There has been a discussion on this site about DNA base editing. Two companies, Beam Therapeutics and Verve Therapeutics, are leading the clinical application of base editing technique. Base editing was invented in 2016, four years after CRISPR–Cas9 editors, by the group of Harvard University researcher David Liu. Liu subsequently co-founded Beam to develop base editor therapeutics. Verve licensed the Beam technology to target genetic loci associated with atherosclerotic cardiovascular disease.
Verve Therapeutics has dosed its first patient with the first in vivo base editing therapy to reach the clinic, a potential treatment for heterozygous familial hypercholesterolemia. This clinical trial will test whether base editing can safely be used to make precise, single-letter changes to a DNA sequence in a cholesterol-regulating gene.
In CRISPR–Cas9 genome editing, the Cas9 enzyme breaks both strands of DNA at the site that is to be edited. The cell’s DNA-repair processes stitch the strands back together, but sometimes make mistakes. This means that a range of DNA sequence changes are possible with each edit.
Base editing, by contrast, avoids cutting both strands of the DNA by coupling a Cas9 protein that only cuts one strand of DNA to another enzyme that chemically converts one DNA base to another. The Cas9 directs the base-editing enzyme to the right location in the genome; the other enzyme then acts on that site, ideally producing only one edit.
How does this clinical application of base editing work?
The target gene is responsible for the production of PCSK9 protein that helps in catabolism of LDL receptors. Previous therapies have already been produced to reduce PCSK9 activity, including monoclonal antibodies and RNA silencing. Reducing PCSK9 activity leads to up-regulation of LDL receptor expression and lower LDL-C levels, and hence a lower risk for atherosclerotic cardiovascular disease.
The Verve trial aims to edit cells directly in the body, disabling PCSK9 gene. Verve said that its VERVE-101 is a single-course gene editing treatment designed to reduce the low-density lipoprotein cholesterol (LDL-C). It has the potential to offer people with heterozygous familial hypercholesterolemia a game-changing treatment option, transforming the traditional chronic care model to a single-course, life-long treatment solution.
VERVE-101 consists of an adenine base editor messenger RNA as well as an optimized guide RNA targeting the PCSK9 gene packaged in an engineered lipid nanoparticle. The nanoparticles will be concentrated in the liver, a key site of PCSK9 production. By making a single A-to-G change in the DNA genetic sequence of PCSK9, VERVE-101 aims to inactivate that target gene.
Researchers will be looking at the efficiency of this treatment as well as to see whether the treatment introduces any off-target genetic changes. We will need long-term safety data before feeling assured that the treatment can be used more widely.
References:
https://www.nature.com/articles/s41587-022-01326-x
https://www.nature.com/articles/d41586-022-01951-1
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The base editing technique can potentially be used to correct single nucleotide mutations, and it is said to be better gene-targeting than the CRISPR-Cas9. However, in this study it is used not to correct a faulty gene, but to disrupt a working gene. CRISPR-Cas9 has also been used, as published on this site, to disrupt working genes aiming to direct the cell to alternative pathways. Have been there any studies that succeeded in repairing a faulty gene?