Detectable photoreceptors and signaling activity in patients with RDH12-associated Leber congenital amaurosis support potential of functional restoration by targeted gene therapy
Strong promoter or codon optimization enhanced MERTK gene expression and encourage further evaluation of gene therapy for MERTK-associated retinitis pigmentosa
Data presented at Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting 2023
Research Triangle Park, N.C. – April 26, 2023 – Opus Genetics, a patient-first, clinical-stage gene therapy company developing treatments for inherited retinal diseases (IRDs), today announced new data to inform 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 due to mutations in the proto-oncogene tyrosine-protein kinase MER (MERTK) gene.
In preparation for IND-enabling trials of Opus’ RDH12 gene therapy, a study was conducted to determine the structural-functional relationships in early-onset and severe inherited retinal degeneration (RDH12-EOSRD). Nineteen patients ages 6-21 years with homozygous or compound heterozygous mutations in RDH12 had a comprehensive ophthalmic evaluation with retinal imaging. The data demonstrated that despite severe retinal degeneration and vision impairment, 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. The data support the therapeutic potential of gene augmentation to address RDH12-EOSRD.
In a preliminary study completed to support Opus’ internal MERTK development program, four MERTK plasmid constructs were evaluated for their efficiency to induce MERTK expression. The data demonstrated the MERTK plasmid design can be optimized to upregulate MERTK protein expression and augment MERTK-dependent phagocytosis. The data provide guidance for future preclinical studies and encourage further evaluation of the efficacy of a MERTK gene therapy.
“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,” said Ash Jayagopal, Ph.D., Chief Scientific Officer of Opus. “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.”
The data were presented at the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting 2023 in New Orleans.
About Opus Genetics
Opus Genetics is a clinical-stage gene therapy company for inherited retinal diseases with a unique model and purpose. Backed by Foundation Fighting Blindness’ venture arm, the RD Fund, Opus combines unparalleled insight and commitment to patient need with wholly owned programs in numerous orphan retinal diseases. Its AAV-based gene therapy portfolio tackles some of the most neglected forms of inherited blindness while creating novel orphan manufacturing scale and efficiencies. Based in Research Triangle Park, N.C., the company leverages knowledge of the best science and the expertise of pioneers in ocular gene therapy to transparently drive transformative treatments to patients. For more information, visit www.opusgenetics.com.
Opus Media Contact: