Laying the foundations for an inherited deafness gene-therapy
Positive results have been reported for the first in-human trial that investigates a gene therapy to treat DFNB9.
Massachusetts Eye and Ear Hospital (MA, USA) and the Eye and ENT Hospital of Fudan University (Shanghai, China) have recently undertaken the first in-human clinical trial for a gene therapy that combats DFNB9. The early-stage trial results, to be presented at the 47th Annual Midwinter Meeting of the Association for Research in Otolaryngology (3–7 February; Anaheim, USA), make the likelihood of a gene therapy to counter genetic deafness imminent.
DFNB9, otherwise known as autosomal recessive deafness 9 is an inherited disease that is characterized by severe or complete hearing loss either from birth or before language development. The autosomal recessive disease is caused by biallelic pathogenic variants of the OTOF gene, meaning that all possible resultant otoferlin proteins are dysfunctional. These proteins are essential for the relaying of auditory signals to the brain.
Now, the first in-human clinical trial that evaluates a gene therapy for DFNB9 has been carried out. The therapy works by delivering a functional OTOF transgene via a dual adeno-associated viral (AAV) vector approach. The OTOF gene is so large that it exceeds the storage capacity of a single virus, so must be delivered in two distinct sections that recombine within the cell to form the full gene.
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The gene therapy (AAV1-hOTOF) was tested in a single-arm, single-center trial of six children between the ages of 1–18 years at the Eye and ENT Hospital of Fudan University. The children all had severe-to-complete hearing loss, biallelic pathogenic variants and were without hearing aids. After the single dose was administered, via their cochlea round window, patients were followed-up for 26 weeks.
Five out of six patients demonstrated hearing recovery of between 40–57 dBs as investigated with average auditory brainstem responses. They also showed improved speech perception and conversational ability.
48 adverse effects were reported, however, 96% of these were low-grade and the remaining 4% were impermanent. In addition to the lack of long-term non-transitory effects, the authors also report no incidence of dose-limiting toxicity.
Alongside remedying the inherited condition, the results also demonstrate the success of using a dual-AAV delivery system, highlighting the utility of this approach in the potential treatment of other conditions that may require the delivery of large genes that exceed the storage capacity of the vector.
“We are the first to initiate the clinical trial of OTOF gene therapy. It is thrilling that our team translated the work from basic research in animal models of DFNB9 to hearing restoration in children with DFNB9,” explained lead author Yilai Shu, “I am truly excited about our future work on other forms of genetic hearing loss to bring treatments to more patients.”
The early-stage clinical trial gives hope for the employment of gene therapies in treating DFNB9 and other inherited deafness conditions, which form the basis of 60% of hearing loss in children.