Scientists have developed a type of gene preparation, creating an experimental treatment that aims to offer great promise for the treatment of high cholesterol – a diagnosis that will affect tens of millions of people. Americans, and linked to a number of serious health problems.
In a new study conducted with mice, researchers used injections of a newly formed lipid nanoparticle to deliver the CRISPR-Cas9 genome editing components to live animals, with one picture of the treatment lowering cholesterol levels low-density lipoprotein (LDL) by up to 56.8 percent.
In contrast, an FDA-approved lipid nanoparticle delivery system (or LNP; bioavailable tiny fat capsule) could only reduce LDLs by 15.7 percent in a test.
Of course, so far these results have only been confirmed in mice, so the new treatment will take a lot of further testing before we know it is safe and just as effective in humans. But based on these results so far, there are promising signs.
The way the treatment works involves a gene in humans called Angiopoietin-like 3 (Angptl3), which releases proteins that prevent the breakdown of some fat in the bloodstream. .
People with a mutation in this gene tend to have lower triglycerides of fat and cholesterol in their blood – not showing other types of health problems – and for years scientists have been experimenting with the process reconstruction, with treatments that effectively signal the effect of the mutation.
“If we can reproduce that condition by breaking down the Angptl3 gene in others, we have a good chance of finding a safe and long-term solution to high cholesterol,” says biochemical engineer Qiaobing Xu from Tufts University.
“We need to make sure we deliver the gene preparation package specifically to the liver so that we don’t create unwanted side effects.”
In the new research, Xu’s team developed a new form of LNP called 306-O12B to target the gene, extracting therapeutic effects in wild-type C57BL / 6 mice that survived at stable levels for 100 days out after only one injection of the treatment.
In addition to the cholesterol reduction, the trial produced a 29.4 percent reduction in triglycerides in the blood of the animals, but the FDA-approved delivery method showed only a 16.3 percent reduction.
The work was built on conclusions published a year or two ago, when Xu’s lab was looking for new ways to turn the efficiency of targeted genomic editing through LNPs, thanks to optimizations that gave molecular structure of tail fingers on it.
By packaging the LNP envelopes with strands of engineered messenger RNA (mRNA) and single-stranded RNA (sgRNA) targeting the Angptl3 gene, the researchers were able to use CRSIPR technology to eliminate it. At the same time, this reduces the production of the Angptl3 protein by about two-thirds (65.2 percent), which helps the body break down fat before it builds up in the bloodstream.
“Importantly, no evidence of off-target mutagenesis at nine potential sites was observed or any liver toxicity,” the researchers explain in their paper.
“The system we have established here offers a clinically feasible approach to the specific delivery of CRISPR-Cas9-based liver genome editing devices.”
The team suggests that the effectiveness of the culling treatment in humans would be about the same as in mice, with the effects of the treatment lasting up to a year (not that their own results confirm that still), due to slow turnover of cells in the liver.
Until we know more about how 306-O12B may be involved in human bodies, this formulation of cholesterol lowering medication will not be available in your local pharmacy.
But with a subsequent test, it is possible one day, the researchers think.
“The results of this study could improve the systematic delivery of the CRISPR genome editing tool in the clinic,” the authors explain.
“To achieve the final clinical application, more detailed preclinical studies should be performed for future malignancy tolerance, off-target effects, and efficacy in large animals.”
The results are reported in PNAS.