Genome editing reduces cholesterol in monkeys

Scientists say human trials will follow in five to ten years.

In a new study, scientists describe how they used gene editing to successfully inactivate the production of a protein called PCSK9 which helps our body regulate low-density lipoprotein (LDL) – the “bad” – cholesterol.

According to the Centers for Disease Control and Prevention, 78 million adults in the United States had high levels of LDL that needed treatment in 2012. Statins have been the go-to drugs since the 1980s, but they come with common side effects like muscle pain, and don’t work for some people.

This is where PCSK9 inhibitors come into play. These monoclonal antibodies were approved by the FDA in 2015. Currently, patients get PCSK9 inhibitors as injections every few weeks. Scientists are hoping that gene editing might offer more sustainable and effective long-term treatment.

We spoke with one of the authors Lili Wang of the University of Pennsylvania about the work.

ResearchGate: Why is PCSK9 relevant for heart disease patients?

Lili Wang: PCSK9 helps our body regulate LDL cholesterol, or “bad” cholesterol. PCSK9 is secreted in the liver where it helps break down LDL receptor—the receptor that removes LDL from blood and maintains LDL homeostasis. Genetic studies have shown that mutations in the PCSK9 gene that block its function are associated with low serum LDL and reduced risk of coronary heart disease.

RG: Since PCSK9 can be inhibited with drugs, why do we need a new way to do it?

Wang: The therapeutic effects of these drugs are short-lived, so patients who can tolerate them require repeated injections every few weeks. Gene editing can permanently alter the genome in target liver cells, hepatocytes, so one drug treatment can last much longer.

RG: How successful was the gene editing approach at lowering the monkeys’ cholesterol in your study?

Wang: A single injection of AAV8-M2PCSK9 vector reduced serum LDL levels by 30‒39 percent in the two treated monkeys, which is a very promising result.

RG: Can you briefly explain how the gene editing technique you tested works?

Wang: The DNA-cutting enzyme (meganuclease) engineered by our collaborators at Precision Biosciences recognizes a specific DNA sequence in the PCSK9 gene. After binding to the target region, the meganuclease cuts the DNA at specific sites creating unnatural breaks in the DNA chain. The cell’s DNA repair machinery mends this break and, in the process, deletes or inserts a fragment of DNA in the region—this disrupts the function of PCSK9.

RG: Do you think this will one day be attempted in humans? When?

Wang: I think so, but we are 5‒10 years away from testing this approach in humans. First, we have to make many improvements and thoroughly evaluate and characterize this technology in large animal models to ensure both safety and efficacy.

RG: Have there been any genome editing clinical trials for other conditions in humans? If so, to what extent are they relevant for moving this research forward?

Wang: Yes, there are quite a few clinical trials based on ex vivo genome editing in patient cells, where the altered cells are then transferred back into the patient for a therapeutic effect. Sangamo Therapeutics is doing very exciting in vivo trials using zinc-finger nuclease-mediated gene targeting to treat hemophilia B, mucopolysaccharidosis I and mucopolysaccharidosis II. If these trials are successful it will be very encouraging for us. However, their approach is more challenging because it requires co-transduction of three vectors and homology-directed-recombination, compared to our single vector-mediated gene disruption approach.

RG: Could your method be adapted for other medical applications?

Wang: Yes, we can engineer the meganuclease to target other disease-relevant genes, although this will require additional research and development.

RG: What’s next for this research?

Wang: Next steps will focus on optimizing the meganuclease, vector components, and the delivery system to improve overall specificity and safety.

Featured image courtesy of Jonathan Forage.