CRISPR Treatment Cuts Cholesterol by Up to 57% in a Single Shot

Scientists have improved upon a form of gene-editing therapy, creating an experimental treatment that looks to hold great promise for treating high cholesterol – a diagnosis affecting tens of millions of Americans, and linked to a number serious health complications. In new research conducted with mice, researchers used an injection of a newly-formulated lipid nanoparticle to deliver CRISPR-Cas9 genome editing components to living animals, with a single shot of the treatment reducing levels of low-density lipoprotein (LDL) cholesterol by up to 56.8 percent. In contrast, an existing FDA-approved lipid nanoparticle (or LNP; a tiny, biodegradable fat capsule) delivery system could only manage to reduce LDLs by 15.7 percent in testing. Of course, these results have so far only been demonstrated in mice, so the new therapy will take a lot of further testing before we know it’s both safe and equally effective in humans. But based on these results so far, signs are promising.

The way the treatment works relates to a gene in humans called Angiopoietin-like 3 (Angptl3), which produces proteins that inhibit the breakdown of certain fats in the bloodstream. People with a mutation in this gene tend to have lower amounts of fatty triglycerides and cholesterol in their blood – without showing other kinds of health complications – and for years scientists have been trying to recreate the process, with treatments that effectively mimic the effects of the mutation.

If we can replicate that condition by knocking out the Angptl3 gene in others, we have a good chance of having a safe and long term solution to high cholesterol,” says biomedical engineer Qiaobing Xu from Tufts University. “We just have to make sure we deliver the gene editing package specifically to the liver so as not to create unwanted side effects.

In the new research, Xu’s team developed a new formulation of LNPs called 306-O12B to target the gene, producing therapeutic effects in wild-type C57BL/6 mice that lasted at stable levels for 100 days after just a single injection of the treatment.

In addition to the cholesterol reduction, the experiment produced a 29.4 percent decrease in triglycerides in the animals’ blood, whereas the FDA-approved delivery method showed only a 16.3 percent reduction.

The findings are reported in PNAS.

CRISPR Treatment Destroys Cancer Cells

Researchers at Tel Aviv University (TAU) have demonstrated that the CRISPR/Cas9 system is very effective in treating metastatic cancers, a significant step on the way to finding a cure for cancer. The researchers developed a novel lipid nanoparticle-based delivery system that specifically targets cancer cells and destroys them by genetic manipulation. The system, called CRISPR-LNPs, carries a genetic messenger (messenger RNA), which encodes for the CRISPR enzyme Cas9 that acts as molecular scissors that cut the cells’ DNA.

The revolutionary work was conducted in the laboratory of Prof. Dan Peer at TAU. Dr. Daniel Rosenblum led the research together with Ph.D. student Anna Gutkin and colleagues.

To examine the feasibility of using the technology to treat cancer, Prof. Peer and his team chose two of the deadliest cancers: glioblastoma and metastatic ovarian cancer. Glioblastoma is the most aggressive type of brain cancer, with a life expectancy of 15 months after diagnosis and a five-year survival rate of only 3%. The researchers demonstrated that a single treatment with CRISPR-LNPs doubled the average life expectancy of mice with glioblastoma tumors, improving their overall survival rate by about 30%. Ovarian cancer is a major cause of death among women and the most lethal cancer of the female reproductive system. Most patients are diagnosed at an advanced stage of the disease when metastases have already spread throughout the body. Despite progress in recent years, only a third of the patients survive this disease. Treatment with CRISPR-LNPs in a metastatic ovarian cancer mice model increased their overall survival rate by 80%.

The CRISPR genome editing technology, capable of identifying and altering any genetic segment, has revolutionized our ability to disrupt, repair or even replace genes in a personalized manner,” said Prof. Peer. “Despite its extensive use in research, clinical implementation is still in its infancy because an effective delivery system is needed to safely and accurately deliver the CRISPR to its target cells. The delivery system we developed targets the DNA responsible for the cancer cells’ survival. This is an innovative treatment for aggressive cancers that have no effective treatments today.

This is the first study in the world to prove that the CRISPR genome editing system can be used to treat cancer effectively in a living animal,” explained Prof. Peer. “It must be emphasized that this is not chemotherapy. There are no side effects, and a cancer cell treated in this way will never become active again. The molecular scissors of Cas9 cut the cancer cell’s DNA, thereby neutralizing it and permanently preventing replication.”

The results of the groundbreaking study were published in November 2020 in Science Advances.

Source: https://english.tau.ac.il/
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 https://www.eurekalert.org/