Natural History of Autosomal Dominant Hearing Loss

Hereditary hearing loss is one of the most common sensory disabilities affecting newborns (approximately 1/1000 live births). Currently, the main treatment options for patients with hereditary hearing loss include hearing aids and cochlear implantation. Both of these treatment options have limitations and are incapable of restoring natural hearing. Over the past few years, several studies have demonstrated the feasibility of using gene therapy to improve hearing in mouse models of human hereditary hearing loss. Nonsyndromic autosomal dominant sensorineural hearing loss (DFNA) is an attractive target for gene therapy since patients with DFNA usually develop hearing loss later during childhood or even adulthood. This allows for a longer time period during which therapeutic intervention can be delivered before the onset of potentially irreversible functional and pathologic changes. The genome editing technology has the potential of correcting the underlying genetic mutations in affected cell types. In this study, we plan to assess the efficacy of genome editing on cultured primary or immortalized fibroblasts obtained from DFNA patients. These patients and their family members will also be followed longitudinally to better characterize the natural history of DFNA. This will provide baseline data for DFNA that will be important for interpreting the results of future clinical trials of inner ear gene therapy.

A summary of the study is listed below:

• Primary objectives

Objective: The primary objective of this study will be to determine if mutant alleles of genes causing autosomal dominant hearing loss (DFNA) can be inactivated by genome editing tools.

Study population: One proband per DFNA mutation.

Study design: Single subject design.

Outcome measures: Determine if genome editing could be applied to modify mutations in cultured primary or immortalized fibroblasts from patients with non- syndromic autosomal dominant hearing loss. The main outcome measure are, 1) efficiency of genome editing in DFNA fibroblasts and 2) specificity of genome editing at targeting the mutant allele.

• Secondary objectives

Objective: The secondary objective of the study is to record the natural history of individuals with DFNA as well as their family members. We will identify the clinical, audiologic, and laboratory markers correlated with different genetic causes of DFNA.

Study population: DFNA subjects and family members.

Study design: Prospective longitudinal study.

Outcome measures: Characterize the natural history of non-syndromic autosomal dominant hereditary disorders affecting hearing and/or balance and determining the variability of phenotypes associated with various mutations. The main outcome measures include, 1) severity of hearing loss at baseline (beginning of the study) and 2) progression of hearing loss.

• INCLUSION CRITERIA:
• Affected persons with autosomal dominant hereditary sensorineural hearing loss, preferably confirmed by prior genetic testing
• Affected family members of enrolled participants with known autosomal dominant hereditary hearing loss
• Unaffected Family Members (Healthy Volunteers) of enrolled participant
• Adults must be able to provide informed consent
• Minors must have a parent or guardian able to provide informed consent
• Subjects must be 3-99 years of age

Exclusion criteria

• Persons with sensorineural hearing loss (SNHL) and/or peripheral vestibular dysfunction associated with a non-genetic etiology such as infection, metabolic or immunologic disorders, or exposure to ototoxic agents such as cisplatin, or aminoglycoside antibiotics will not be included in this protocol.
• Persons with sensorineural hearing loss known to be associated with surgical intervention (e.g. acoustic neuroma removal, failed stapedectomy).

Prospective study subjects who are cognitively impaired and lack consent capacity, will not be enrolled. The pre-screening eligibility checklist, which will be used and documented for registration under this protocol, is provided in a separate document.