Dual AAV-based PCDH15 gene therapy achieves sustained rescue of visual function in a mouse model of Usher syndrome 1F

Sehar Riaz; Saumil Sethna; Todd Duncan; Muhammad A Naeem; T Michael Redmond; Sheikh Riazuddin; Saima Riazuddin; Livia S Carvalho; Zubair M Ahmed

doi:10.1016/j.ymthe.2023.10.017

Dual AAV-based PCDH15 gene therapy achieves sustained rescue of visual function in a mouse model of Usher syndrome 1F

Mol Ther. 2023 Dec 6;31(12):3490-3501. doi: 10.1016/j.ymthe.2023.10.017. Epub 2023 Oct 20.

Authors

Sehar Riaz¹, Saumil Sethna², Todd Duncan³, Muhammad A Naeem⁴, T Michael Redmond³, Sheikh Riazuddin⁵, Saima Riazuddin⁶, Livia S Carvalho⁷, Zubair M Ahmed⁸

Affiliations

¹ Department of Otorhinolaryngology - Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54500, Pakistan.
² Department of Otorhinolaryngology - Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
³ Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁴ National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54500, Pakistan.
⁵ Jinnah Burn and Reconstructive Surgery Centre, Allama Iqbal Medical Research, University of Health Sciences, Lahore 54500, Pakistan.
⁶ Department of Otorhinolaryngology - Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Molecular Biology and Biochemistry, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
⁷ Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA 6009, Australia; Retinal Genomics and Therapy Group, Lions Eye Institute Ltd, Nedlands, WA 6009, Australia.
⁸ Department of Otorhinolaryngology - Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Molecular Biology and Biochemistry, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Ophthalmology and Visual Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: zmahmed@som.umaryland.edu.

PMID: 37864333
PMCID: PMC10727994 (available on 2024-12-06)
DOI: 10.1016/j.ymthe.2023.10.017

Abstract

Mutations in the PCDH15 gene, encoding protocadherin-15, are among the leading causes of Usher syndrome type 1 (USH1F), and account for up to 12% USH1 cases worldwide. A founder truncating variant of PCDH15 has a ∼2% carrier frequency in Ashkenazi Jews accounting for nearly 60% of their USH1 cases. Although cochlear implants can restore hearing perception in USH1 patients, presently there are no effective treatments for the vision loss due to retinitis pigmentosa. We established a founder allele-specific Pcdh15 knockin mouse model as a platform to ascertain therapeutic strategies. Using a dual-vector approach to circumvent the size limitation of adeno-associated virus, we observed robust expression of exogenous PCDH15 in the retinae of Pcdh15^KI mice, sustained recovery of electroretinogram amplitudes and key retinoid oxime, substantially improved light-dependent translocation of phototransduction proteins, and enhanced levels of retinal pigment epithelium-derived enzymes. Thus, our data raise hope and pave the way for future gene therapy trials in USH1F subjects.

Keywords: PCDH15; USH1F; arrestin; dual-AAV; photoreceptors; protocadherin-15; retinitis pigmentosa; retinoid oxime; transducin.

MeSH terms

Animals
Cadherins / genetics
Cadherins / metabolism
Humans
Mice
Mutation
Retina / metabolism
Retinitis Pigmentosa* / genetics
Retinitis Pigmentosa* / metabolism
Retinitis Pigmentosa* / therapy
Usher Syndromes* / genetics
Usher Syndromes* / therapy

Dual AAV-based PCDH15 gene therapy achieves sustained rescue of visual function in a mouse model of Usher syndrome 1F

Authors

Affiliations

Abstract

MeSH terms

Substances

Supplementary concepts

Grants and funding