*As Verve Therapeutics Begins Human Trials for CRISPR That Could Also Provide Sickle Cell Succour
The CRISPR treatment for high cholesterol is already being touted to be a potential permanent cholesterol lowering antidote. That is, in addition to permanently reducing the risk of a heart attack. That certainly is the mood in research circles as human trials tees off officially in New Zealand.
According to researchers, the new CRISPR, described as a one-and-done regime for high cholesterol control could, If it works as well as it did in animal trials, save countless lives by permanently lowering cholesterol and the risk of a heart attack in human beings.
Developed by Verve Therapeutics, a Cambridge, Massachusetts based outfit founded in 2018, the CRISPR therapy is designed to permanently deactivate a gene in the liver that controls the production of PCSK9, a protein that prevents the removal of excess cholesterol from the body. According to the researchers, the therapy reduced cholesterol level in monkey by 70 per cent in two weeks of clinical trials and kept the levels low for at least two years, a feat that suggests it could also function as well in reducing high cholesterol in human beings.
CRISPR works through a process researchers described as ‘base editing’. Whereas it is sometimes used to cut DNA, it simply exchanges a single letter in the PCSK9 gene for another in treating cholesterol with the CRISPR. More so, rather than follow the traditional approach to gene therapy-using a hollowed-out virus to deliver its CRISPR therapy, Verve deployed nanoparticles to deliver genetic instructions into cells, similar to the ones used to package the mRNA vaccines for COVID-19.
Piter Bosma, who studies liver diseases at the Amsterdam University Medical Centers points out that no apparent harmful side effects were identified in the pre-clinical results in macaques, Macaca fascicularis, published last year. The trials, he adds, showed that the treatment reduced blood levels of PCSK9 by 81% and lowered blood cholesterol levels.
“It could be very promising,” he says
But cautiously optimistic as researchers feel, they are however, on the look-out for any possible off-target genetic changes resulting from the treatment. Apart from the risk of side effects that might be balanced by the benefit of treatment for people with severely high cholesterol levels, there is the need for long-term safety data before any assurance that the treatment can be used more widely.
“Maybe we will know that many years from now, but not for the time being,” Bosma adds.
Indeed, there are still fears that as promising as the CRISPR appears, its potentials may also be limited by the fact that therapies that are often successful in the treatment of animals don’t usual turn out as successful in the treatment of humans. More so that the therapy is a permanent procedure that comes with no undo or reverse button. However, hopes are high that it will turn out a success in human trials given the fact that people born with mutations in PCSK9 that lower their cholesterol also have a significantly lower risk of heart disease.
In the main, the Verve trial aims to edit cells directly in the body. However, the team is reported to have encased the base-editing components, messenger RNA encoding the enzyme required to alter DNA. That is, in addition to an extra snippet of RNA that will direct the enzymes to the correct location in lipid nanoparticles.
In contrast to its liver location, the upcoming sickle-cell trial will use base editing to alter DNA in blood stem cells already extracted from the body which will be reinfused into participants in a trial to be conducted by Beam Therapeutics, another Cambridge based outfit that collaborated with Verve to develop the CRISPR cholesterol base-editing therapy.
Yet, there are more CRISPR derived approaches in place for more inroads into genetics. For instance, apart from the one being developed to treat leukemia and Stargardt’s disease, which can cause blindness, the therapy also came in handy in the development of Alternative Cas enzymes which have been discovered to have only RNA editing ability.
Meanwhile, CRISPR clinical result is expected in 2023.
“It’s very exciting that the first clinical trials are starting, with CRISPR–Cas9 and now also with base editing. We’ve got a lot to learn,” says Gerald Schwank, Researcher in the use of Genome Editing in disease treatment, University of Zurich, Switzerland.