Gene Therapy for Hearing Loss

Recruiting at5 trial locations

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Akouos, Inc.

Disqualifiers: Ear infections, Cochlear implants, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests a new gene therapy delivered to the ear to help people with hearing issues. The therapy aims to improve ear cell function by introducing a healthy gene. Two different doses will be tested to ensure safety and effectiveness. Gene therapy has emerged as a promising strategy for treating hearing loss by addressing genetic dysfunction.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. Please consult with the trial coordinators for more details.

What data supports the effectiveness of the treatment AAVAnc80-hOTOF for hearing loss?

Research shows that similar gene therapy approaches using AAV vectors have been effective in restoring hearing in animal models with hearing loss due to OTOF gene mutations. The AAVAnc80 vector has been shown to efficiently target hair cells in the inner ear, which is crucial for hearing restoration. ^{1 2 3 4 5}

Is the gene therapy for hearing loss using AAV vectors safe in humans?

Research in animals, including mice and nonhuman primates, shows that the gene therapy using AAV vectors is generally safe, with no significant toxic effects observed and no impact on normal hearing. ^{1 2 3 4 6}

What makes the treatment AAVAnc80-hOTOF unique for hearing loss?

AAVAnc80-hOTOF is a gene therapy that uses a viral vector to deliver the otoferlin gene directly into the cochlea, potentially restoring hearing by addressing genetic defects at the source, unlike traditional treatments like cochlear implants that only bypass the damaged parts. ^{2 5 7 8 9}

Research Team

Kathy Reape, MD

Principal Investigator

Akouos, Inc.

Eligibility Criteria

This trial is for children and teens aged 2 to 17 with profound bilateral sensorineural hearing loss due to biallelic mutations in the otoferlin gene. They must be able to follow the study's procedures, including a long-term follow-up. Those with cochlear implants, persistent ear infections, or conditions that make surgery risky can't participate.

Inclusion Criteria

I am between 2 and 17 years old.

I have two mutations in my otoferlin gene.

I have severe hearing loss in both ears, confirmed by a hearing test.

Exclusion Criteria

Bilateral cochlear implants

Prior participation in a clinical trial with an investigational drug, within six months prior to administration, or any prior participation in a gene therapy clinical trial

I do not have ear conditions or other health issues that prevent surgery or gene therapy.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single unilateral administration of AAVAnc80-hOTOF using an investigational medical device

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety, tolerability, and device performance, including auditory brainstem response threshold changes

1 year

Treatment Details

Interventions

• AAVAnc80-hOTOF (Virus Therapy)
• Akouos Delivery Device (Procedure)

Trial Overview The trial tests a gene therapy called AAVAnc80-hOTOF delivered through an Akouos device into one ear. It aims to see if it's safe and works as intended at two different dose levels.

Participant Groups

Group I: Cohort 2 Experimental Treatment 1 Intervention

Cohort 2: Up to six eligible participants will be enrolled to receive intracochlear administration of AAVAnc80-hOTOF (dose level 2) in the study ear using a sterile, one-time use investigational medical device; the first three participants will be at least two years of age at the time of AAVAnc80-hOTOF administration and the next three participants may be of any age

Group II: Cohort 1a and Cohort 1b Experimental Treatment 1 Intervention

Cohort 1a: Two participants aged 7 to 17 years old (inclusive) to receive intracochlear administration of AAVAnc80-hOTOF (dose level 1) in the study ear using a sterile, one-time use investigational medical device Cohort 1b: Up to six eligible participants will be enrolled to receive intracochlear administration of AAVAnc80-hOTOF (dose level 1) in the study ear using a sterile, one-time use investigational medical device; the first three participants will be at least two years of age at the time of AAVAnc80-hOTOF administration and the next three participants may be of any age

Who Is Running the Clinical Trial?

Akouos, Inc.

Lead Sponsor

Trials

4

Recruited

220+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Findings from Research

The AAV1-hOTOF gene therapy significantly improved hearing in mice with OTOF gene mutations, indicating its potential efficacy for treating autosomal recessive hearing loss (DFNB9) without harming normal hearing in healthy mice.

Safety evaluations showed that AAV1-hOTOF did not cause any obvious toxic effects in mice, and a related AAV1-GFP therapy successfully transduced a high percentage of inner hair cells in non-human primates without significant adverse effects, supporting its clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of the efficacy and safety of AAV1-hOTOF in mice and nonhuman primates. Zhang, L., Wang, H., Xun, M., et al.[2023]

A gene therapy approach using Anc80L65 in rhesus macaques demonstrated high efficiency, with up to 90% of inner hair cells transduced, indicating its potential effectiveness for treating hearing disorders.

The surgical method used to deliver the gene therapy was well tolerated in the macaques, suggesting that this approach could be safely translated to human patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Choice of vector and surgical approach enables efficient cochlear gene transfer in nonhuman primate. Andres-Mateos, E., Landegger, LD., Unzu, C., et al.[2022]

A new gene therapy strategy using Anc80L65 and the Myo15 promoter effectively restored hearing in mice with OTOF mutations for at least 150 days, showing no significant difference in hearing compared to normal mice.

The therapy was also tested in cynomolgus monkeys, demonstrating safety and efficacy without affecting normal hearing or causing systemic toxicity, paving the way for potential clinical applications in patients with DFNB9.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Efficacy And Safety Evaluation of AAV-OTOF in DFNB9 Mouse Model And Nonhuman Primate. Qi, J., Zhang, L., Tan, F., et al.[2023]

Anc80L65 is a newly designed synthetic vector that safely and efficiently delivers genes to the cochlea in mice, outperforming traditional adeno-associated virus (AAV) vectors.

The method of injecting Anc80L65 through the round window membrane resulted in effective targeting of inner and outer hair cells, which is crucial for restoring hearing and balance functions, while showing no adverse effects on sensory cell function or overall health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear. Landegger, LD., Pan, B., Askew, C., et al.[2021]

A novel gene therapy using a single overloaded adeno-associated virus (AAV) vector successfully delivered the full-length otoferlin gene to about 30% of inner hair cells in deaf otoferlin knock-out mice, showing promise for treating genetic hearing impairments.

This approach demonstrated partial restoration of hearing in the mice, suggesting that using a single AAV vector simplifies the gene transfer process compared to previous dual-AAV methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overloaded Adeno-Associated Virus as a Novel Gene Therapeutic Tool for Otoferlin-Related Deafness. Rankovic, V., Vogl, C., Dörje, NM., et al.[2021]

Exosome-associated AAV (exo-AAV) is a highly effective gene delivery system that successfully targets all inner ear hair cells, outperforming conventional AAV in both laboratory and live mouse models.

In a mouse model of hereditary deafness, exo-AAV1 gene therapy demonstrated the ability to partially restore hearing without causing any toxicity, indicating its potential for safe and effective treatment of hearing disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rescue of Hearing by Gene Delivery to Inner-Ear Hair Cells Using Exosome-Associated AAV. György, B., Sage, C., Indzhykulian, AA., et al.[2020]

Adeno-associated viruses (AAVs) are promising tools for gene therapy due to their safety, ability to provide long-lasting gene expression, and low risk of immune response, making them suitable for treating genetic hearing loss in animal models.

While AAVs have shown potential in gene therapy for genetic hearing loss, their application for preventing or managing acquired hearing loss is still limited, but there is optimism that AAV-mediated gene manipulation could eventually help in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Advances in Adeno-Associated Virus-Mediated Gene Therapy to Prevent Acquired Hearing Loss. Wu, F., Sambamurti, K., Sha, S.[2023]

AAV2.7m8 is a highly effective viral vector for delivering gene therapy to both inner and outer hair cells in the mouse inner ear, which are crucial for hearing.

This vector also efficiently targets supporting cells in the cochlea, suggesting it could enhance the effectiveness of gene therapy for various forms of hereditary hearing loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV2.7m8 is a powerful viral vector for inner ear gene therapy. Isgrig, K., McDougald, DS., Zhu, J., et al.[2020]

The AAV-ie-K558R mutant vector effectively delivers genes to hair cells and supporting cells in the cochleae of neonatal mice, showing high efficiency and safety without causing hearing deficits.

This gene therapy approach can partially restore hearing loss in Prestin knockout mice and successfully introduces Atoh1 into supporting cells, promoting the generation of hair cell-like cells, highlighting its potential for treating hearing loss due to hair cell death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV-ie-K558R mediated cochlear gene therapy and hair cell regeneration. Tao, Y., Liu, X., Yang, L., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of the efficacy and safety of AAV1-hOTOF in mice and nonhuman primates. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Choice of vector and surgical approach enables efficient cochlear gene transfer in nonhuman primate. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

Preclinical Efficacy And Safety Evaluation of AAV-OTOF in DFNB9 Mouse Model And Nonhuman Primate. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Overloaded Adeno-Associated Virus as a Novel Gene Therapeutic Tool for Otoferlin-Related Deafness. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Rescue of Hearing by Gene Delivery to Inner-Ear Hair Cells Using Exosome-Associated AAV. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Current Advances in Adeno-Associated Virus-Mediated Gene Therapy to Prevent Acquired Hearing Loss. [2023]

8. England pubmed.ncbi.nlm.nih.gov

AAV2.7m8 is a powerful viral vector for inner ear gene therapy. [2020]

9. England pubmed.ncbi.nlm.nih.gov

AAV-ie-K558R mediated cochlear gene therapy and hair cell regeneration. [2022]