Jim Wilson's team hands Precision Bio a big proxy win for its PCSK9 gene editing tech with 3-year monkey data
James Wilson and his gene editing team at UPenn have published a new paper into a one-time PCSK9 therapy, one that Precision Biosciences hopes can turn up the heat on its competitors at Verve.
Using Precision’s proprietary ARCUS gene editing platform, Wilson was able to demonstrate that PCSK9 protein and LDL cholesterol reductions could be sustained in monkeys for at least three years after treatment, Precision announced Friday. Researchers administered the therapy to 10 monkeys back in 2017 and reported reductions of up to 85% in PCSK9 protein levels and a 56% reduction of LDL cholesterol levels.
Those levels are slightly lower than the figures posted by Verve last month at JP Morgan, when the Sek Kathiresan-led biotech said it observed a 61% LDL cholesterol reduction and 89% cut in average blood PCSK9 protein level. But Verve’s data was recorded after only six months — or one-sixth the time of Precision’s.
That difference in time is significant because Precision’s monkeys have had the chance to go through several generations of liver cell turnover, and the cholesterol and PCSK9 protein reductions have remained stable, CSO Derek Jantz told Endpoints News. Liver cells, or hepatocytes, typically only live for about 200 days before they die off and are replenished.
“What we’ve been able to show is that those subsequent generations of cells are inheriting the gene edit,” Jantz said. “We are beyond the lifetime of a typical non-human primate hepatocyte.”
Friday’s study is a follow-up from a paper published in 2018, which Jantz said demonstrated short-term benefits of their gene editing treatment. At that time, Precision saw PCSK9 reductions of more than 90% at the highest dose, after which they fell slightly over the first nine months when the first liver cells were being replaced.
Since then, the levels have plateaued, giving Precision what it says is early evidence that the treatment can be permanent. Even more promising is that researchers didn’t see any major safety issues manifest in the three years since the monkeys were dosed, Jantz said.
Precision used its ARCUS genome editing platform, coming from a group of North Carolina scientists, which they claim has a better way to accomplish DNA hacking than the gene editing promoted by biotechs working on CRISPR/Cas9 technologies. ARCUS deals with what’s known as the ARC nuclease, and the company says it provides a simpler, more effective way of completing the gene editing process to allow for lower costs when production eventually has to scale up, as well as lower rates of off-target editing.
ARCUS can be used to either insert, remove or repair DNA in in vivo settings. In this instance, the PCSK9 gene was “knocked out,” resulting in lower levels of the protein, Jantz said.
That’s a different approach than the one used by Verve, which is aiming to utilize the next-generation gene editing tool called base editing. Whereas the first generation of CRISPR gene editing molecules would snip the DNA sequence and let it repair on its own, base editing works by converting one letter on the genome to another.
In Verve’s case, researchers made a single change from A to G in the genetic sequence of the PCSK9 gene in the liver.
Both companies are looking at familial hypercholesterolemia as a potential indication, with Verve aiming to dose its first patient in the heterozygous form of the disease sometime in 2022. Precision, however, isn’t giving any timetables as to when it could launch an in-human trial, with Jantz saying any such study is still “a ways away.” Both are aiming to replace chronic treatments for disease with one-time injections.
Though excited by Friday’s results, Precision is not targeting PCSK9 as its lead program. That would be an off-the-shelf CAR-T therapy for acute lymphoblastic leukemia and non-Hodgkin lymphoma, aiming to target CD19. The program read out interim results from a Phase I/IIa trial last December.