The associate professor of otolaryngology from Harvard Medical School also shared other big takeaways from the landmark trial for the gene therapy field.
“For this gene therapy, you have to use dual AAV because otoferlin is too big for normal AAV...[The capacity] has actually become a major issue for AAV, since it cannot be used to treat many other genetic diseases. In this case, the gene is over 6-kb, so we actually have to break it into 2halves and to use 1 AAV to carry 1 half and the other 1 to carry the other half. So, we mix them to inject into the ear and the 2 halves get in the cells, express the gene, the gene recombines, and then becomes a whole otoferlin gene and produces the protein product. So this way, we actually overcome the size limitation of AAV... So, this is really proof that we can solve that problem.”
AAV1-hOTOF gene therapy yielded significant, clinically meaningful improvements in hearing in 5 of 6 children with autosomal recessive deafness 9 (DFNB9) caused by mutations of the OTOF gene. The children were treated at the Eye & ENT Hospital of Fudan University in Shanghai, China, as part of a clinical trial conducted in collaboration with investigators from Mass Eye and Ear.
The participants had hearing recovery, significant reductions in the average auditory brainstem response, and improvements in speech recovery. There were no serious adverse events or dose-limiting toxicities. The investigators theorized that the nonresponse in 1 participant may have been due to their higher concentration of neutralizing antibodies at baseline,or, alternatively, a possible leakage of the AAV1-hOTOF solution from the round window membrane during or after surgery.
CGTLive spoke with study investigator Zheng-Yi Chen, DPhil, associate scientist, Eaton-Peabody Laboratories, Mass Eye and Ear, and associate professor, Otolaryngology–Head and Neck Surgery, Harvard Medical School, to learn more about the main takeaways of the preliminary data from the trial and implications the findings may have on the gene therapy field as a whole.