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Gene Therapy Shown to Reduce Extreme High Cholesterol

Heart check

(Gerd Altmann, Pixabay)

9 July 2018. A gene therapy technique that stops production of a targeted protein is shown in tests with monkeys to reduce levels of harmful cholesterol, but also expose potential risks associated with the technique. A team from the University of Pennsylvania medical school in Philadelphia and the biotechnology company Precision Biosciences in Durham, North Carolina describe the technique and test results in today’s issue of the journal Nature Biotechnology (paid subscription required).

UPenn researchers from the lab of inherited disease specialist James Wilson are seeking better treatment options for people with hypercholesterolemia, a condition marked by high levels of low-density lipoprotein, or LDL, cholesterol. LDL cholesterol, also known as “bad” cholesterol, is produced in the liver and can build up as waxy plaque deposits in arteries, contributing to atherosclerosis, or hardening of the arteries, a risk factor of heart disease.

Hypercholesterolemia can result from lifestyles with little physical activity and high fat diets, but it can also be caused by an inherited condition. The inherited form of hypercholesterolemia results from mutations in the PCSK9 gene that change the chemistry of PCSK9 proteins. Healthy PCSK9 proteins regulate production of LDL cholesterol in the liver, but the mutated forms appear to reduce PCSK9’s regulatory functions, allowing more LDL cholesterol to be produced. Currently approved synthetic antibody drugs on the market can block the actions of mutated PCSK9 proteins, but in some people, the drugs caused serious adverse hypersensitivity reactions.

Wilson and colleagues tested a gene therapy developed by Precision Biosciences that deactivates the mutated PCSK9 gene, thus preventing the gene’s harmful effects. The therapy acts like the genome editing technique Crispr, but instead of removing the offending gene from the genome, a complex synthetic enzyme called a meganuclease developed by Precision Biosciences on the company’s Arcus platform seeks out and silences the gene preventing production of LDL-supporting proteins. The meganuclease enzyme is delivered with engineered adeno-associated viruses, benign microbes designed to transfer genetic-related material, in this case to the liver.

The researchers tested single doses of the therapy at various dosage levels with 6 rhesus macaque monkeys induced with PCSK9 mutations. The middle to high doses of the meganuclease reduced PCSK9 protein levels from 45 to 84 percent, and lowered LDL cholesterol levels as much as 60 percent in the monkey’s blood and livers. DNA remains of the adeno-associated viruses and residual meganuclease declined as well, leaving stable functioning liver cells.

The team highlighted potential risks with the technique, however, that will need to be monitored in future clinical trials.. The monkeys experienced temporary elevations of transaminases in their blood, attributed to immune-system reactions to the meganuclease. Elevated transaminases, while in mild cases do not cause symptoms, are indicators of more serious liver disease. Also, initial tests with transferring meganuclease enzymes caused some off-target edits, which the researchers say was corrected by more precise engineering of the enzyme to focus on the PCSK9 gene.

Precision Biosciences helped fund the project, and owns the process used in the study. However, Wilson and first author Lili Wang are listed as inventors on patents owned by UPenn for technologies related to those in the study, some of which are licensed to other biotechnology enterprises.

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