RPE and mutations of the gene can affect fluid transport across the RPE leading to an accumulation of debris between the photoreceptors and RPE.
Figure 1. BEST1 disease is an inherited retinal disease that causes macular degeneration. The BEST1 gene encodes for bestrophin-1, a protein that functions as a retinal pigment epithelial (RPE) cell membrane channel. The BEST1 channel, when activated by calcium (Ca2+) ions, controls chloride (Cl-) ion transfer into and out of the RPE cell. This function is crucial to maintaining homeostasis between rod and cone photoreceptors and RPE cells. Mutations in BEST1 disrupt this homeostasis and result in the breakdown of the rod and cone interphotoreceptor matrix (cIPM) and microvilli (cMV) connection with the RPE. Retinal lesions form containing vitelliform material (“egg-yolk” like) between the RPE and Bruch’s membrane (BM)/choroid (CH). These vitelliform lesions disrupt and cause atrophy of the RPE. Without support from the RPE, photoreceptor cells critical for normal vision die, resulting in progressive vision loss. (Available at https://opusgtx.com/pipeline-programs/ird-programs/)
According to the company, George Magrath, M.D., Chief Executive Officer stated that, “the FDA’s clearance of our BEST1 IND is a significant step forward for the IRD community and for our mission at Opus Genetics focused on restoring vision for patients. BEST-related IRDs have no approved treatments today, leaving patients and families with uncertainty about the future of their vision. The OPGx-BEST1 trial will be our third ongoing clinical program, reflecting the depth of our pipeline and our commitment to advancing multiple therapies in parallel for patients with urgent, unmet needs.”