Destination Brain: the Past, Present, and Future of Therapeutic Gene Delivery

Abstract

Neurological diseases and disorders (NDDs) present a significant societal burden and currently available drug- and biological-based therapeutic strategies have proven inadequate to alleviate it. Gene therapy is a suitable alternative to treat NDDs compared to conventional systems since it can be tailored to specifically alter select gene expression, reverse disease phenotype and restore normal function. The scope of gene therapy has broadened over the years with the advent of RNA interference and genome editing technologies. Consequently, encouraging results from central nervous system (CNS)-targeted gene delivery studies have led to their transition from preclinical to clinical trials. As we shift to an exciting gene therapy era, a retrospective of available literature on CNS-associated gene delivery is in order. This review is timely in this regard, since it analyzes key challenges and major findings from the last two decades and evaluates future prospects of brain gene delivery. We emphasize major areas consisting of physiological and pharmacological challenges in gene therapy, function-based selection of an ideal cellular target, available therapy modalities, and diversity of viral vectors and nanoparticles as vehicle systems. Further, we present plausible answers to key questions such as strategies to circumvent low blood-brain barrier permeability, most suitable CNS cell types for targeting. We compare and contrast pros and cons of the tested viral vectors in context of delivery systems used in past and current clinical trials. Gene vector design challenges are also evaluated in the context of cell-specific promoters. Key challenges and findings reported for recent gene therapy clinical trials, assessing viral vectors and nanoparticles, are discussed in the context of bench to bedside gene therapy translation. We conclude this review by tying together gene delivery challenges, available vehicle systems and comprehensive analysis of neuropathogenesis to outline future prospects of CNS-targeted gene therapies.

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“…Finally, the absence of leukocyte adhesion molecules, together with tight junctions, prevents the entry of peripheral immune cells in the absence of trauma or disease ( Abbott et al, 2006 ; Chow and Gu, 2015 ). These BMEC specific features are a physical challenge and rate-limiting step for therapeutically targeting brain cells ( Joshi et al, 2017 ). Importantly, the microvascular network of the brain is dense and so intricate that every neuron or glial cell is less than 20 μm from a blood capillary.…”

“…Their delivery to the brain after intravenous injection could be also slightly improved by co-administration of low doses of a hyperosmolar solution ( Gray et al, 2010 ; Kwon et al, 2010 ) or by disrupting the BBB with microbubble-enhanced ultrasound ( Tan et al, 2016 ). Gene vectors have been injected directly into the brain to circumvent the BBB ( Do Thi et al, 2004 ; Yang et al, 2013 ) but the innate difficulty of the method and the risks induced by such an approach make it hardly applicable over long-term clinical trials ( Joshi et al, 2017 ).…”

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