Gene Therapy for Hearing Loss

Recruiting at 8 trial locations

Overseen By Akouos Clinical Trials

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Akouos, Inc.

Disqualifiers: Ear infections, Cochlear implants, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 day

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy treatment, AAVAnc80-hOTOF, for individuals with significant hearing loss due to genetic issues. Researchers aim to determine if this therapy can be safely delivered to the ear using the Akouos Delivery Device and whether it can improve hearing. The trial includes different groups, each receiving varying doses or having therapy in one or both ears. Suitable candidates have profound hearing loss from otoferlin gene mutations and do not have cochlear implants in the ears that will receive the treatment. Participants must also agree to join a follow-up study after the trial concludes. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that AAVAnc80-hOTOF, the gene therapy being tested, is generally safe and well-tolerated. In earlier studies, neither the surgery to deliver the therapy nor the therapy itself caused any serious side effects. Participants reported no major problems, indicating a positive response to the treatment.

Experts agree that gene therapies like AAVAnc80-hOTOF are safe and can help improve hearing. Long-term studies continue to monitor safety over time, ensuring no hidden issues arise later.

While the therapy remains under study, these findings encourage those considering joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for hearing loss involve hearing aids or cochlear implants, which amplify sound or bypass damaged parts of the ear. But AAVAnc80-hOTOF works differently, using gene therapy to address the root cause of hearing loss by delivering a healthy version of the OTOF gene directly to the ear. Researchers are excited about this treatment because it has the potential to restore natural hearing by repairing the underlying genetic defect rather than just managing symptoms. This innovative approach could offer a long-term solution for people with certain types of genetic hearing loss, potentially transforming how we treat this condition.

What evidence suggests that this trial's treatments could be effective for hearing loss?

Research has shown that the AAVAnc80-hOTOF gene therapy, which participants in this trial may receive, could help treat hearing loss. Early results from clinical trials indicated that this treatment can restore hearing in people with severe hearing loss. This gene therapy targets the otoferlin (OTOF) gene, essential for hearing. By addressing the root genetic cause, the therapy aims to improve hearing. Initial data suggests it positively affects hearing restoration, offering hope to those affected by this condition. ^{1 2 5 6 7}

Who Is on the Research Team?

Kathy Reape, MD

Principal Investigator

Akouos, Inc.

Are You a Good Fit for This Trial?

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

Preserved distortion product otoacoustic emissions (DPOAEs)

Able and willing to comply with all study requirements, including willingness to participate in a separate long term follow-up study after completion of this trial

I am between 2 and 17 years old.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• AAVAnc80-hOTOF
• Akouos Delivery Device

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.

How Is the Trial Designed?

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

Group III: Bilateral Expansion Experimental Treatment 1 Intervention

Bilateral Expansion: up to four eligible participants of any age, and no cochlear implants, may be eligible for enrollment into the Bilateral Expansion Cohort (simultaneous bilateral administration of AAVAnc80-hOTOF).

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

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06696456

Long Term Follow-up Study of AAVAnc80-hOTOF Gene ... This multi-center, observational, post-intervention long term follow-up (LTFU) study will monitor for safety and efficacy of AAVAnc80-hOTOF in individuals with ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05821959

Gene Therapy Trial for Otoferlin Gene-mediated Hearing ... An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...

3. clinicaltrialsarena.com clinicaltrialsarena.com/news/akouos-gene-therapy-trial/

Akouos reports positive data from gene therapy trial for ... Initial results from the clinical trial indicate that AK-OTOF gene therapy restored hearing in patients with profound loss.

4. chop.edu chop.edu/research-studies/otof-hearing-loss-gene-therapy

OTOF Hearing Loss Gene Therapy In this gene therapy study, we will treat children with deafness caused by an abnormal gene called otoferlin (OTOF).

5. investor.lilly.com investor.lilly.com/node/50201/pdf

Positive Phase 1/2 Clinical Trial Data for an Investigational ... AK-OTOF (AAVAnc80-hOTOF) is a dual adeno-associated viral (AAV) vector-based gene therapy designed to restore auditory function by gene transfer ...

6. clinicaltrials.eu clinicaltrials.eu/trial/study-on-long-term-safety-of-aavanc80-hotof-gene-therapy-for-patients-with-sensorineural-hearing-loss-due-to-otoferlin-gene-mutations/

Study on Long-Term Safety of AAVAnc80-hOTOF Gene ... This clinical study investigates the long-term safety of AAVAnc80-hOTOF gene therapy in treating sensorineural hearing loss caused by Otoferlin gene ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2666634025003137

Article International expert consensus on gene therapy for ... Publicly available preliminary clinical trial data have shown that gene therapy is well tolerated and safe, with the recovery of hearing and ...