In one of the first examples of gene-editing technology being effectively used to knock out the expression
of a gene in non-human primates, researchers from the University of
Pennsylvania have lowered the blood cholesterol in monkeys by
disabling a single gene in the liver. The successful experiments pave
the way for future human trials in five to 10 years.
The target of the research is a
well-known protein called PCSK9. A great deal of prior study has
established that PCSK9 is a protein that inhibits the liver's ability
to remove harmful cholesterol. Several drugs have been developed to
inhibit the activity of PCSK9 but they are expensive and not
So some scientists have been
investigating ways of genetically inhibiting PCSK9. This new study is
the first to show effective reduction of PCSK9 in the liver through
gene editing in a non-human primate. Rather than the more popular and recent CRISPR
gene-editing technique, the study used a slightly older and different technique
called meganuclease-based gene-editing.
Identified in the 1990s, meganucleases
are enzymes that can be engineered for precision gene editing. In the
case of this experiment the enzyme was engineered to inactivate the
PCSK9 gene and was delivered to the liver by a harmless adeno-associated
virus. The results were impressive, with the rhesus macaque monkeys showing
between 45 and 84 percent reductions in PCSK9 levels, and associated
cholesterol levels dropping by up to 60 percent. Analysis of liver
tissue found effective mutations in 40 to 65 percent of PCSK9 genes.
"Our initial work with several
delivery and editing approaches produced the most impressive data in
non-human primates when we paired AAV for delivery with the
engineered meganuclease for editing," says James Wilson, senior
author on the new study.
Several other research teams have also
been working to switch off PCSK9 genes as a potential treatment for
heart disease, and there have been successful experiments using the
CRISPR gene-editing technique to silence PCSK9 in mouse models. The
team at UPenn was unable to successfully replicate these results in
primates, which led them to experimenting with the meganuclease gene-editing method.
The experiments were not without
unwanted side effects, though. The researchers report the treatment
triggering a rise in liver enzymes, suggesting a degree of immune
response to the treatment. This is not entirely unexpected but may
suggest multiple treatments could results in the body developing a
more heightened immune response. Some off-target genetic cuts were
also identified that have the potential to lead to the development of cancers.
It is obviously still very early in the
development of these treatments and the researchers suggest further
refinement certainly needs to be done before human trials are
considered. Lili Wang, one of the authors on the study, thinks the
work is about five to 10 years away from human testing.
have to make many improvements and thoroughly evaluate and
characterize this technology in large animal models to ensure both
safety and efficacy," says Wang.
However, the team is confident that
this approach could lead to a promising treatment for patients
suffering from more extreme and life-threatening forms of heart
disease. Permanently editing out a gene to help reduce cholesterol
levels seems to be a promising future treatment for cardiovascular
disease, but it certainly looks to be at least 10 or 20 years
away from real-world clinical use.
The study was published in the journal