Researchers have successfully used a base editing technique to extend the lifespan of mice with the genetic variant associated with progeria.
Hutchinson–Gilford progeria syndrome (HGPS or progeria) is a rare genetic disease that is characterised by accelerated ageing. In over 90% of patients with HGPS, the disease is caused by a single de novo point mutation (c.1824 C>T; p.G608G) in the lamin A (LMNA) gene. This mutation leads to a mis-splicing event that results in the loss of 50 amino acids from the lamin A protein. The truncated protein (progerin) impairs nuclear structure and function, leading to premature senescence and cell death. This pathogenic mutation is dominant-negative. Therefore, a single copy of the allele is sufficient to cause progeria. The average lifespan in children with progeria is approximately 14 years. Moreover, cardiovascular disease is the predominant cause of death in these children. Unfortunately, there are currently no approaches that are able to reverse the mutation that causes HGPS.
Although CRISPR-based gene editing can disable the mutant gene, it often disables the health copy too and can cause other unwanted changes. Base editors are emerging genome editing tools that can directly convert targeted base pairs without making double-stranded DNA breaks. Cytosine base editors (CBEs) convert C•G to T•A, whereas adenine base editors (ABEs) convert A•T to G•C.
Base editing corrects mutation
In a study, published in Nature, researchers described the use of an ABE to directly correct the pathogenic HGPS mutation in cultured fibroblasts derived from children with progeria. They also applied this editor to a mouse model of HGPS (homozygous for the human LMNA c.1824 C>T allele).
The team found that lentiviral delivery of the ABE to fibroblasts resulted in 87-91% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities. In the transgenic mice, the team also found that a single retro-orbital injection of adeno-associated virus 9 (AAV9) encoding the ABE resulted in substantial, durable correction of the pathogenic mutation (around 20–60% across various organs six months after injection). It also restored normal RNA splicing and resulted in the reduction of progerin protein levels. Moreover, they also observed that in vivo based editing rescued the vascular pathology of the mice. Importantly, they found that a single injection greatly extended the median lifespan of the mice from 215 to 510 days.
These findings hold promise for the treatment of many other conditions through base editing. Many of the known disease-causing mutations involve a single-letter change, which can potentially be corrected with existing base editors.
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