Recombinant adeno-associated viruses (rAAVs) have emerged as an attractive tool for gene delivery, and demonstrated tremendous promise in gene therapy and gene editing-therapeutic modalities with potential "one-and-done" treatment benefits compared to conventional drugs. Given their tropisms for the central nervous system (CNS) across various species including humans, rAAVs have been extensively investigated in both pre-clinical and clinical studies targeting neurodegenerative disease. However, major challenges remain in the application of rAAVs for CNS gene therapy, such as suboptimal vector design, low CNS transduction efficiency and specificity, and therapy-induced immunotoxicity. Therefore, continuing efforts are being made to optimize the rAAV vectors from their "core" genetic payloads to their "coat" or capsid structure. In this review, we describe current approaches for rAAV vector design tailored for transgene expression in the CNS, summarize the development of CNS-targeting AAV serotypes, and highlight recent advancements in AAV capsid engineering, aimed at generating a new generation of rAAVs with improved CNS tropism. Additionally, we discuss various administration routes for delivering rAAVs to the CNS and provide an overview of AAV-mediated gene therapies currently under investigation in clinical trials for the treatment of neurodegenerative diseases.
[1]Soochow Univ, Clin Res Ctr Neurol Dis, Jiangsu Key Lab Neuropsychiat Dis, Suzhou, Peoples R China.
[2]Soochow Univ, Affiliated Hosp 2, Inst Neurosci, Suzhou, Peoples R China.
[3]Soochow Univ, Dept Neurosurg, Affiliated Hosp 2, Suzhou, Jiangsu, Peoples R China.
[4]Sun Yat Sen Univ, Affiliated Hosp 1, Dept Neurosurg, Guangzhou, Peoples R China.
[5]Harvard Med Sch, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA.
[6]Nanjing Med Univ, Affiliated Hosp 1, Dept Lab Med, Nanjing, Peoples R China.
[7]Soochow Univ, Dushu Lake Hosp, Ctr Clin Lab, Suzhou 215123, Peoples R China.
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