Scientists know that there is a link between a protein called PCSK9 and cholesterol; when the protein is not active, cholesterol levels go down. Therapies that aim to use this relationship to the patient’s advantage have focused on inhibiting drugs. A new study has used gene editing to inactivate the protein in rhesus macaque monkeys; the researchers were able to successfully lower cholesterol levels in those monkeys. This work, reported in Nature Biotechnology, may open up new approaches for treating patients with heart disease that cannot take PCSK9 inhibitors, which are often used to control high cholesterol.
In healthy people, PCSK9 can stop receptors from taking up excess bad cholesterol, called LDL, in the liver. It’s been found that drugs that inhibit the PCSK9 protein can lower cholesterol in people. However, some people with a severe type of cardiovascular disease called hypercholesterolemia cannot take these drugs. This research has shown that gene editing may be helpful for these cases.
"Most often these patients are treated with repeated injections of an antibody to PCSK9," noted first author Lili Wang, Ph.D., a research associate professor of Medicine. "But, our study shows that with successful genome editing, patients who cannot tolerate inhibitor drugs might no longer need this type of repeat treatment."
A Durham, NC biotech called Precision Biosciences coauthored this work. They created an enzyme that could recognize PCSK9, and inactivate it. The enzyme, called a meganuclease, was used along with a molecular tool called an adeno-associated virus (AAV) to target the therapeutics to the liver of the primate research model.
In animals that were exposed to middle- and high-dose AAV vectors, the levels of PCSK9 were reduced from 30 to 60 percent. The AAV vector that was used in this study has been shown in clinical trials to be safe and effective.
"Our initial work with several delivery and editing approaches produced the most impressive data in non-human primates when we paired AAV for delivery with the engineered meganuclease for editing," said senior author James M. Wilson, MD, Ph.D., a professor of Medicine and Pediatrics and director of the Gene Therapy Program at Penn. "We leveraged our 30-plus years of experience in gene therapy to progress the translational science of in vivo genome editing, and in doing so, reinforced the importance of early studies in nonhuman primates to assess safety and efficacy."
The researchers want to be sure that any gene edits they make in patients are limited to the PCSK9 gene. They also need to monitor for effects on the immune system. This work will hopefully help those suffering not only from hypercholesterolemia but a variety of metabolic diseases caused by gene mutations, and which affect the liver.