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Gene therapy in the CNS—one size does not fit all

Gene Therapy volume 28, pages 393–395 (2021)Cite this article

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Gene therapy in the central nervous system (CNS) has taken centre stage in the past two decades due to significant advancements in lentiviral (LV) and adeno-associated viral (AAVs) technologies. Viral vectors have been utilised for a variety of applications from labelling axons for fluorescent tract tracing to treatment-based strategies such as re-expression of missing proteins. Many viral vectors can retrogradely or anterogradely transport within axons giving rise to neuronal/axonal tract tracing approaches. Rabies virus takes this ‘technology’ one step further giving the user the ability to transynaptically trace neurons/axons to study neuronal connections. The field is continuously evolving with cutting-edge technologies such as optogenetics leading to modulation of gene expression in real time [1], inducible viral vectors such as those able to evade the immune system [2] and engineered AAV capsids able to cross the blood brain barrier (BBB) [3,4,5].

Despite the numerous advantages available for gene therapy, fundamental questions still plague this area of research, specifically how best to optimise transduction efficiency in target cells. Research has shown that transduction efficiency varies widely depending on the target cell type, particularly whether dividing or non-dividing, with AAVs being the gold standard for use in the latter. This potential variability has led to the design and optimisation of viral vectors specific for an experimental paradigm that may not equate to efficient expression in other, even similar, cell types within the nervous system. Whilst the field has excelled with potential therapeutic applications, many viral vector studies have instead focused on improving methodology to efficiently transduce specific neuronal subtypes. Although researchers may be looking to modify gene expression within all cell types within the nervous system, neuronal transduction has received significant attention. Therefore, neuronal transduction provides an excellent platform to examine important factors which can be applied to other cells and systems. Some of the main considerations for increasing neuronal transduction efficiency include: (1) viral serotype (for AAVs); (2) promoter type; and (3) method of administering/delivering the virus to the target cell. In addition, a fourth factor should also be included when considering transduction efficiency which includes the experimental species used in these studies, whereas some researchers have noted significant variability in transduction efficiency amongst different species.

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Acknowledgements

I thank Dr. David Tumbarello for critically reading this manuscript.

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Funding from the Biotechnology and Biological Sciences Research Council to MRA.

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  1. School of Biological Sciences, University of Southampton, Southampton, SO171BJ, UK

    Melissa R. Andrews

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Correspondence to Melissa R. Andrews.

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Andrews, M.R. Gene therapy in the CNS—one size does not fit all. Gene Ther 28, 393–395 (2021). https://doi.org/10.1038/s41434-020-00196-9

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