Inner-Ear Gene Therapy for Hereditary Hearing Loss: A PubMed-Based Scoping Review of Published Human Studies and the Clinical Trial Registry Landscape

Efficacy, Safety, and Durability of Gene Therapy for Inherited Retinal Diseases in the Paediatric Population: A Scoping Review.

PURPOSE To map the published interventional gene-based therapies relevant to children with inherited retinal diseases (IRDs), with a focus on efficacy, safety, and durability, including paediatric-versus-adult patterns where available. METHODS This scoping review followed a prospectively registered protocol specifying the search strategy, eligibility criteria, screening process, data-charting framework, and synthesis plan. PubMed and Embase were searched from January 1, 2008, to April 13, 2026. Retrieved records were independently screened by two reviewers to identify prospective interventional studies of gene-targeted therapies for molecularly confirmed IRDs enrolling participants younger than 18 years; unresolved disagreements were adjudicated by a third reviewer. Overlapping reports were grouped into trial clusters with a primary anchor record. Records with at least three paediatric participants and separately extractable paediatric data were classified as Tier 1 and included in the main synthesis; other eligible records were retained as Tier 2 contextual evidence. Where sufficient individual-level or subgroup-level data were available, review authors extracted descriptive paediatric-versus-adult patterns. RESULTS Twenty-four records, grouped into 17 trial clusters across eight genotypes, were included; 14 met Tier 1 criteria. RPE65-associated disease provided the largest paediatric evidence base and the most consistent efficacy and durability signals, although responses varied between trial clusters. AIPL1 gene supplementation showed substantial treated-eye functional gains with relative structural preservation at up to 4 years in four very young children, and high-dose GUCY2D gene supplementation improved retinal sensitivity in three children within a mixed-age cohort. CEP290-targeted splice modulation and gene editing showed early functional signals, but interpretation was limited by dose-related cataract with sepofarsen and few paediatric participants with EDIT-101. Evidence for RPGR, CNGB3, RS1, and MERTK did not support robust paediatric-specific efficacy conclusions. Serious ocular events were predominantly procedure-related, with no reproducible paediatric-specific toxicity signal. Formal age-stratified analyses were uncommon, and several paediatric-versus-adult patterns required review-author extraction. CONCLUSIONS Paediatric benefit from IRD gene therapy depends on genotype, residual retinal structure, therapeutic platform, dose, surgical strategy, and outcome measure. The major evidence gaps are long-term paediatric durability and inconsistent age-stratified reporting. Future paediatric-inclusive trials should pre-specify subgroup analyses, embed prospective long-term follow-up, use developmentally appropriate endpoints, and report individual-level data sufficient to support paediatric inference.

A translational framework for early-phase inner-ear gene therapy: clinical trial design, regulatory strategy, and ethical considerations.

The genetics of hearing loss is transitioning from a diagnostic modality to an interventional one, with emphasis on emerging gene-based therapies, clinical trial design, regulatory and ethical considerations, and practical implications for otolaryngologists as biologic treatment enters clinical practice.

Gene Therapy for Autism Spectrum Disorder: Preclinical Advances, Translational Barriers, and Ethical Dimensions - A Scoping Review.

BACKGROUND Autism spectrum disorder (ASD) lacks disease-modifying therapies. Gene therapy offers a promising avenue to target the underlying molecular causes of ASD, particularly in monogenic or syndromic forms where single-gene mutations play a central role. METHODS A scoping review was conducted following the PRISMA-ScR framework. We searched PubMed, Scopus, Web of Science, PsycINFO, and the Cochrane Library (2000-July 2025), with the last search completed in July 2025. Eligible studies included preclinical or translational investigations involving gene-therapy modalities (e.g., AAV vectors, ASOs, CRISPR-based editing) targeting high-confidence ASD-linked genes; non-gene-therapy studies, unrelated conditions, reviews, and non-English papers were excluded. Data were charted using a standardized extraction form and synthesized descriptively across two evidence streams. Stream 1 evaluated preclinical studies of gene therapy, while Stream 2 examined translational advances and ethical considerations. RESULTS Twenty-one preclinical studies were identified in Stream 1, focusing on genes such as UBE3A, MECP2, FMR1, SHANK3/2, SCN2A, and SYNGAP1. Most demonstrated molecular correction and improvements in synaptic, electrophysiological, and behavioral outcomes, with therapeutic effects observed from early developmental to adult timepoints. Stream 2 synthesized 12 studies highlighting translational challenges, including delivery innovations (e.g., engineered viral capsids, nanoparticles), safety concerns (immune responses, dose-dependent toxicities), and ethical considerations (pediatric consent, neurodiversity perspectives, equity in access). Limitations include heterogeneity across models, reliance on rodent studies, and absence of completed human clinical trials. CONCLUSIONS Gene therapy for ASD shows considerable promise but faces significant translational and ethical hurdles. Standardized study designs, comprehensive safety evaluation, and transparent stakeholder engagement will be critical for developing responsible and effective clinical applications.

Gene therapy clinical trials for inherited eye diseases: The pediatric perspective.

Gene therapy is an increasingly useful treatment option, especially in children, where most inherited diseases manifest. This review provides a literature synthesis of current gene therapy treatments in pediatric ophthalmology. Our search encompassed the ClinicalTrials.gov database. Sixteen clinical trials with published results reporting gene therapy for genetic ocular diseases in children (under 18 years) were included. Diseases under investigation for gene therapy in children included Leber's Congenital Amaurosis (CEP290, RPE65 genes), Leber's Hereditary Optic Neuropathy (ND4), Retinitis Pigmentosa (MERTK), Usher Syndrome Type 2 (USH2A), X-linked Retinitis Pigmentosa (RPGR), Achromatopsia (CNGA3, CNGB3), and X-linked Retinoschisis (RS1). Most clinical trials in our search were in Phases 1 or 2, with five studies having progressed to Phase 3. In certain cases, treatment demonstrated encouraging results, providing the patients with an improvement in BCVA, retinal sensitivity, and quality of life. However, the outcome measures regarding the efficacy and tolerability of gene therapy varied and some studies noted adverse events. Clinical trials that have yet to publish their results were also recorded. While the field of pediatric ophthalmology shows promise for gene therapy options, future strategies should include stratified enrollment based on age, separate cohorts for pediatric and adult patients, or adaptive trial designs.

Cochlear Implantation in Sickle Cell Disease: A Systematic Review of Feasibility and Outcomes.

INTRODUCTION Sickle cell disease (SCD) is associated with systemic complications, including sensorineural hearing loss (SNHL) from microvascular occlusion and chronic inflammation. Although reports link SCD to higher rates of SNHL, current evidence is limited by small sample size, varied audiologic methods, and lack of standardized screening. This systematic review summarizes available literature on SNHL and cochlear implantation (CI) in SCD. METHODS A literature search of PubMed MEDLINE, Embase, Scopus, Web of Science, and CINAHL identified 79 citations. After removal of duplicates, 35 records were screened in Rayyan. Studies published between January 1, 2000, and June 30, 2025, were eligible if they reported patients with SCD who developed hearing loss and underwent CI. Nine full texts were reviewed, and 4 met the inclusion criteria. Screening and review were performed independently by 2 authors per PRISMA guidelines. RESULTS Across 4 case reports, a total of 5 patients with SCD underwent CI, ranging in age from 2 to 42 years. Four presented with bilateral severe-to-profound SNHL and one with unilateral loss. Implantation was technically feasible in all cases, including patients with cochlear fibrosis or ossification requiring modified insertion techniques. Postoperative outcomes were favorable: all patients demonstrated reliable device function and low impedances. Only 60% showed meaningful auditory benefit, characterized by improved functional speech perception in 2 patients (40%) and access to the speech frequency range with hearing testing going from moderate/profound hearing loss to mild hearing loss in 3 patients (60%). Complications occurred in 2 patients (40%): one developed unilateral middle ear infection leading to meningitis, and another experienced a postoperative pulmonary embolism requiring anticoagulation. The remaining 3 patients (60%) had uncomplicated recoveries with reported improved hearing from moderate/profound hearing loss to mild hearing loss post implantation. CONCLUSION While CI appears feasible in SCD, our findings suggest that additional data are needed to assess its effectiveness in this patient population. However, evidence is limited to case reports, and complications such as thromboembolism and rapid cochlear fibrosis highlight the need for close perioperative management. More comprehensive studies with larger sample size are required to define surgical risk, optimize management, and establish best practices for timely implantation in this population.

Stem Cell and Gene Therapies in Congenital Heart Disease: A Systematic Review.