Crossing the blood-brain barrier with AAV vectors
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REVIEW ARTICLE
Crossing the blood-brain barrier with AAV vectors Dan Liu 1,2
&
Mingyang Zhu 1 & Yuqian Zhang 1 & Yong Diao 1
Received: 15 July 2020 / Accepted: 12 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Central nervous system (CNS) diseases are some of the most difficult to treat because the blood-brain barrier (BBB) almost entirely limits the passage of many therapeutic drugs into the CNS. Gene therapy based on the adeno-associated virus (AAV) vector has the potential to overcome this problem. For example, an AAV serotype AAV9 has been widely studied for its ability to cross the BBB to transduce astrocytes, but its efficiency is limited. The emergence of AAV directed evolution technology provides a solution, and the variants derived from AAV9 directed evolution have been shown to have significantly higher crossing efficiency than AAV9. However, the mechanisms by which AAV crosses the BBB are still unclear. In this review, we focus on recent advances in crossing the blood-brain barrier with AAV vectors. We first review the AAV serotypes that can be applied to treating CNS diseases. Recent progress in possible AAV crossing the BBB and transduction mechanisms are then summarized. Finally, the methods to improve the AAV transduction efficiency are discussed. Keywords Adeno-associated virus (AAV) . Blood-brain barrier . Gene therapy . Transduction mechanism
Introduction CNS diseases are many and variable, including infectious diseases, tumors, cerebrovascular diseases, neurodegenerative diseases, epilepsy, and mental diseases. These diseases have a wide range of causes including hereditary or currently unknown origins, but their common characteristic is that part of the nervous structure is rendered dysfunctional or is lost, causing the loss of critical bodily functions; associated symptoms are frequently serious enough to affect the patient’s normal life and work, and in severe cases CNS disease can lead to death (Kreutzberg 1996; Yi et al. 2015; De Luca et al. 2017). CNS disease is one of the most difficult categories of disease to treat, with conditions that have high associated disability rate and are usually difficult to cure completely. Treatment difficulty is largely due to the existence of the BBB, a selectively permeable barrier consisting of tight junctions between brain endothelium, astrocytes, extracellular matrix and endothelial cells (Paradis et al. 2016) (Fig. 1).
* Dan Liu [email protected] 1
School of Biomedical Sciences, College of Chemical Engineering, Huaqiao University, Xiamen, Fujian, China
2
State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China
The BBB selectively limits or blocks the passage of many hydrophilic molecules, or macromolecules, allowing only a few small molecules such as O2 and CO2 to pass through, while transporting specific nutrients to the CNS via transport proteins. Thus, the BBB protects brain tissue, but also limits the delivery of many therapeutic drugs. (Abbott et al. 2010; A
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