Adeno-Associated Virus Vector for Central Nervous System Gene Therapy

The past several years have witnessed significant advances in the development of therapeutic gene delivery for neurological disorders of the central nervous system (CNS). In particular, genome-wide sequencing analysis has deepened our understanding of mutations that underlie many monogenic disorders, which in turn has contributed to clinical advances involving adeno-associated virus (AAV) vector delivery of replacement genes to treat recessive disorders. Moreover, gene therapy has been further bolstered with advances in genome editing tools that allow researchers to silence, repair, and amend endogenous genes. However, despite strong preclinical and clinical progress, challenges remain, including delivery and safety. Here, we discuss advances in AAV engineering, recent developments in cargo design, and translation of these technologies towards clinical progress. Recent regulatory approvals have been granted to adeno-associated virus (AAV)-based gene therapies for type 2 Leber congenital amaurosis and spinal muscular atrophy type 1.AAV-based gene therapies for lysosomal storage disorders, retinitis pigmentosa, and Parkinson’s disease have shown promising early-stage clinical results in the past 4 years and are being further investigated in numerous ongoing and planned clinical trials.Recent discoveries in AAV virology and advancements in AAV vector and cargo engineering have uncovered new opportunities to engineer improvements in the efficiency and specificity of gene delivery.