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
Gates backs gene technologies in fight to end malaria
on April 18, 2018 at 11:22 am
LONDON, April 18 (Reuters) - Gene-editing technologies that alter mosquitoes’ DNA could prove critical in the fight against malaria, Bill Gates said on Wednesday, and ethical concerns should not block progress in such gene-modifying research. Speaking at ... […]
Leptin's neural circuit identified—Genome-editing study reveals how hormone helps prevent both obesity and diabetes
on April 18, 2018 at 10:01 am
Subsequently, however, most scientists had discarded that idea because deleting leptin receptors in AgRP neurons using the popular Cre-LoxP gene editing system had failed to replicate either obesity or diabetes found in mice bred to lack leptin receptors. […]
Breakthrough CRISPR Gene Editing Trial Set to Begin This Year
on April 16, 2018 at 3:08 am
Biotech company CRISPR Therapeutics is set to treat Europe’s patients with the CRISPR gene-editing tool this year following regulatory approval for trials. Researchers will apply the much-hyped tool to patients with beta thalassaemia, an inherited ... […]
Is This Tomato Engineered? Inside the Coming Battle Over Gene-Edited Food
on April 15, 2018 at 2:56 pm
Zachary Lippman, a plant biologist at Cold Spring Harbor Laboratory, stood among 2 acres of his experimental crops, including some altered with a gene-editing technology called Crispr-Cas9, one of the most ambitious efforts yet to improve on what nature ... […]
Is Gene Editing the Future of Farming?
on April 15, 2018 at 10:50 am
A research team at Cold Spring Harbor Laboratory is developing higher-yielding tomato plants with a gene-editing tool called Crispr-Cas9. Are these products different from traditional GMOs? Photo: Richard Beaven for The Wall Street Journa […]
Brainstorm Health: Gene Editing Arms Race, Pfizer Duchenne Drug, Concentrated Caffeine
on April 15, 2018 at 8:52 am
Happy Friday, readers! This is Sy. In recent years, the advent of gene editing and cell-engineering technologies to fight rare diseases, cancer, and a number other serious conditions has taken the biopharma world by storm across the globe. The Food and ... […]
Breakthrough brings gene-editing medicine one step closer to patient applications
on April 13, 2018 at 2:42 pm
A UAlberta study led by Basil Hubbard is bringing gene-editing technology closer to therapeutic reality by making it more precise. Credit: Ross Neitz Imagine a future where a guided biomachine put into your body seeks out defective gene sequences in each ... […]
Gene-editing patient applications closer with new technique
on April 13, 2018 at 11:20 am
April 13 (UPI) --A new technique in gene editing greatly improves the technology's precision, so much so that it may one day treat some genetic diseases, according to a new study. At the University of Alberta, researchers have improved the accuracy using ... […]
Bill Gates says it would be a 'tragedy' to pass up a controversial, revolutionary gene-editing technology
on April 12, 2018 at 6:58 am
Bill Gates is advocating for the use of genetic editing tools like CRISPR. CRISPR allows scientists to edit DNA, eliminating undesirable genes and potentially swapping in preferable alternatives. Gates thinks we could use genetic editing to make livestock ... […]
via Google News and Bing News