Dual AAV retinal gene therapy approach for Usher 1F treatment

Project Aim

Usher Syndrome is a rare genetic disorder that results in a combination of deafness and blindness due to Retinitis Pigmentosa (RP). Retinal gene therapy, a potential future treatment to prevent blindness in people with Usher Syndrome, has come along way in the last decades with the exponential development and improvement in gene delivery technologies.

However, the genes responsible for certain types of Usher Syndromes, like type 1F and 1B, are too large for traditional gene therapy approaches that use an adeno-associated virus (AAV) vector.

This project will explore the split gene treatment approach, called dual AAV approach, to test its therapeutic potential for Usher type 1F caused by mutations in the PCDH15 gene. This will be performed by deriving induced pluripotent stem cells (iPSCs) from skin fibroblasts from an Usher 1F patient and generating patient-specific retinal organoids (“retina in a dish”) for evaluation of the AAV treatment approach.

Project Results and Impact

This Retina Australia grant has allowed us to develop an effective in vitro model for Usher 1F and demonstrate proof-of-principle expression restoration of PCDH15 using dual AAV vectors.

Low-level dosage of hybrid AAV2/9 vectors was the most effective strategy tested to induce PCDH15 expression.

Overall, our results are a starting point for follow-up studies, which can aim to investigate the viability of an optimised dual AAV approach for the therapeutic delivery of PCDH15 to Usher 1F patients.

Download the Researcher's Final Report