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<p>Diseases of the central nervous system represent a significant challenge in the field of medical research and clinical practice. The utilization of gene therapy technology represents a promising therapeutic strategy aimed at ameliorating diseases at the genetic level. Nonetheless, the presence of the blood–brain barrier (BBB) and challenges pertaining to delivery efficiency, expression site and level, along with the potential risks linked to overexpression and prolonged expression, raise considerable safety concerns. The design, production, delivery, and expression of adeno-associated virus (AAV) vectors significantly influence both clinical efficacy and safety considerations. This article examines the factors contributing to and potential strategies for addressing the low transduction efficiency associated with the blood–brain barrier, focusing on the optimization of vector design, delivery methods, specific expression, and distribution. The study examines the optimization of promoter synthesis, the application of machine learning algorithms for the enhancement of AAV capsid evolution, and the evaluation of various administration routes. Additionally, it explores innovative delivery methods, including mannitol intra-arterial delivery and focused ultrasound strategies, aimed at improving efficacy and safety. These initiatives offer valuable guidance and insights pertaining to gene therapies aimed at addressing neurodegenerative diseases and various disorders of the central nervous system.</p>

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Key Challenges and Optimization Practices for Non-clinical Evaluation of AAV based Gene Therapy for Central Nervous System Disease

  • 期刊论文

  • 发表日期：

    2025年10月1日

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  • Dehu Dou,
  • Jing Lu,
  • Xijing Chen,
  • Xuefeng Zhang

摘要

Diseases of the central nervous system represent a significant challenge in the field of medical research and clinical practice. The utilization of gene therapy technology represents a promising therapeutic strategy aimed at ameliorating diseases at the genetic level. Nonetheless, the presence of the blood–brain barrier (BBB) and challenges pertaining to delivery efficiency, expression site and level, along with the potential risks linked to overexpression and prolonged expression, raise considerable safety concerns. The design, production, delivery, and expression of adeno-associated virus (AAV) vectors significantly influence both clinical efficacy and safety considerations. This article examines the factors contributing to and potential strategies for addressing the low transduction efficiency associated with the blood–brain barrier, focusing on the optimization of vector design, delivery methods, specific expression, and distribution. The study examines the optimization of promoter synthesis, the application of machine learning algorithms for the enhancement of AAV capsid evolution, and the evaluation of various administration routes. Additionally, it explores innovative delivery methods, including mannitol intra-arterial delivery and focused ultrasound strategies, aimed at improving efficacy and safety. These initiatives offer valuable guidance and insights pertaining to gene therapies aimed at addressing neurodegenerative diseases and various disorders of the central nervous system.