Gene Therapy for Congenital Hearing Loss (CHORD Trial)
Palo Alto (17 mi)Age: < 18
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Regeneron Pharmaceuticals
No Placebo Group
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)
Is the treatment DB-OTO a promising treatment for congenital hearing loss?Yes, DB-OTO is a promising treatment for congenital hearing loss. It uses gene therapy to potentially restore hearing by fixing genetic issues that cause deafness. Studies have shown that this approach can partially or even fully restore hearing in animal models, suggesting it could be effective in humans too.235710
What safety data is available for the gene therapy treatment for congenital hearing loss?The provided research does not contain any safety data related to the gene therapy treatment for congenital hearing loss, including DB-OTO, DB-OTO, or DB XX2. The studies focus on migraine treatments and do not mention the gene therapy in question.1491112
What data supports the idea that Gene Therapy for Congenital Hearing Loss is an effective treatment?The available research shows that gene therapy for congenital hearing loss, specifically using a dual AAV approach, has been successful in animal models. For example, in a study with mice that had a genetic form of deafness, the therapy restored hearing by fixing the gene responsible for the condition. This suggests that gene therapy could be a promising treatment for hearing loss caused by genetic issues. Compared to other treatments, like pharmacotherapy, gene therapy directly targets the root cause of hearing loss, which could lead to more lasting improvements.23568
Do I have to stop taking my current medications for the trial?The trial protocol does not specify whether you need to stop taking your current medications. Please consult with the trial coordinators for more information.
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 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.
My child's ear function for hearing has been confirmed to be normal.
My child under 2 years doesn't respond to certain sounds and is in the UK or Spain.
My child has severe hearing loss and struggles to understand words.
My child does not respond to certain sounds and is between 2 and 18 years old.
I am under 18 and fit the age group needed for this study.
I have genetic mutations in both copies of my OTOF gene.
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.
I have permanent hearing loss not related to treatment.
I have previously undergone gene therapy.
Treatment Details
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.
2Treatment groups
Experimental Treatment
Group I: DB-OTO - Dose ExpansionExperimental Treatment1 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 EscalationExperimental Treatment1 Intervention
Unilateral intracochlear dosing
Find a clinic near you
Research locations nearbySelect from list below to view details:
The Nemours Foundation d/b/a Nemours Children's HealthOrlando, FL
UCLA Health- Department of MedicineLos Angeles, CA
The Nemours Foundation d/b/a Nemours Children's HealthJacksonville, FL
Children's Hospital Medical CenterCincinnati, OH
More Trial Locations
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Who is running the clinical trial?
Regeneron PharmaceuticalsLead Sponsor
Decibel TherapeuticsLead Sponsor
References
Rapid absorption of sumatriptan powder and effects on glyceryl trinitrate model of headache following intranasal delivery using a novel bi-directional device. [2013]The aim was to investigate the pharmacokinetics of intranasal sumatriptan (administered using a novel bi-directional powder delivery device) and study its effects on quantitative electroencephalography in patients with migraine. The safety profiles of the two formulations were also compared.
Gene transfer in inner ear cells: a challenging race. [2013]Recent advances in human genomics led to the identification of numerous defective genes causing deafness, which represent novel putative therapeutic targets. Future gene-based treatment of deafness resulting from genetic or acquired sensorineural hearing loss may include strategies ranging from gene therapy to antisense delivery. For successful development of gene therapies, a minimal requirement involves the engineering of appropriate gene carrier systems. Transfer of exogenous genetic material into the mammalian inner ear using viral or non-viral vectors has been characterized over the last decade. The nature of inner ear cells targeted, as well as the transgene expression level and duration, are highly dependent on the vector type, the route of administration and the strength of the promoter driving expression. This review summarizes and discusses recent advances in inner ear gene-transfer technologies aimed at examining gene function or identifying new treatment for inner ear disorders.
Gene therapy for sensorineural hearing loss. [2014]Gene therapy is a promising treatment modality that is being explored for several inherited disorders. Multiple human gene therapy clinical trials are currently ongoing, but few are directed at hearing loss. Hearing loss is one of the most prevalent sensory disabilities in the world, and genetics play an important role in the pathophysiology of hearing loss. Gene therapy offers the possibility of restoring hearing by overcoming the functional deficits created by the underlying genetic mutations. In addition, gene therapy could potentially be used to induce hair cell regeneration by delivering genes that are critical to hair cell differentiation into the cochlea. In this review, we examine the promises and challenges of applying gene therapy to the cochlea. We also summarize recent studies that have applied gene therapy to animal models of hearing loss.
Safety of galcanezumab in patients with episodic migraine: A randomized placebo-controlled dose-ranging Phase 2b study. [2022]Background Safety findings from a Phase 2b study of galcanezumab, a humanized monoclonal antibody against calcitonin gene-related peptide, for prevention of migraine (NCT02163993) are reported here. Methods Patients aged 18-65 years with episodic migraine were evaluated in this multicenter, double-blind, randomized study. After randomization, 410 patients were administered 5, 50, 120 or 300 mg of galcanezumab or placebo subcutaneously once every 4 weeks for 12 weeks, followed by a post-treatment off-drug period lasting 12 weeks. Results Treatment-emergent adverse events (TEAEs) were primarily rated as mild to moderate. Serious adverse events reported in galcanezumab dose groups were appendicitis, Crohn's disease, suicidal ideation, and congenital ankyloglossia in an infant of a paternal pregnancy; each of these were reported by one patient. Adverse events leading to discontinuation with galcanezumab treatment were abdominal pain, visual impairment, and upper limb fracture, each reported by one patient. Treatment-emergent injection-site reactions were reported significantly more frequently ( p = 0.013) with galcanezumab (13.9%) than with placebo (5.8%). Injection-site pain was the most common injection-site reaction (galcanezumab 11.4%; placebo 2.9%, p = 0.004). Upper respiratory tract infection (galcanezumab 10.0%; placebo 8.8%) and nasopharyngitis (galcanezumab 7.0%; placebo 2.2%) also occurred more frequently with galcanezumab treatment. Potential hypersensitivity events were reported at similar frequencies in galcanezumab (3.3%) and placebo (5.1%) groups. Incidence of treatment-emergent anti-drug antibodies in galcanezumab dose groups (4.6% of patients during treatment period) did not appear to have any meaningful effects on safety, the pharmacokinetics of galcanezumab, or its ability to bind to the target ligand. Conclusion The results from this 3-month Phase 2b study support the initiation of larger Phase 3 trials of longer duration.
Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model. [2020]Autosomal recessive genetic forms (DFNB) account for most cases of profound congenital deafness. Adeno-associated virus (AAV)-based gene therapy is a promising therapeutic option, but is limited by a potentially short therapeutic window and the constrained packaging capacity of the vector. We focus here on the otoferlin gene underlying DFNB9, one of the most frequent genetic forms of congenital deafness. We adopted a dual AAV approach using two different recombinant vectors, one containing the 5' and the other the 3' portions of otoferlin cDNA, which exceed the packaging capacity of the AAV when combined. A single delivery of the vector pair into the mature cochlea of Otof-/- mutant mice reconstituted the otoferlin cDNA coding sequence through recombination of the 5' and 3' cDNAs, leading to the durable restoration of otoferlin expression in transduced cells and a reversal of the deafness phenotype, raising hopes for future gene therapy trials in DFNB9 patients.
Fetal gene therapy and pharmacotherapy to treat congenital hearing loss and vestibular dysfunction. [2021]Disabling hearing loss is expected to affect over 900 million people worldwide by 2050. The World Health Organization estimates that the annual economic impact of hearing loss globally is US$ 750 billion. The inability to hear may complicate effective interpersonal communication and negatively impact personal and professional relationships. Recent advances in the genetic diagnosis of inner ear disease have keenly focused attention on strategies to restore hearing and balance in individuals with defined gene mutations. Mouse models of human hearing loss serve as the primary approach to test gene therapies and pharmacotherapies. The goal of this review is to articulate the rationale for fetal gene therapy and pharmacotherapy to treat congenital hearing loss and vestibular dysfunction. The differential onset of hearing in mice and humans suggests that a prenatal window of therapeutic efficacy in humans may be optimal to restore sensory function. Mouse studies demonstrating the utility of early fetal intervention in the inner ear show promise. We focus on the modulation of gene expression through two strategies that have successfully treated deafness in animal models and have had clinical success for other conditions in humans: gene replacement and antisense oligonucleotide-mediated modulation of gene expression. The recent establishment of effective therapies targeting the juvenile and adult mouse provide informative counterexamples where intervention in the maturing and fully functional mouse inner ear may be effective. Distillation of the current literature leads to the conclusion that novel therapeutic strategies to treat genetic deafness and imbalance will soon translate to clinical trials.
Overloaded Adeno-Associated Virus as a Novel Gene Therapeutic Tool for Otoferlin-Related Deafness. [2021]Hearing impairment is the most common sensory disorder in humans. So far, rehabilitation of profoundly deaf subjects relies on direct stimulation of the auditory nerve through cochlear implants. However, in some forms of genetic hearing impairment, the organ of Corti is structurally intact and therapeutic replacement of the mutated gene could potentially restore near natural hearing. In the case of defects of the otoferlin gene (OTOF), such gene therapy is hindered by the size of the coding sequence (~6 kb) exceeding the cargo capacity (<5 kb) of the preferred viral vector, adeno-associated virus (AAV). Recently, a dual-AAV approach was used to partially restore hearing in deaf otoferlin knock-out (Otof-KO) mice. Here, we employed in vitro and in vivo approaches to assess the gene-therapeutic potential of naturally-occurring and newly-developed synthetic AAVs overloaded with the full-length Otof coding sequence. Upon early postnatal injection into the cochlea of Otof-KO mice, overloaded AAVs drove specific expression of otoferlin in ~30% of all IHCs, as demonstrated by immunofluorescence labeling and polymerase chain reaction. Recordings of auditory brainstem responses and a behavioral assay demonstrated partial restoration of hearing. Together, our results suggest that viral gene therapy of DFNB9-using a single overloaded AAV vector-is indeed feasible, reducing the complexity of gene transfer compared to dual-AAV approaches.
Advances and challenges in adeno-associated viral inner-ear gene therapy for sensorineural hearing loss. [2021]There is growing attention and effort focused on treating the root cause of sensorineural hearing loss rather than managing associated secondary characteristic features. With recent substantial advances in understanding sensorineural hearing-loss mechanisms, gene delivery has emerged as a promising strategy for the biological treatment of hearing loss associated with genetic dysfunction. There are several successful and promising proof-of-principle examples of transgene deliveries in animal models; however, there remains substantial further progress to be made in these avenues before realizing their clinical application in humans. Herein, we review different aspects of development, ongoing preclinical studies, and challenges to the clinical transition of transgene delivery of the inner ear toward the restoration of lost auditory and vestibular function.
Long term safety, tolerability, and efficacy of intracutaneous zolmitriptan (M207) in the acute treatment of migraine. [2021]To determine the long-term safety and tolerability profile of M207 in the acute treatment of migraine.
Hearing of Otof-deficient mice restored by trans-splicing of N- and C-terminal otoferlin. [2023]Mutations to the OTOF gene are among the most common reasons for auditory neuropathy. Although cochlear implants are often effective in restoring sound transduction, there are currently no biological treatments for individuals with variants of OTOF. Previous studies have reported the rescue of hearing in DFNB9 mice using OTOF gene replacement although the efficacy needs improvement. Here, we developed a novel dual-AAV-mediated gene therapy system based on the principles of protein trans-splicing, and we show that this system can reverse bilateral deafness in Otof -/- mice after a single unilateral injection. The system effectively expressed exogenous mouse or human otoferlin after injection on postnatal day 0-2. Human otoferlin restored hearing to near wild-type levels for at least 6 months and restored the release of synaptic vesicles in inner hair cells. Our study not only provides a preferential clinical strategy for the treatment of OTOF-related auditory neuropathies, but also describes a route of development for other large-gene therapies and protein engineering techniques.
Open-label trials for CGRP-targeted drugs in migraine prevention: A narrative review. [2023]Calcitonin gene-related peptide-targeted drugs have proven safe and effective for migraine prevention in large randomized-controlled, double-blind trials with an average duration of six months. Open-label studies may provide additional information on the long-term safety and efficacy of these substances.
Pharmacokinetics and Safety of Single and Multiple Daily Dosing of 75-mg Rimegepant Orally Disintegrating Tablets in Healthy Chinese Adults: A Randomized Placebo-Controlled Trial. [2023]Rimegepant is an oral small-molecule calcitonin gene-related peptide antagonist for acute migraine treatment with or without aura and prevention of episodic migraine in adults. This was a rimegepant single- and multiple-dose phase 1, randomized, placebo-controlled, double-blind study to evaluate the pharmacokinetics and confirm safety in healthy Chinese participants. Participants received a 75-mg rimegepant orally disintegrating tablet (ODT) (N = 12) or matching placebo (N = 4) ODT on days 1 and 3-7 after fasting for pharmacokinetic assessments. Safety assessments included 12-lead electrocardiograms, vital signs, clinical laboratory data, and adverse events (AEs). After a single dose (9 females, 7 males) median time to maximum plasma concentration was 1.5 hours; mean values were 937 ng/mL (maximum concentration), 4582 h*ng/mL (area under the concentration-time curve, 0 to infinity), 7.7 hours (terminal elimination half-life), and 19.9 L/h (apparent clearance). Similar results were seen after 5 daily doses, with minimal accumulation. Six (37.5%) participants experienced ≥1 treatment-emergent AE: 4 (33.3%) had received rimegepant and 2 (50.0%) had received placebo. All AEs were grade 1 and resolved by the end of the study with no deaths, serious/significant AEs, or AEs leading to discontinuation. Overall, single- and multiple-dose rimegepant ODT 75 mg was safe and well-tolerated in healthy Chinese adults with similar pharmacokinetics to non-Asian healthy participants. Trial registration: This trial is registered with the China Center for Drug Evaluation (CDE): CTR20210569.