Opus Genetics Inc., a private ocular gene therapy company based in Raleigh, North Carolina, has announced new data on preparing AAV-based gene therapy programs to address two forms of rare inherited retinal diseases (IRDs): Leber congenital amaurosis (LCA), due to mutations in the retinal dehydrogenase (RDH12) gene, and retinitis pigmentosa (RP), due to mutations in the proto-oncogene tyrosine-protein kinase MER (MERTK) gene. According to the company, the potential treatment of RDH12-associated Leber congenital amaurosis encourages functional restoration of photoreceptors while strong promoter or codon optimization expects enhancement of MERTK gene expression for MERTK-associated retinitis pigmentosa.
In their announcement, IND-enabling trials of Opus’ RDH12 gene therapy are to determine the structural-functional relationships in early-onset and severe inherited retinal degeneration (RDH12-EOSRD). Nineteen patients (aged 6-21 years), with homozygous or compound heterozygous mutations in RDH12, had a comprehensive ophthalmic evaluation with retinal imaging. Despite severe retinal degeneration and vision impairment in the cohort, the company reported that patients displayed retinal regions with clearly detectable photoreceptors and signals distal to the photoreceptor inner segment, which suggest the potential for functional restoration of these areas. “The structural-functional relationships in relatively preserved regions suggest vision loss does not result directly from the RDH12 insufficiency, but from resulting outer segment abnormalities and ultimately photoreceptor and retinal pigment epithelium degeneration and loss”, according to the company announcement. The data from Opus supports the therapeutic potential of gene augmentation to address RDH12-EOSRD. In addition, Opus’ MERTK development program indicated that four MERTK plasmid constructs were evaluated for their efficiency to induce MERTK expression. The company data demonstrated the MERTK plasmid design “can be optimized to upregulate MERTK protein expression and augment MERTK-dependent phagocytosis”. As a result, the data provides guidance for future preclinical studies and encourage further evaluation of the efficacy of the experimental MERTK gene therapy.
Commenting on the announcement, Ash Jayagopal, Ph.D., Chief Scientific Officer of Opus stated that, “patients with inherited retinal diseases due to mutations of the RDH12 or MERTK genes experience progressive vision loss and eventual blindness, and are currently without treatment options. Patients with RDH12 gene mutations have severe deterioration of the central retina; however, identification of structural-functional relationships in areas of preserved photoreceptors suggest a therapeutic window when functional restoration is possible. In addition, the ability to upregulate MERTK expression in patients with MERTK-associated retinitis pigmentosa suggests the possibility of delivering a functional MERTK gene to retinal cells to produce the normal protein. There is significant need for novel treatment options and these data further support the potential for targeted gene therapy to transform the lives of people living with inherited retinal diseases.”