Gene therapy for hearing loss caused by OTOF gene changes

Who can take part

• Age seven to 17 years old (inclusive) for Cohort #1a; age two to 17 years old (inclusive) at the time of AAVAnc80-hOTOF administration for Cohorts #1b and #2
• Biallelic mutations in the OTOF gene confirmed by: 1) a European Conformity (CE)-marked genetic test for OTOF, including as part of a clinical panel for hearing loss/deafness genes; or 2) a Clinical Laboratory Improvements Amendment (CLIA)-certified or equivalent laboratory’s genetic test for OTOF, including as part of a clinical panel for hearing loss/deafness genes
• Clinical presentation of Profound bilateral sensorineural hearing loss as assessed by ABR threshold OR absent or abnormal diagnostic ABR (i.e., no click-evoked ABR for levels up to and including 90 dB nHL, consistent with diagnosis of Profound bilateral sensorineural hearing loss); when afebrile
• Preserved OAEs (distortion product OAEs [DPOAEs]), defined as more than one frequency within normal response limits in the speech frequency range, in the study ear
• Participants of child-bearing potential (males and females) agree to use effective contraceptive methods for one year after administration of AAVAnc80-hOTOF. Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical trials as described in the corresponding Informed Consent Form (ICF). • Females of child-bearing potential include those who have experienced menarche. • Males who have reached sexual maturity are considered to be of child-producing potential unless they have had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy
• Legally authorized representative and/or participant willingness to comply with all trial requirements, as evidenced by successful completion of the informed consent process and participant assent process (where appropriate)
• Legally authorized representative and/or participant willingness to participate in separate LTFU protocol after completion of this trial

Who cannot take part

• Prior middle or inner ear surgery in the study ear, with the exception of tympanostomy tubes or tympanocentesis, within six months prior to administration (Day 0)
• Known sensitivity or contraindications to medications planned for use in the peri-operative period, including corticosteroids
• Prior participation in a clinical trial with an investigational drug, within six months prior to administration (Day 0), or any prior participation in a gene therapy clinical trial
• Anatomic abnormalities of the ear that preclude the surgical approach, e.g., canal atresia
• Congenital malformations of the inner ear, as confirmed by non-contrast, high-definition magnetic resonance imaging (MRI), including but not limited to: cochlear malformations (e.g., Mondini malformation); cochlear nerve dysplasia; congenital atresia; absence of round and oval windows; Scheibe dysplasia; membranous labyrinth; Large Vestibular Aqueduct; and anomalies of the eustachian tube and accessory structures. Note: historic MRI data OR historic computed tomography (CT) data (high resolution, no contrast) obtained prior to enrollment are acceptable, provided the studies are adequate to assess inner ear morphology. A CT scan may be obtained at the discretion of the surgeon to further evaluate the bony anatomy, if the MRI and/or historic imaging studies are indeterminate
• Hearing loss attributed mainly to past ototoxic exposures (e.g., severe prematurity, hypoxia, ototoxic medication such as chemotherapy)
• Bilateral cochlear implants
• Word recognition score (for individuals capable of performing the assessment) as follows: > 30% in the best aided condition in the study ear or > 30% in the best aided (hearing aid) condition in the contralateral ear, without cochlear implant use
• Any other condition that would not allow the potential participant to complete follow-up examinations during the course of the trial and/or, in the opinion of the Investigator, makes the potential participant unsuitable for the trial
• Chronic otitis media or chronic eardrum perforation in the study ear
• Medical or psychological conditions that contraindicate undergoing surgery, general anaesthesia, and/or investigational gene therapy administration, including: a) Recurrent or persistent hypertension with systolic and/or diastolic blood pressure (BP) more than 10mm Hg above the 90th percentile for age b) Recurrent or persistent hepatic dysfunction indicated by bilirubin > 1.5X the upper limit of normal (ULN) for age, AST > 2X the ULN for age, or ALT > 2X the ULN for age c) Renal glomerular dysfunction requiring treatment, including diuretics and/or dialysis; or estimated glomerular filtration rate (GFR) < 60mL/min/1.73m2 d) Recurrent or persistent pulmonary dysfunction that requires intermittent supplemental oxygen or persistent oxygen saturation less than 95% on room air (at rest) e) Recurrent or persistent hemoglobin < 10 g/dL (or equivalent) f) Recurrent or persistent platelet count of < 100,000/mL g) Other applicable conditions
• Individuals of childbearing potential who are pregnant and/or breastfeeding or unwilling to use effective contraception for one year following AAVAnc80-hOTOF administration
• Unwillingness or inability of the potential participant (and legally authorized representative, if participant is a minor) to comply with all investigational requirements and follow up
• Evidence of persistent middle ear dysfunction, as demonstrated by repeated abnormal tympanometry (an immittance measure of middle ear function). Note: in the presence of tympanostomy tubes, large volume tympanograms are not exclusionary
• Clinical history consistent with endolymphatic hydrops (documented fluctuating sensorineural hearing loss in the affected ear and/or episodic vertigo attributable to the study ear)
• Evidence of patent cochlear aqueduct