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
- Raymond James Picks Editas Medicine Over Gene Editing Rival on September 21, 2018 at 6:33 am
Gene editing stocks have cooled in recent months after a big start to 2018. However, CRISPR Therapeutics AG (NASDAQ:CRSP) and Editas Medicine Inc (NASDAQ:EDIT) are back in focus today following analys... […]
- Gene editing pioneer (and Hilo High grad) has warm homecoming on September 20, 2018 at 4:50 pm
Jennifer Doudna is a proud 1981 graduate of Hilo High School. She's also one of the world's most recognized scientists in the world, after co-inventing CRISPR-Cas9 gene editing, which is seen by many ... […]
- Why the Gene Editors of Tomorrow Need to Study Ethics Today on September 18, 2018 at 3:00 am
October 2018. Subscribe to WIRED. Two years after biochemist Jennifer Doudna helped introduce the world to the gene-editing tool known as Crispr, a 14-year-old from New Jersey turned it loose on a pet... […]
- CRISPR gene editing creates cocaine-proof mice, aims to crack addiction puzzle on September 17, 2018 at 3:23 pm
Gene editing has already given us malaria-resistant mosquitoes and heat-resistant cows. Now, researchers from the University of Chicago may have topped both of those feats with their latest ... […]
- These Companies Want to Combine Stem Cells and CRISPR Gene Editing to Treat Diabetes on September 17, 2018 at 2:38 pm
Some news from the land of CRISPR gene-editing to start off this week: The appropriately named CRISPR Therapeutics—a biotech that, it should be noted, was co-founded by Dr. Emmanuelle ... […]
- This Gene-Editing Biotech Toppled On A Deal In Diabetes on September 17, 2018 at 12:12 pm
Crispr Therapeutics (CRSP) stock toppled Monday after the biotech announced a collaboration deal with privately held ViaCyte to work on a gene-edited diabetes treatment. ViaCyte is working on a diabet... […]
- Rice gene editing research cited as among world-changing science on September 14, 2018 at 6:17 am
Research published by a University of Arkansas System Division of Agriculture scientist has been recognized by an international publisher for its high-impact potential. Vibha Srivastava, professor of ... […]
- Gilead Inks Gene Editing Collaboration Deal for HBV Infection on September 13, 2018 at 9:04 am
Gilead Sciences, Inc. GILD announced that it has entered into a strategic collaboration with privately held Precision BioSciences to develop therapies aimed at eliminating hepatitis B virus (HBV ... […]
- Kansas Wheat Commission to fund gene editing research at Kansas State University on September 12, 2018 at 7:35 am
The Kansas Wheat Commission has announced that it is putting its support behind a technology being advanced at Kansas State University and that one researcher says will bring “many new discoveries” in ... […]
- Early results boost hopes for gene editing on September 11, 2018 at 5:33 pm
PHOENIX—Early, partial results from a historic gene editing study give encouraging signs that the treatment may be safe and having at least some of its hoped-for effect, but it's too soon to know whet... […]
via Google News and Bing News