Current Status and Challenges Associated with CNS-Targeted Gene Delivery across the BBB

Abstract

The era of the aging society has arrived, and this is accompanied by an increase in the absolute numbers of patients with neurological disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Such neurological disorders are serious costly diseases that have a significant impact on society, both globally and socially. Gene therapy has great promise for the treatment of neurological disorders, but only a few gene therapy drugs are currently available. Delivery to the brain is the biggest hurdle in developing new drugs for the central nervous system (CNS) diseases and this is especially true in the case of gene delivery. Nanotechnologies such as viral and non-viral vectors allow efficient brain-targeted gene delivery systems to be created. The purpose of this review is to provide a comprehensive review of the current status of the development of successful drug delivery to the CNS for the treatment of CNS-related disorders especially by gene therapy. We mainly address three aspects of this situation: (1) blood-brain barrier (BBB) functions; (2) adeno-associated viral (AAV) vectors, currently the most advanced gene delivery vector; (3) non-viral brain targeting by non-invasive methods.

Keywords: AAV; BBB; Gene therapy; neurological disorders; non-invasive delivery; non-viral vectors.

Figure 1

Treatment satisfaction and drug contribution. This figure is based on a medical need survey concerning medical satisfaction and drug contribution for physicians in Japan (2014~2019). Treatment satisfaction% was defined as the percentage of physicians who chose “Fully satisfied” and “Satisfied to some extent” from four options (1. Fully satisfied; 2. Satisfied to some extent; 3. Dissatisfied; 4. Not being treated) for the disease in the questionnaire. Drug contribution% was defined as the percentage of respondents who chose “Fully contributed” and “Contributed to some extent” of the four options (1. Fully contributed; 2. Contributed to some extent; 3. Not contributed; 4. No effective drugs) for each disease in questionnaire. This 2-axis dot plot based on a Japan questionnaire survey for physicians indicates the requirement of developing new drugs for the treatment of neurological disorders. There are 10 diseases with less than 50% of both treatment satisfaction and drug contribution, and 4 of them are neurological disorders including atrophy lateral sclerosis (ALS), Alzheimer’s disease (AD), multiple sclerosis (MS), and vascular dementia, figure is adopted with permission from [2], Japan Health Sciences Foundation, 2019.

Figure 2

Diseases where there is an urgent need to develop new treatments and drugs. The pie chart is the result of a questionnaire concerning diseases that require the development of new drugs in Japan, figure is adopted with permission from [2], Japan Health Sciences Foundation, 2019. This figure was based on data from survey participants that were asked to list three diseases that they considered to be in urgently in need of new treatments and therapeutics, and then categorized those diseases into central nervous system (CNS), neoplasm, cardiovascular system, metabolic, etc. The result shows the diseases in most need of new drug development are CNS disorders.

Figure 3

General structure of the BBB. Figure 3A,B show different cross-sectional views of brain blood vessels, respectively. The upper left picture shows the direction of cross-section of (A) (cut in round slices) and (B) (cut into squares) when the brain blood vessels are viewed as a cylinder. BL; basal lamina.

Figure 4

Main internalization pathways for receptors/transporters expressed on the BBB. (A) Transporter-mediated pathway: This pathway implies only an interaction between the ligand and the receptor. Conformation change is induced after ligand binding; (B) Clathrin-dependent pathway: This pathway requires the association of specific endocytic proteins, promoting the formation of clathrin-coated vesicles. The vesicles then dissociate from the membrane and undergo pH changes which promote the dissociation of clathrin and the ligand/receptor complex. The receptor is recycled; (C) The caveolae-dependent pathway: This pathway is regulated by the caveolin-1 and cavin proteins. The caveolae-dependent pathway has the ability to bypass lysosomal storage, which is different from the clathrin-dependent pathway. Little precise information if available regarding the BBB transcytosis mechanism, which is referred to as “Vesicular trafficking” in the figure, despite several reports indicating that transcytosis is regulated by Rab GTPases, which are a known group of molecules that control intracellular vesicle transport [82]. EE—Early Endosome.

Figure 5

Non-viral strategies for brain targeting by non-invasive methods.