Gene editing successfully lowers monkey cholesterol levels
In one of the first examples of gene-editing technology being effectively used to knock out the expressionof a gene in non-human primates, researchers from the University ofPennsylvania have lowered the blood cholesterol in monkeys bydisabling a single gene in the liver. The successful experiments pavethe way for future human trials in five to 10 years.
The target of the research is awell-known protein called PCSK9. A great deal of prior study hasestablished that PCSK9 is a protein that inhibits the liver's abilityto remove harmful cholesterol. Several drugs have been developed toinhibit the activity of PCSK9 but they are expensive and notconsistently effective.
So some scientists have beeninvestigating ways of genetically inhibiting PCSK9. This new study isthe first to show effective reduction of PCSK9 in the liver throughgene editing in a non-human primate. Rather than the more popular and recent CRISPRgene-editing technique, the study used a slightly older and different techniquecalled meganuclease-based gene-editing.
Identified in the 1990s, meganucleasesare enzymes that can be engineered for precision gene editing. In thecase of this experiment the enzyme was engineered to inactivate thePCSK9 gene and was delivered to the liver by a harmless adeno-associatedvirus. The results were impressive, with the rhesus macaque monkeys showingbetween 45 and 84 percent reductions in PCSK9 levels, and associatedcholesterol levels dropping by up to 60 percent. Analysis of livertissue found effective mutations in 40 to 65 percent of PCSK9 genes.
"Our initial work with severaldelivery and editing approaches produced the most impressive data innon-human primates when we paired AAV for delivery with theengineered meganuclease for editing," says James Wilson, seniorauthor on the new study.
Several other research teams have alsobeen working to switch off PCSK9 genes as a potential treatment forheart disease, and there have been successful experiments using theCRISPR gene-editing technique to silence PCSK9 in mouse models. Theteam at UPenn was unable to successfully replicate these results inprimates, which led them to experimenting with the meganuclease gene-editing method.
The experiments were not withoutunwanted side effects, though. The researchers report the treatmenttriggering a rise in liver enzymes, suggesting a degree of immuneresponse to the treatment. This is not entirely unexpected but maysuggest multiple treatments could results in the body developing amore heightened immune response. Some off-target genetic cuts werealso identified that have the potential to lead to the development of cancers.
It is obviously still very early in thedevelopment of these treatments and the researchers suggest furtherrefinement certainly needs to be done before human trials areconsidered. Lili Wang, one of the authors on the study, thinks thework is about five to 10 years away from human testing.
"First, wehave to make many improvements and thoroughly evaluate andcharacterize this technology in large animal models to ensure bothsafety and efficacy," says Wang.
However, the team is confident thatthis approach could lead to a promising treatment for patientssuffering from more extreme and life-threatening forms of heartdisease. Permanently editing out a gene to help reduce cholesterollevels seems to be a promising future treatment for cardiovasculardisease, but it certainly looks to be at least 10 or 20 yearsaway from real-world clinical use.
The study was published in the journalNature Biotechnology.