Split otoferlins reunited

Abstract

Gene therapy for genetic hearing loss is a nascent field with just a handful of studies published to date that demonstrate proof‐of‐concept recovery of auditory function (reviewed in Ahmed et al, 2017; Lustig & Akil, 2018). One challenge that faces the inner ear field, as well as the broader gene therapy field, is the need to deliver large gene sequences despite the limited genetic capacity (~4.5 kB) of delivery vehicles such as adeno‐associated viral vectors (AAV). In this issue, Al‐Moyed et al have overcome this conundrum by using two AAV vectors to deliver the coding sequence for otoferlin, which is ~6 kB. With dual‐AAV delivery of split otoferlin and a trans‐splicing approach, they demonstrate recombination of full‐length otoferlin in sensory hair cells of the inner ear, enabling partial restoration of auditory function in deaf, otoferlin‐null mice.

Single and Dual Vector Gene Therapy with AAV9-PHP.B Rescues Hearing in Tmc1 Mutant Mice

“…Delivery of large gene sequences to the inner ear is limited by the capacity of AAV vectors (≤5 kb). 24 , 25 , 26 In addition, many gene-therapy studies require two vectors to deliver multiple genetic elements. 22 , 24 , 27 Whereas dual delivery of large sequences to IHCs has yielded partial success, 22 , 28 the efficiency of dual delivery to OHCs has been limited.…”

“… 24 , 25 , 26 In addition, many gene-therapy studies require two vectors to deliver multiple genetic elements. 22 , 24 , 27 Whereas dual delivery of large sequences to IHCs has yielded partial success, 22 , 28 the efficiency of dual delivery to OHCs has been limited. 29 The increased efficacy of gene delivery with AAV9-PHP.B presents an opportunity to improve gene expression of two vectors delivered simultaneously, while being limited by total volume and titer.…”

Therapeutic strategies for aberrant splicing in cancer and genetic disorders

“…106 The combination of AAV recombinant vectors and gene editing techniques has emerged as a highly promising strategy for a wide range of congenital genetic diseases. [107][108][109][110] AONs cannot be efficiently transported through AAV vectors and necessitate repeated administrations. To tackle this challenge, antisense circRNA (AS-circRNA) emerges as a promising solution.…”

“…AAV‐based gene therapy has shattered the “incurable” label associated with several congenital diseases, including Leber congenital amaurosis, where the dual AAV‐ABE system successfully restored the function of the RPE65 protein in cases with nonsense mutations 106 . The combination of AAV recombinant vectors and gene editing techniques has emerged as a highly promising strategy for a wide range of congenital genetic diseases 107–110 …”