Abstract
Purpose :
Deep intronic mutations can be amenable to antisense oligonucleotide therapy to improve normal splicing. We describe the pathogenic deep intronic mutation in the FLVCR1 gene in a patient with posterior column ataxia with retinitis pigmentosa (PCARP), the development of an intravitreal custom antisense treatment, and the improved splicing ratio in patient-derived cells treated with this ASO.
Methods :
Multiple ASO candidates were evaluated in patient-derived cells to determine a candidate that caused improved amount of normal protein. Next, toxicology studies on mice were performed with intrathecal injections.
Results :
A final ASO candidate was chosen after further toxicology studies in collaboration with the n-Lorem Foundation. Finally, investigational new drug application approval by the FDA was obtained for the final ASO candidate.
Conclusions :
With improved access to whole genome sequencing, disease causing intronic mutations will more frequently be identified. Since deep intronic mutations are potentially modifiable with ASO therapy, a pathway to identify patients and a pipeline to therapy is important to scale these treatments.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.