CTX310 CRISPR Treatment Could Lower LDL Cholesterol After One Dose

Excess levels of ‘bad’ cholesterol in the blood - low-density lipoprotein (LDL) cholesterol - can help plaques accumulate in the arteries. This raises the likelihood of cardiovascular conditions, including heart attacks and strokes.

LDL cholesterol is influenced by several factors, such as genetics, diet and age. High cholesterol is commonly managed with dietary adjustments and statins.

Researchers are developing a targeted DNA-editing method that uses CRISPR technology to create a permanent genetic alteration. A single treatment could potentially provide a lasting reduction in LDL cholesterol.

CTX310 CRISPR treatment targets LDL cholesterol

Known as CTX310, the treatment is designed to replicate a naturally occurring genetic variant that reduces LDL cholesterol by lowering the expression of ANGPTL3, a protein produced in the liver.

Fresh findings from a clinical trial, led by the Cleveland Clinic Coordinating Center for Clinical Research and published in the New England Journal of Medicine, indicate that the method may remain both safe and effective after one year.

"CTX310 was associated with few adverse events and produced sustained changes in the levels of ANGPTL3 and atherogenic lipoproteins at 1 year, further supporting its potential as a one-time treatment," write the researchers in their published paper.

Some individuals are born with loss-of-function variants in the gene responsible for producing ANGPTL3 protein. Lower levels of this protein enable the body to process fats circulating in the bloodstream more effectively, helping to keep cholesterol in balance.

CTX310 is intended to artificially introduce this same genetic alteration, with the aim of producing comparable effects on LDL cholesterol.

One-year clinical trial results

The trial, now assessed again after 12 months, involved 15 people with serious cholesterol- or triglyceride-related health conditions. Triglycerides are a type of fat found in the blood. Participants received an intravenous infusion that delivered nanoparticles carrying the CRISPR instructions.

One participant died 179 days after receiving the treatment, although the researchers determined that the death was not related to CTX310.

Among the remaining 14 participants, the reduced cholesterol and triglyceride profile has been maintained, with no additional serious adverse events reported.

For the four participants given the highest dose of nanoparticles directed to liver cells, known as hepatocytes, ANGPTL3 levels fell by an average of 78.6 percent.

Their LDL cholesterol declined by an average of 52.5 percent, while triglycerides decreased by an average of 47.8 percent.

Although the trial involved only a small number of patients, the initial findings are encouraging and suggest that the treatment merits further development.

"Among patients with lipid disorders, the potential of a one-time treatment to produce a loss-of-function mutation in hepatocytes that mimics natural variants associated with a reduced risk of atherosclerotic cardiovascular disease represents a unique therapeutic opportunity," write the researchers.

A one-off CRISPR treatment could be simpler for patients than therapies requiring daily or weekly administration. The participants were selected specifically because they had lipid disorders that had not responded to conventional medicines.

Further testing of CTX310

Further research, involving more people and longer follow-up periods, is required to establish whether the approach is genuinely viable.

Gene editing carries risks, despite the researchers intentionally targeting variants that occur naturally in some people and have not been linked to harmful effects on their health.

The phase 1a trial described here was the first to include humans. A phase 1b trial is now in progress to expand on these results. Phase 1b is examining a fixed dose equivalent to the highest dose used in the phase 1a trial, which proved particularly effective.

"Efficacy in phase 1b is being assessed in separate cohorts of patients with specific lipid disorders," write the researchers.

The research was published in the New England Journal of Medicine.

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