Aug 2026· Signal Transduction and Targeted Therapy· Vol 11· 0 citations· 5 references
Medicine
TL;DR
This study offers the most compelling clinical evidence so far that gene replacement therapy can safely restore signi fi cant hearing in children with OTOF-related deafness, with bene fi ts lasting up to 2.5 years, setting a new standard for treating inherited sensory disorders.
Abstract
A recent study published in Nature by Jiang et al. delineates a breakthrough in the treatment of inherited hearing loss through gene therapy. 1 This study offers the most compelling clinical evidence so far that gene replacement therapy can safely restore signi fi cant hearing in children with OTOF-related deafness, with bene fi ts lasting up to 2.5 years, setting a new standard for treating inherited sensory disorders. The bespoke cell and gene therapy approach is revolutionizing precision medicine for genetically diverse diseases. The OTOF gene encodes otoferlin, a transmembrane protein involved in signal transduction that functions as a calcium sensor for synaptic vesicle fusion within the inner hair cells of the cochlea. This gene was linked to hereditary deafness in 1999 by Christine Petit ’ s group. 2 Here, in pediatric patients with autosomal recessive deafness caused by OTOF mutations, dual adeno-associated virus (AAV) – mediated delivery of the OTOF transgene was developed. 3 As the OTOF gene ’ s coding sequence exceeds the packaging capacity of a single AAV vector, the study employed a dual-AAV1 vector strategy to reconstitute the full-length OTOF coding sequence under the control of a Myo15 promoter in vivo following cochlear delivery. 3 In the earlier reported clinical trial, about 75% of children met both behavioral pure-tone audiometry (PTA) and auditory brainstem response (ABR) criteria. 3 Across multiple clinical centers, treated children demonstrated substantial and durable improvements in auditory function, including the restoration of ABRs, enhanced speech perception, and signi fi cant gains in sound detection and communication skills. Importantly, therapeutic bene fi ts were observed relatively quickly after treatment and persisted during extended follow-up periods, indicating stable transgene expression and enduring cochlear rescue. 1 Younger patients generally exhibited the most pronounced outcomes, underscoring the
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.
Emma Dunn, Spencer H Short, Ravi N Samy· Current Opinion in Otolaryng...· 0 citations
Recent advances in the molecular mechanisms, immune microenvironment involvement, and gene therapy strategies for hereditary hearing impairment are summarized, which delineates the research trajectory from gene discovery and mechanistic elucidation to therapeutic development, and discusses future translational research directions and clinical challenges.
X. Yang, Y. Q. Gao, L. Huang et al.· Zhonghua yu fang yi xue za z...· 0 citations
Several therapies using adeno-associated virus (AAVs) as gene delivery tool have received marketing approval in the past. However, potential applications of AAVs are limited by their restricted gene packaging capacities (<4,7kb). Many monogenic diseases are caused by large complex genes with hundreds of pathogenic variants that exceed AAV capacity. Merosin-deficient Congenital Muscular dystrophy type 1A is a severe monogenic recessive disease caused by the absence of functional copies of the LAMA2 gene. To date, no treatment options are available, with the most promising approach being gene replacement therapy to provide a functional copy. The LAMA2 coding sequence, spanning 9,3 kb, encodes for the laminin-α2, a subunit of the trimeric protein Laminin-211 found in the basement membrane of skeletal muscle cells and Schwan cells. Efforts have been focused on gene or protein replacement along with basement membrane engineering. Here, we exploit the ability of inteins to reconstitute full-length protein in a scarless manner. Using a combination of three AAVs, each encoding for one fragment of the laminin-α2 protein flanked by short split intein, resulted in the complete reconstitution of the Laminin-α2 and an improvement of the histopathological features of the dy2j dystrophic mouse model.
Núria Rafel-Millan, Carles Bayod-Girón, Maria Pallarès-Masmitjà et al.· Molecular Therapy· 0 citations
This review evaluates the potential of CRISPR-based editing as a therapeutic strategy for monogenic NDDs and evaluates the limitations that must be addressed before its widespread application in human patients.
Julia Mulles· American Journal of Student...· 0 citations
Cockayne Syndrome (CS) is an autosomal recessive, progressive developmental and neurodegenerative disease. Approximately 30% of cases are caused by mutations in the ERCC8/CSA gene. Patients with CS present with cutaneous photosensitivity, growth failure, shorter life span, and a progressive degeneration of the central nervous system. Loss-of-function mutations in CSA result in deficiencies in the transcription-coupled nucleotide excision repair (TC-NER). Currently, no therapies are available for these patients. Adeno-associated virus (AAV)-mediated gene therapy offers an opportunity to address this unmet need. We designed a new AAV vector encoding human CSA under a ubiquitous promoter. We tested the therapeutic efficacy of this AAV9-CSA vector by neonatal intracerebroventicular injection in the Csa-/-;Xpa-/- mouse model. Treatment with AAV9-CSA resulted in a significant increase in lifespan, and broad distribution of human CSA in the brain and heart, without evidence of vector-related toxicity. Despite clear therapeutic benefit, we also observed neuroradiological abnormalities, and neuropathologic alterations, including hypomyelination, astrocytosis, and microgliosis, as well as likely life-limiting transcriptomic alterations in liver at endpoint. Nonetheless, the success of these experiments paves the way for the first clinical translation of an AAV gene therapy for CS patients into humans.
A. R. Batista, Aine C. Scholand, William S. Callahan et al.· Journal of Clinical Investig...· 0 citations
Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability. It is caused by a trinucleotide expansion in the 5' UTR of the Fragile X messenger ribonucleoprotein 1 (FMR1) gene leading to loss of expression of Fragile X messenger ribonucleoprotein (FMRP). There is currently no cure for FXS. We developed an FMR1 gene therapy based on an adeno-associated viral vector designed with strong translational potential for future clinical testing. The viral vector was tested in Fmr1 knockout mice using two translationally relevant delivery routes and ages corresponding to in utero, toddler, and adolescent ages in humans. Functional studies showed that the FMR1 gene therapy improved select translational FXS phenotypes spanning three critical domains: sensory hyperexcitability, adaptation to change, and altered brain activity. Expression after intracerebroventricular injection was most prominent in the forebrain, whereas intravenous delivery predominantly led to expression across midbrain and brainstem, suggesting that a dual route may be needed to achieve full brain coverage. Biodistribution analyses further suggested that FMRP expression must be titrated carefully for optimal rescue. In summary, we show that FMR1 gene therapy using delivery routes and vehicles approved for clinical use improves core phenotypes in a mouse model for FXS.
Richard K Lacher, Kari Henson, Lindsay N Wathen et al.· Gene Therapy· 0 citations