CRISPR-like technique offers clues to mimic protective genetic mutations
Using a variation of CRISPR gene editing may be a potential strategy for mimicking the protective effects of a genetic mutation linked to lower cholesterol levels and heart disease risks, according to new mouse research from the Perelman School of Medicine at the University of Pennsylvania published this week in Circulation.
People with naturally occurring mutations that cause a loss of function in the gene for ANGPTL3 have reduced blood triglycerides, LDL cholesterol, and risk of coronary heart disease, with no apparent detrimental consequences to their health. This makes the ANGPTL3 protein an attractive target for new heart disease drugs. Earlier studies at Penn found that single copies of inactivating mutations in ANGPTL3 are found in about one in every 250 people of European heritage; however, people with mutations in both copies of the gene are more rare.
A team led by Kiran Musunuru, MD, PhD, MPH, an associate professor of Cardiovascular Medicine, assessed in a mouse model whether base editing – a variation of CRISPR genome editing that does not require breaks in the double-strand of DNA – might be used in humans one day to introduce mutations into ANGPTL3 to reduce blood lipid levels.
“This proof-of-principle study showed that base-editing of ANGPTL3 is a potential way to permanently treat patients with harmful blood lipid levels,” Musunuru said. “It would be especially useful in patients with a rare condition called homozygous familial hypercholesterolemia, which causes sky-high cholesterol levels and dramatically increased risk of heart attack. They are very difficult to treat with today’s medications, and a one-time CRISPR ‘vaccination’ might be ready to use in these patients within five years.”
The study took a three-part approach. First, the team injected normal mice with the base-editing treatment for the ANGPTL3 gene. After a week, sequencing of the ANGPTL3 target site in liver samples from the mice revealed a median 35 percent editing rate in the target gene and no off-target mutations. In addition, the mean levels of blood lipids were significantly lower in the treated mice by up to 30 percent compared to untreated mice.
Second, the researchers compared mice with the modified ANGPTL3 gene to those injected with a base-editing treatment for another liver gene, PCSK9, for plasma cholesterol and triglycerides. After a week, ANGPTL3 targeting caused a similar reduction in cholesterol but a much greater decline in triglycerides compared to targeting PCSK9. The PCSK9 protein is the target of currently available medications, including evinacumab, which has been shown to reduce cholesterol (but not triglycerides) as well as the risk of heart attack and stroke.
Third, they looked at how base editing of the ANGPTL3 gene performed in a mouse model of homozygous familial hypercholesterolemia (in which knocking out PCSK9 had little effect). After two weeks, the treated mice showed substantially reduced triglycerides (56 percent) and cholesterol (51 percent) compared to untreated mice.
Musunuru’s lab is now preparing to test CRISPR-based treatments against the human ANGPTL3 gene in human liver cells transplanted into mice. This will provide important information on efficacy and safety that will be needed before human trials can move forward.
The Latest on: Gene editing
- Gene Editing: Innovation and Impact in Missouri on November 12, 2018 at 11:01 pm
Renowned panelists come together to discuss cutting-edge gene editing technology; how it will help improve human health, grow the food we need with fewer resources, manage environmental changes, and c... […]
- More than 60% of Chinese people view gene editing therapeutics favorably on November 12, 2018 at 9:44 pm
On November 9, 2018, China's first public opinion poll on the therapeutic use of gene editing was released today, with a condensed English version entitled "Report on Chinese Public Attitudes on Gene ... […]
- How moth viruses, magnetic particles and gene editing could cure disease on November 12, 2018 at 6:04 pm
For medical treatments to be most effective, they need to be localized exactly where they're needed, not roam free throughout body and potentially cause other problems. Researchers at Rice ... […]
- Gene Editing: A Powerful Tool That Should Be Used Wisely on November 12, 2018 at 8:03 am
DNA IS THE CODE of life that governs the essence of every organism and drives many disease states, including cancer. Deciphering the language of the genome and the actual nucleotide sequence, using th... […]
- How Religion Shapes Thinking on Gene Editing on November 9, 2018 at 10:09 pm
It is difficult to examine society's acceptance or rejection of key biotech developments without considering the role played by the world's major religions and their belief structures. Christianity, J... […]
- Cambridge's Editas asks FDA to start gene editing trial on November 7, 2018 at 3:46 pm
Cambridge's Editas Medicine could be the next to test the closely watched gene editing technology CRISPR/Cas9 after filing a clinical trial application late last month, the company revealed Wednesday. ... […]
- The Applications and Ethics of Gene Editing on November 7, 2018 at 1:57 am
Biotechnology and genetic engineering have both come a long way. In terms of gene editing, Nobel laureate Sydney Brenner’s words could not be truer: “Progress in science depends on new techniques, new ... […]
- Only the USDA can unlock gene editing’s potential on November 6, 2018 at 6:30 am
The views expressed by contributors are their own and not the view of The Hill Nov. 3 marked One Health Day (www.onehealthcommission.org) – an international campaign to recognize the importance ... […]
- Scientists propose panel to guide gene-editing decisions regarding conservation on November 5, 2018 at 6:45 am
An Oregon State University environmental ethicist and scientists from nine other universities say an international oversight panel is needed to guide decisions about whether and when to employ ... […]
- Editing nature: Scientists call for careful oversight of environmental gene editing on November 1, 2018 at 11:03 am
In Burkina Faso, the government is considering the use of genetically modified mosquitoes to eradicate malaria. In Nantucket, Mass., officials are looking at gene editing as a tool in the fight ... […]
via Google News and Bing News