Further, non-dividing cells are incapable of undergoing homology-directed repair (HDR)-mediated editing which reduces the overall efficiency of these processes ( Iyama and Wilson, 2013 Kantor et al., 2020). The non-homologous end joining (NHEJ) pathway is error-prone and often associated with undesired insertion or deletion (indel) mutations ( Moore and Haber, 1996 Kosicki et al., 2018 Song et al., 2021). While we expect CRISPR-based gene editing will soon change the therapeutic landscape of complex neurological disorders, the double-stranded break it creates in the host genome is the major drawback of Cas9-mediated editing. Moreover, a recent report suggests that CRISPR technology is in fact promising in clinical trials ( Frangoul et al., 2021). Studies employing CRISPR have already exhibited efficiency in preclinical models of neurological disorders ( Gaj et al., 2017 Yang et al., 2017 György et al., 2018 Lee et al., 2018 Ekman et al., 2019 Ricci and Colasante, 2021).
CRISPR/Cas9-mediated genome engineering is quite precise and straightforward due to the target specificity and simple design of gRNA. This method requires the delivery of Cas9 ribonucleoprotein (RNP) consisting of the Cas9 protein with guide RNA (gRNA) to the target cells. Such an approach is known as gene editing ( Li et al., 2020).Ĭlustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 is one of the widely used gene editing tools. Besides these, studies have been conducted in recent years to edit the mutated copy of the gene itself in vitro and in vivo. RNA interference (RNAi) technology, has been one of the popular approaches to inactivate target gene expression accomplished by a small non-coding RNA of varying length that binds a complementary sequence of the mRNA target ( Davidson and Boudreau, 2007 Jagannath and Wood, 2007 Aguiar et al., 2017 Balwani et al., 2020). These investigations advocate for the further development of gene therapy strategies to treat neurological conditions by replacing the disease-causing mutant gene with a healthy copy or inactivating the malfunctioning disease-causing mutant gene. Recent groundbreaking gene therapy trials on patients with spinal muscular atrophy type 1 (SMA1) resulted in superior motor function and longer survival compared to the control group ( Mendell et al., 2017). Therefore, it is imperative to explore novel treatment modalities like gene therapy. Many of these debilitating neurological conditions do not respond to conventional therapies. The prevalence of neurological disorders has been rising across the globe and is often associated with an increasing socioeconomic burden. Given recent advancements, gene therapy shows great promise to emerge as a next-generation therapeutic for many of the neurodevelopmental and neurodegenerative conditions. Recent developments such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated gene editing and its use in vivo have been described here as well. We have summarized the relative advantages and drawbacks of viral and non-viral vectors from the perspectives of safety, efficiency, and productivity. Here, we have discussed both of these delivery methods and their properties. Consistent efforts have been made to develop gene therapy strategies using viral and non-viral vectors of gene delivery. Considering the current drug development landscape, gene therapy is giving us hope as one such effective therapeutic strategy. The lion’s share of the treatments that are available only provide symptomatic relief, as such, we are in desperate need of an effective therapeutic strategy for these conditions.
There is no cure for the majority of these neurological conditions and the availability of disease-modifying therapeutics is quite rare. Most of these conditions are due to a mutation in a critical gene. Neurological conditions like neurodevelopmental disorders and neurodegenerative diseases are quite complex and often exceedingly difficult for patients. Department of Cellular and Integrative Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
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