OBJECTIVES: Despite proven potential through empirical evidence, gene therapies for Usher syndrome (USH) are not approved yet. This scoping review aimed to systematically evaluate the challenges reported in the existing literature on USH gene therapy.

METHODS: We conducted a literature search using PubMed and Google Scholar through the artificial intelligence (AI)-powered tool – MaiA. We included clinical trials, observational studies, reviews, systematic literature reviews, and meta-analyses published within the last 10 years (until June 01, 2023) related to USH. Data charting elements included type of USH mutation, type of gene therapy, preclinical model, clinical trial (phase, sample size, efficacy, safety assessments), cost outcomes (diagnostic, manufacturing), regulatory compliances, and description of challenges.

RESULTS: Of total 517 matching records, 92 full-text articles were eligible for final analysis. The reported challenges were two-fold: Clinical, and Economic. Clinical challenges pertained to inadequate sample size (due to rare indications with heterogenous patient profiles) and complexity related to endpoints (subjective improvement in vision and/or hearing or deceleration of blindness progression). Long-term safety and efficacy follow-ups due to the usage of adeno-associated viral (AAV)/ lentiviral vectors and assessment need for sustained vision restoration were found to be additional challenges. Economic challenges entailed the cost of genetic testing for deep intronic variants of the USH genes, and the manufacturing expenses of dual AAV vectors to accommodate large USH variants. Other challenges included knowledge gap about genetic mechanisms, lack of animal models with specific mutations, regulatory bottlenecks for orphan drug designation, and collaborative work models.

CONCLUSIONS: We discovered strong evidence of clinical trial-related challenges in USH. Researchers are employing novel delivery methods (minigenes and nanoparticles), genetic counselling, and advanced sequencing techniques to mitigate these challenges. Clinical trial innovative designs, harmonized regulations, market assessment schemes, and research collaborations, can drive disease-cure/modifying interventions in enhancing the quality of life of USH patients.