Binocular benefit following monocular subretinal AAV injection in a mouse model of autosomal dominant retinitis pigmentosa (adRP)

Autcsomal dominant pigmentosa (adRP) is fr=,;iota iota epsilon ntly caust d by mutations in t:HU, the gene toi rhodopsin. In previous expetiments in dugs with the 14R mutation in RHO, an AAV2/5 vector expressing an s1iRNA directed to human and dog RHO mRNA and an shRNA-resistant human RHO cDNA (AAV-RHO820shRNA820) prevented retinal degeneration for mote than eight months fohowing injection. It is crucial, however, to detemine if this RNA replacernent vector acts in a mutation-independent and species-independent mannet. We, theretore, injected mice transgenic for human P23H RHO with this vector unilaterally at postnatal day 30. We monitored their retinal stnicture by using spectral-domain optica! coherence tomography (SD-OCT) and retinal function using electroretinogiuphy (ERG) for nine months. We compared these to P23H RHO transgenic rnice injected unilaterally with a control vector. Though retinas continued to thin over time, compared to conuol injected eyes, treatment with AAV-RII0820-shRNA820 slowed the loss of photoreceptor cells and the decrease in ERG amplitudes duting the nine-month snidy pefiod. Unexpectedly, we also observed the preservation of retinal snom-tire and function in the untreated contralateral eyes of AAV-RHO820-shRNA820 treated mice. PCR analysis and westem blots showed that a low amount of vector front injected eyes was presen in uninjected eyes. In addition, protective neurottophic factom bFGF and GDNF were elevated in both eyes of treated ritke. Otu finding suggests that using this or similar RNA replacement vectors in human gene therapy may provide clinical benefit to both eyes of patients with adRP.

Automated summary

This study found that AAV-RHO820-shRNA820 can slow the loss of photoreceptor cells and preserve retinal function in P23H RHO transgenic mice. Moreover, the untreated contralateral eyes also showed the same protective effect. This suggests that RNA replacement therapy may provide clinical benefit to both eyes of adRP patients.