Good news! "may yield other treatments for more of the 30 million kids with genetic hearing loss"
"A novel gene therapy approach has given five children who were born deaf the ability to hear. The method, which overcomes a roadblock presented by large genes, may be useful in other treatments, according to researchers. ...
treated six children aged 1 to 7 who were suffering from an inherited mutation of the OTOF gene, which manufactures a protein important in transmitting signals from the ear to the brain.
Five of the six children showed improvement in hearing over the 26-week trial, with four outcomes described by researchers as “robust.” ...
The three older children, with cochlear implants turned off, could understand and respond to speech by 26 weeks, with two able to recognize speech in a noisy room and have a telephone conversation. ...
Before the trial began, researchers had to tackle a significant technical problem related to the size of the OTOF gene. The procedure called for the gene to be inserted into the cochlea using a type of virus researchers commonly use for this purpose.
The virus inserts the gene into the DNA of target cells, which then begin to manufacture the missing protein. The problem in this case is that the OTOF gene is too big for the virus to hold. Researchers got past this by dividing the gene into two, encapsulating the halves into separate viruses, and then injecting a mixture with both halves of the gene into the cochlea. ..."
"... the researchers found the novel gene therapy to be an effective treatment for patients with a specific form of autosomal recessive deafness caused by mutations of the OTOF (otoferlin) gene, called DFNB9. With its first patient treated in December 2022, this research represents the first human clinical trial to administer gene therapy for treating this condition ..."
From the abstract:
"Background
Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9.
Methods
This single-arm, single-centre trial enrolled children (aged 1–18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF, and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063181, and is ongoing.
Findings
Between Oct 19, 2022, and June 9, 2023, we screened 425 participants for eligibility and enrolled six children for AAV1-hOTOF gene therapy (one received a dose of 9 × 1011 vector genomes [vg] and five received 1·5 × 1012 vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1–2 and two (4%) were grade 3 (decreased neutrophil count in one participant). Five children had hearing recovery, shown by a 40–57 dB reduction in the average auditory brainstem response (ABR) thresholds at 0·5–4·0 kHz. In the participant who received the 9 × 1011 vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 1·5 × 1012 AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in four children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery.
Interpretation
AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9. ..."
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