Heterozygous mutations in the gene encoding the RNA splicing factor pre-mRNA processing factor 31 (PRPF31) have been identified as a major cause of autosomal dominant retinitis pigmentosa (RP), a debilitating and currently incurable blinding disease. The severity and progression of RP vary significantly among patients, with some carriers remaining asymptomatic. Intriguingly, asymptomatic mutation carriers exhibit higher expression levels of the PRPF31 wild-type (WT) allele, suggesting that maintaining adequate PRPF31 expression is crucial for preserving normal retinal function.
We developed a novel retinal cell line and conducted a comprehensive high-throughput screen (HTS) of FDA-approved drugs to identify potential candidates capable of enhancing the expression of PRPF31 in retinal cells. Through this screening process, we successfully identified a promising molecule that demonstrated the ability to augment PRPF31 WT allele expression levels.
Based on these findings, we propose the utilization of this identified molecule as a potential therapeutic approach for arresting and ultimately curing autosomal dominant PRPF31-RP. To advance this treatment strategy, we intend to develop a new formulation for the identified molecule, ensuring its optimal ocular delivery and efficacy in retinal cells.
The successful implementation of this novel therapeutic approach holds significant promise for individuals affected by autosomal dominant PRPF31-RP, potentially providing a means to halt disease progression and restore visual function. Further investigations and formulation optimization are warranted to advance this exciting prospect towards clinical application.

UNMET NEED
Currently, there is a lack of effective treatment options for PRPF31-RP. The approved genetic treatment for RP focuses on the RPE65 gene and is not applicable to PRPF31 patients. Furthermore, gene therapy surgery, which is the standard approach, is invasive and associated with significant side effects. There is a need for alternative treatments that are less invasive and capable of enhancing PRPF31 expression to reduce retinal degeneration.

OUR SOLUTION
A novel method for treating PRPF31-RP by repurposing an FDA-approved drug that was identified by HTS. This drug elevated the expression of PRPF31 WT allele in PRPF31-RP patient derived retinal cell models, improved cell polarization and metabolic functions. The drug exhibits known properties such as a favorable safety profile, established side effects, and appropriate dosage, making it an ideal candidate for enhancing PRPF31 expression and rescue vision. By repurposing this drug, the invention substantially reduces the timeline between drug identification and clinical testing in PRPF31 RP patients.

APPLICATIONS
We propose the repurposing of the identified drug for vision rescue in patients with PRPF31-RP. The drug has a high potential to be a valuable treatment for the targeted retinal disease. This newfound application opens a new avenue of research, providing opportunities for further development, optimization, and potential therapeutic interventions.

STATUS
In vitro assays using patient derived retinal models showed higher RNA and protein expression levels of WT PRPF31 allele, rescue of cell polarity, ciliopathy phenotype and mitochondrial function following treatment with the drug.
In vivo studies are planned next. In addition, new formulation will be developed for the drug to be administered used as eye drops or injection into the eye, preferably in a slow-release manner. The formulation will aim to achieve a controlled and sustained release, optimizing therapeutic effects and minimizing the need for frequent administration. This slow-release mechanism is intended to enhance patient compliance, reduce potential side effects, and provide a more consistent therapeutic outcome. The development process will include rigorous testing and validation to ensure the efficacy, safety, and stability of the new formulation for ocular use.

INTELLECTUAL PROPERTY
The invention is being submitted for a patent.

REFERENCES
Ifat Sher-Rosenthal, Shada Dallasheh, Tal Shadi, Ludmila Buzhansky, Sharon Gilad, Inna Shomer, Nofar Mor, Dan Dominissini, Ehud Gazit, Ygal Rotenstreich; Disease modeling and treatment development for PRPF31-retinitis pigmentosa using iPSC-derived retinal pigment epithelium cell models. Invest. Ophthalmol. Vis. Sci. 2024;65(7):3822.