A first-in-class therapeutic for the treatment of visual loss in Retinitis Pigmentosa Type 11 patients

Abstract

Purpose : No therapeutic options exist for patients with Retinitis Pigmentosa type 11 (RP11), a blinding inherited retinal disease caused by haploinsufficiency of PRPF31 (pre-mRNA processing factor 31). Due to incomplete penetrance, RP11 has a subtle disease-correction threshold. A first-in-class precision therapeutic has been developed to address this unmet need.

Methods : An exon skipping oligonucleotide conjugated to a cell-penetrating peptide (VP-001) was developed, designed to alter splicing of CNOT3, a negative regulator of PRPF31. Preclinical efficacy data was generated in RP11 patient iPSC-derived retinal pigment epithelium (RPE) and retinal organoids (RO) following a single dose of VP-001. Levels of CNOT3 exon skipping, CNOT3 protein, PRPF31 mRNA and protein were determined. The impact of VP-001 on iPSC-RPE morphology was assessed via a machine learning driven cell segmentation analysis. Preclinical safety, tolerability and durability studies were performed in rabbits and non-human primates. A Natural History Study in RP11 patients is in progress.

Results : VP-001-mediated CNOT3 exon skipping downregulated CNOT3 protein by 50%, increased PRPF31 mRNA expression by up to 1.7-fold and restored cellular morphology in iPSC-RPE derived from three RP11 patients. Treatment elicited a ~1.2-fold increase in PRPF31 protein in iPSC-ROs derived from two RP11 patients. In non-human primate neural retina and RPE-choroid VP-001 was observed up to 120 days with a retina and RPE-choroid half-life of about 20 days. The no observed adverse effect level was established in rabbits (10 µg) and non-human primate (50 µg). The Natural History Study is following patients with RP11 at 4-month intervals to determine outcome measures that are associated with disease progression.

Conclusions : The therapeutic action and mutation agnostic nature of VP-001 has been validated at both the gene modulation and cellular level in RP11 patient-derived target cells. VP-001 is found to be safe, tolerable, and durable in preclinical animal studies. Integration of preclinical pharmacodynamic and pharmacokinetic data indicates VP-001 may elicit therapeutic benefit in RP11 patients. This first-in-class and potentially disease-modifying drug addresses an unmet patient need in a rare disease.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.