Gene Therapy for Congenital Hearing Loss

(CHORD Trial)

Recruiting at 21 trial locations

Overseen By Clinical Trials Administrator

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Regeneron Pharmaceuticals

Disqualifiers: Cochlear implants, Malignancies, Meningitis, others

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

Compensation: Varies

Number of Visits: Unknown

22 Participants Needed

Trial Summary

What is the purpose of this trial?

Regeneron is conducting a study of an investigational new drug called DB-OTO. DB-OTO is a gene therapy that is being developed to treat children who have hearing loss due to changes in the otoferlin gene. The purpose of this study is to: * Learn about the safety of DB-OTO * Determine how well DB-OTO is tolerated (does not cause ongoing discomfort) * Evaluate the efficacy of DB-OTO (how well DB-OTO works)

Will I have to stop taking my current medications?

The trial information does not specify whether participants must stop taking their current medications. It is best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment DB-OTO for congenital hearing loss?

Research shows that gene therapy, like DB-OTO, has successfully restored hearing in animal models with genetic forms of deafness. For example, a study using a similar approach with dual AAV vectors restored hearing in mice with a specific type of genetic deafness, suggesting potential for human treatment. ^{1 2 3 4 5}

How is the treatment DB-OTO unique for congenital hearing loss?

DB-OTO is a novel gene therapy that uses a dual AAV (adeno-associated virus) approach to deliver the otoferlin gene, which is too large for a single AAV vector, directly into the cochlea. This method aims to restore hearing by addressing the genetic cause of deafness, unlike traditional treatments like cochlear implants that only bypass the damaged parts of the ear. ^{1 2 3 6 7}

Research Team

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Eligibility Criteria

This trial is for children under 18 with profound sensorineural hearing loss due to OTOF gene mutations, who meet cochlear implant criteria and have not benefited from ear amplification. They must not have had previous gene therapy or cochlear implants in the affected ear(s), nor other untreatable hearing conditions.

Inclusion Criteria

My child's inner ear function is confirmed normal for DB-OTO treatment.

My child has severe hearing loss diagnosed by tests.

My child's ears can produce sounds in response to a test, and they are 24 months old or younger.

Exclusion Criteria

I have had meningitis before.

I have had cancer before or have it now.

My ear structure allows for the planned surgery based on my scans.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive unilateral intracochlear dosing to evaluate safety and tolerability

4-6 weeks

Dose Expansion

Participants receive bilateral intracochlear dosing using the dose selected based on safety and efficacy data from the Dose Escalation phase

8-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• DB-OTO

Trial Overview DB-OTO, an AAV based gene therapy, is being tested on pediatric patients with biallelic OTOF mutations. The study has two parts: Part A tests increasing doses in patients, while Part B expands to more participants receiving the treatment bilaterally.

Participant Groups

Group I: DB-OTO - Dose Expansion Experimental Treatment 1 Intervention

Bilateral intracochlear dosing using the dose selected based on safety and efficacy data from the Dose Escalation phase (Part A).

Group II: DB-OTO - Dose Escalation Experimental Treatment 1 Intervention

Unilateral intracochlear dosing

Who Is Running the Clinical Trial?

Regeneron Pharmaceuticals

Lead Sponsor

Trials

690

Recruited

948,000+

Founded

1988

Headquarters

Tarrytown, USA

Known For

Precision medicine

Top Products

Dupixent, EYLEA, Libtayo, Praluent

Leonard Schleifer

Regeneron Pharmaceuticals

Chief Executive Officer since 1988

MD and PhD in Medicine

George Yancopoulos

Regeneron Pharmaceuticals

Chief Medical Officer since 1997

MD from Harvard Medical School

Decibel Therapeutics

Lead Sponsor

Trials

3

Recruited

60+

Findings from Research

Gene therapy shows great potential for treating hearing loss, a common sensory disability, by addressing genetic mutations that cause the condition and possibly restoring hearing function.

Recent studies in animal models suggest that gene therapy could not only restore hearing but also promote hair cell regeneration in the cochlea, which is crucial for hearing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for sensorineural hearing loss. Chien, WW., Monzack, EL., McDougald, DS., et al.[2014]

A dual adeno-associated virus (AAV) approach successfully restored otoferlin expression in the cochlea of deaf mice, demonstrating a potential method for treating DFNB9 congenital deafness.

This method allowed for the reconstitution of the otoferlin gene, leading to a reversal of the deafness phenotype, which suggests promising implications for future gene therapy trials in humans with DFNB9.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model. Akil, O., Dyka, F., Calvet, C., et al.[2020]

Recent advancements in human genomics have identified defective genes linked to deafness, presenting new potential targets for gene-based therapies.

Successful gene therapies for hearing loss will depend on effective gene carrier systems, with the choice of vector and administration route significantly influencing the success of gene transfer to inner ear cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene transfer in inner ear cells: a challenging race. Sacheli, R., Delacroix, L., Vandenackerveken, P., et al.[2013]

Recent advances in understanding the mechanisms behind sensorineural hearing loss have led to gene delivery being recognized as a promising strategy for treating the root causes of this condition.

While there are successful examples of gene delivery in animal models, significant challenges remain before these methods can be effectively applied in human clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances and challenges in adeno-associated viral inner-ear gene therapy for sensorineural hearing loss. Bankoti, K., Generotti, C., Hwa, T., et al.[2021]

Hearing loss is projected to affect over 900 million people by 2050, highlighting the urgent need for effective treatments, especially given its significant economic impact of $750 billion annually.

Recent research indicates that fetal gene therapy and pharmacotherapy could be promising strategies for treating congenital hearing loss, with mouse models showing success in early intervention that may translate to human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fetal gene therapy and pharmacotherapy to treat congenital hearing loss and vestibular dysfunction. Hastings, ML., Brigande, JV.[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]

A novel dual-AAV-mediated gene therapy successfully reversed bilateral deafness in Otof -/- mice with a single injection, demonstrating the potential for treating auditory neuropathy caused by OTOF gene mutations.

The therapy effectively restored hearing to near normal levels for at least 6 months and improved synaptic vesicle release in inner hair cells, indicating a promising approach for future treatments in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hearing of Otof-deficient mice restored by trans-splicing of N- and C-terminal otoferlin. Tang, H., Wang, H., Wang, S., et al.[2023]

References

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

Gene therapy for sensorineural hearing loss. [2014]

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

Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Gene transfer in inner ear cells: a challenging race. [2013]

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

Advances and challenges in adeno-associated viral inner-ear gene therapy for sensorineural hearing loss. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Fetal gene therapy and pharmacotherapy to treat congenital hearing loss and vestibular dysfunction. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

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

7. Germany pubmed.ncbi.nlm.nih.gov

Hearing of Otof-deficient mice restored by trans-splicing of N- and C-terminal otoferlin. [2023]