中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (10): 2157-2165.doi: 10.4103/1673-5374.335830

• 综述:神经损伤修复保护与再生 • 上一篇    下一篇

靶向mTOR途径大脑传递RNA治疗实现中枢神经系统损伤后的轴突再生

  

  • 出版日期:2022-10-15 发布日期:2022-03-16

Brain delivering RNA-based therapeutic strategies by targeting mTOR pathway for axon regeneration after central nervous system injury

Ming-Xi Li1, Jing-Wen Weng2, Eric S. Ho3, Shing Fung Chow2, Chi Kwan Tsang1   

  1. 1Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China; 2Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong Special Administrative Region, China; 3Department of Biology and Department of Computer Science, Lafayette College, Easton, PA, USA
  • Online:2022-10-15 Published:2022-03-16
  • Contact: Eric S. Ho, PhD, hoe@lafayette.edu; Shing Fung Chow, PhD, asfchow@hku.hk; Chi Kwan Tsang, PhD, tsangch@jnu.edu.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China (No. 81974210), the Science and Technology Planning Project of Guangdong Province, China (No. 2020A0505100045) and the Natural Science Foundation of Guangdong Province (No. 2019A1515010671), all to CKT.

摘要: https://orcid.org/0000-0002-0713-9545 (Eric S. Ho); https://orcid.org/0000-0002-4588-5346 (Shing Fung Chow); 
https://orcid.org/0000-0002-0133-1544 (Chi Kwan Tsang)

Abstract: Injuries to the central nervous system (CNS) such as stroke, brain, and spinal cord trauma often result in permanent disabilities because adult CNS neurons only exhibit limited axon regeneration. The brain has a surprising intrinsic capability of recovering itself after injury. However, the hostile extrinsic microenvironment significantly hinders axon regeneration. Recent advances have indicated that the inactivation of intrinsic regenerative pathways plays a pivotal role in the failure of most adult CNS neuronal regeneration. Particularly, substantial evidence has convincingly demonstrated that the mechanistic target of rapamycin (mTOR) signaling is one of the most crucial intrinsic regenerative pathways that drive axonal regeneration and sprouting in various CNS injuries. In this review, we will discuss the recent findings and highlight the critical roles of mTOR pathway in axon regeneration in different types of CNS injury. Importantly, we will demonstrate that the reactivation of this regenerative pathway can be achieved by blocking the key mTOR signaling components such as phosphatase and tensin homolog (PTEN). Given that multiple mTOR signaling components are endogenous inhibitory factors of this pathway, we will discuss the promising potential of RNA-based therapeutics which are particularly suitable for this purpose, and the fact that they have attracted substantial attention recently after the success of coronavirus disease 2019 vaccination. To specifically tackle the blood-brain barrier issue, we will review the current technology to deliver these RNA therapeutics into the brain with a focus on nanoparticle technology. We will propose the clinical application of these RNA-mediated therapies in combination with the brain-targeted drug delivery approach against mTOR signaling components as an effective and feasible therapeutic strategy aiming to enhance axonal regeneration for functional recovery after CNS injury.

Key words: axon sprouting, axon regeneration, brain targeted drug delivery, CNS injury, ischemic stroke, mTOR, nanoparticle, neural circuit reconstruction, PTEN, RNA-based therapeutics