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Genetic Limitations to Athletic Performance
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
A significant recent advancement in the field of gene therapy is the discovery and development of the CRISPR–Cas9 system for modifying DNA. The Cas9 protein assembles with a guide RNA, enabling DNA binding and cutting much more precisely than has previously been possible in humans. This opens up possibilities for gene therapy but also for gene doping. The CRISPR–Cas9 system can create either permanent or temporary changes to the genome causing insertion, deletion, or replacement of gene(s), single-base changes, or gene suppression or activation (36). New, potentially even better, genome editing tools are also emerging, such as prime editing, CRISPR–Cas3, and EvolvR (36). Whilst gene therapy is not currently mainstream, we move ever closer to that scenario.
MERTK missense variants in three patients with retinitis pigmentosa
Published in Ophthalmic Genetics, 2023
Federica E. Poli, Imran H. Yusuf, Penny Clouston, Morag Shanks, Jennifer Whitfield, Peter Charbel Issa, Robert E. MacLaren
A more recent alternative to gene therapy is the utilisation of RNA-programmable CRISPR-associated (CRISPR-Cas) nuclease technology, a powerful tool which allows precise and site-specific modifications of genomic DNA. Base-editing tools consist of catalytically inactivated Cas-nucleases programmed to localize target DNA loci, paired with a base-modification enzyme (36). They permit the direct and irreversible conversion of a specific target DNA base, theoretically enabling the correction of point missense transition mutations in a programmable manner (37–39). The cytosine to thymine single base mutation in the c.1133C>T variant here described might therefore be suitable for targeting with adenine base editors to revert the mutated A•T base pair back to G•C on the reverse strand (39). Prime-editing—a complementary DNA-editing tool that utilises the CRISPR-Cas9 targeting specificity with an RNA template that is inserted following reverse transcription—may edit transversion mutations (40). Therefore, the c.2163T>A and c.1866 G>C variants are theoretically correctable using this technology, or alternatively, by gene replacement therapy.
CRISPR/Cas9 gene editing therapies for cystic fibrosis
Published in Expert Opinion on Biological Therapy, 2021
Prime editing represents an opportunity to pair the advantages of single-stranded DNA cuts (as explored in base editing) with the expanded precision editing capabilities of homology-directed repair. However, rather than chemical modification of individual nucleotides (as in the case of base editing), the prime editing approach rebuilds damaged DNA by using an engineered reverse transcriptase and an RNA repair template [100]. The reverse transcriptase is fused with a prime editing gRNA (pegRNA), which contains an RNA template for the desired edits. Similar to base editing, after editing has occurred, the non-edited strand is nicked and subsequently repaired according to complementarity to the edited strand, thus perpetuating the desired changes [100]. This allows editing on a larger scale than the single-nucleotide edits of base editing and eludes the issue of base editors indiscriminately editing all A or C nucleotides within the editing window. As in the case of base editing, the lack of double-strand break formation leads to lower rates of apoptosis and off-target DNA damage [93,94,100].
Common therapeutic advances for Duchenne muscular dystrophy (DMD)
Published in International Journal of Neuroscience, 2021
Arash Salmaninejad, Yousef Jafari Abarghan, Saeed Bozorg Qomi, Hadi Bayat, Meysam Yousefi, Sara Azhdari, Samaneh Talebi, Majid Mojarrad
Prime editing is a massive breakthrough in cutting-edge genome editing. This technology introduces desired modification at target site without inducing DSB and using donor DNA. In this system impaired Cas9 is fused to a manipulated reverse transcriptase and a prime editing gRNA recruits this established editor to target site. Surprisingly, prime editor was able to perform editing at targeted deletion, insertion, and all twelve types of point mutations. Prime editing showed lower off-target than wild-type Cas9 and has complementary capability respect to base editors. It is estimated that prime editing is capable in principle to edit 89% of known modification correlated with human disease [173]. Altogether, base editors and prime editing open new perspectives for therapeutic applications on DMD.