Safety, Tolerability, Efficacy of EA0010 in OTOF Patients With CI

This study is a single-center, single-arm, open-label, non-randomized clinical study.

To prevent or mitigate potential immune responses to EA0010, participants will receive daily oral or intravenous dexamethasone (0.3 mg/kg) for nine consecutive days, from 3 days before to 5 days after administration (day -3 to day 5). Investigators may adjust the duration and dosage based on clinical requirements. Participants may be admitted to hospital between Day -3 and Day -1. On the day of surgery (Day 0), EA0010 will be administered through the round window under general anesthesia and aseptic conditions.

Participants will receive adeno-associated virus (AAV) at a dose of 2.0×1011 vg/ear/total virus via unilateral cochlear injection (EA0010 Injection is supplied as Solution A and Solution B, each with a titer of 2.0×1013 vg/mL or subject to the actual labeled titer; the two solutions will be mixed at a 1:1 ratio prior to cochlear injection, with a total volume of 10-40 μL); Participants will be closely monitored for 10 days after cochlear injection, may return home after surgical recovery, and will then undergo a 52-week follow-up; the clinical study will end after the last follow-up visit. Subsequent annual follow-ups may be conducted as needed.

Participants will return to the hospital for safety and efficacy assessments at the time points specified in the protocol (D10±3d, W4±3d, W13±7d, W26±14d, W52±14d/EOS/unscheduled) (excluding circumstances of force majeure) during the study period.

Inclusion criteria

• Subjects must meet all of the following inclusion criteria to be enrolled in the study:

• Age between 1 year and 17 years (inclusive) at the time of signing the ICF, male or female;
• Confirmed homozygous or compound heterozygous mutation in the OTOF gene as documented in a report issued by a qualified genetic testing institution;
• Audiometric testing (reports from within 6 months prior to signing the ICF are acceptable): Severe or profound deafness (Click ABR ≥ 80 dBnHL);
• Has received cochlear implantation and has reasonable expectations;
• Vital signs, physical examination, laboratory tests (complete blood count, blood biochemistry, coagulation function, urinalysis, etc.), and 12-lead ECG are all normal or show abnormalities judged by the investigator to be clinically insignificant;
• Subject and/or their legal guardian signs the informed consent form.

Exclusion criteria

• Subjects who meet any of the following criteria are not eligible for enrollment:

• Presence of other definite genetic mutations causing deafness other than the OTOF gene that may affect the judgment of the treatment effect of the OTOF investigational drug;
• History of severe allergic reactions to any drug or its components in this study;
• Prior gene therapy and/or oligonucleotide drug treatment in the ear that has undergone cochlear implantation;
• Blood AAV2 neutralizing antibody titer > 1:2000;
• Presence of systemic diseases or receipt of related treatments that may affect hearing or surgical procedures;
• Inability to undergo general anesthesia;
• History of major inner ear surgery (judged by the investigator as inappropriate for gene therapy);
• Other types of deafness unsuitable for otologic surgery, such as deafness caused by middle-inner ear developmental abnormalities or malformations, vestibulocochlear nerve abnormalities, conductive hearing loss, mixed hearing loss, or syndromic malformations as detected by CT/MRI;
• Otologic diseases that may interfere with the planned surgery or interpretation of study endpoints, such as acute-chronic otitis media, Meniere's disease, acoustic neuroma, sudden deafness with no hearing recovery, etc.;
• History of drug abuse, or receipt of any known ototoxic drug therapy within 6 months (e.g., aminoglycosides, cisplatin, loop diuretics, etc.), or receipt of antiviral and immunosuppressive therapy within 3 months, or vaccination within 1 month;
• Subjects currently receiving or likely to receive immunosuppressive therapy other than that required for this study;
• Allergy or intolerance to glucocorticoids;
• History of malignant tumors or meningitis;
• Presence of persistent or active infection; subjects who are HBsAg positive with peripheral blood HBV DNA titer above the lower limit of detection; subjects who are HCV antibody positive with peripheral blood HCV RNA titer above the lower limit of detection; subjects who are HIV antibody positive or have other immunodeficiency diseases; subjects with positive syphilis serology;
• Subjects of childbearing potential who refuse to use effective contraceptive measures (hormonal, barrier methods, or abstinence) from the time of signing the ICF through 12 months after AAV injection;
• Female subjects of childbearing potential with a positive serum pregnancy test, or who are currently pregnant or breastfeeding;
• Subjects who have participated in any other clinical study within 4 weeks prior to the first dose and have already received study drug or treatment (including drug and device clinical studies, excluding non-interventional studies);
• Unwilling or unable to comply with this study protocol;
• Subjects whom the investigator judges to have any medical condition that renders them unable to participate in this study or complete the subsequent follow-up.