Development of AAV-Mediated Gene Therapy Approaches to Treat Skeletal Diseases.

Adeno-associated viral (AAV) vectors have emerged as crucial tools in advancing gene therapy for skeletal diseases, offering the potential for sustained expression with low post-infection immunogenicity and pathogenicity. Preclinical studies support both the therapeutic efficacy and safety of these vectors, illustrating the promise of AAV-mediated gene therapy. Emerging technologies and innovations in AAV-mediated gene therapy strategies, such as gene addition, gene replacement, gene silencing, and gene editing, offer new approaches to clinical application. Recently, the increasing pre-clinical applications of AAV to rare skeletal diseases, such as fibrodysplasia ossificans progressiva (FOP) and osteogenesis imperfecta (OI), and prevalent bone diseases, such as osteoporosis, bone fracture, critical-sized bone defects, and osteoarthritis, have been reported. Despite existing limitations in clinical use, such as high cost and safety, the AAV-mediated gene transfer platform is a promising approach to deliver therapeutic gene(s) to the skeleton to treat skeletal disorders, including those otherwise intractable by other therapeutic approaches. This review provides a comprehensive overview of the therapeutic advancements, challenges, limitations, and solutions within AAV-based gene therapy for prevalent and rare skeletal diseases.