Researchers from the National Institutes of Health (MD, USA) and Harvard University (MA, USA) have used second-generation CRISPR gene-editing technology termed ‘base editing’ to revolutionize gene therapy in order to tackle a genetic disorder called Hutchinson–Gilford progeria syndrome (HGPS).

Their results, which have been tested in cultured fibroblasts and mice, were published in Nature.

HGPS is typically caused by a dominant-negative C–G to T–A mutation in the LMNA gene. This mutation results in the production of a toxic protein known as progerin, which induces rapid aging and shortens the lifespan of children with progeria to approximately 14 years.

Within the study, the researchers used an adenine base editor to directly correct the pathogenic HGPS mutation in both cultured fibroblasts derived from children with progeria and in a mouse model of HGPS.

The team used a lentiviral delivery method to deliver the adenine base editor to cultured fibroblasts. According to their study, this resulted in 87–91% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities. They did not detect any off-target editing in these patient-derived fibroblasts.

In their transgenic mouse model of HGPS, which were homozygous for human LMNA, their study stated that “a single retro-orbital injection of AAV9 encoding the adenine base editor resulted in substantial, durable correct of the pathogenic mutation (around 20–60%) across various organs 6 months after injection), restoration of normal RNA splicing and reduction of progerin levels.”

Additionally, it was reported that a single injection of adenine base editor-expressing AAV9 at postnatal day 14 greatly extended the median lifespan of mice from 215 to 510 days.

As this research was conducted in mice, it is difficult to determine whether it would be possible to upscale this CRISPR gene-editing technology in humans. However, the investigators concluded in their study that: “these findings demonstrate the potential of in vivo base editing as a possible treatment for HGPS and other genetic diseases by directly correcting their root cause.”

Link: https://www.regmednet.com/new-crispr-technology-helps-revolutionize-gene-therapy/