In a landmark study, researchers successfully used CRISPR to directly edit DNA in humans, a milestone that could pave the way for treatments for scores of serious genetic and non-genetic diseases.
Intellia, a biotech co-founded by 2020 Nobel laureate Jennifer Doudna, used CRISPR-Cas9 to cut a gene out of the liver cells of patients with ATTR amyloidosis, a deadly disease where a misshapen protein called TTR builds up and damages organs throughout the body. Patients who received a high dose of the therapy saw their protein levels fall between 80% and 96%, indicating the therapy permanently cut the genome where desired.
The Phase I results were published Saturday in the New England Journal of Medicine and presented at a scientific conference.
“This is the result that the field has been waiting for to really scale up,” Fyodor Urnov, a gene editing expert at UC-Berkely who was not affiliated with the work, told Endpoints News. “If anyone had a shred of doubt, that there was a future in CRISPR editing as a therapeutic that will have a broad impact, those doubts can be put to rest.”
This is not the first time CRISPR has been used as a therapy. Vertex and CRISPR Therapeutics have used it to effectively treat sickle cell disease and beta-thalassemia. Academics and other companies have, with somewhat less success, used it in treatments for cancer and HIV. But in each case, researchers removed blood stem cells from the patients, edited them in a lab and then returned them to the patient — a simpler, safer and more controllable procedure.
Most conditions, though, can’t be addressed by editing cells outside the body. Devastating genetic diseases such as cystic fibrosis and Duchenne muscular dystrophy could be treated through CRISPR gene editing, but only if researchers can deliver the therapy directly into patients. The same holds true for some of the more common ailments where companies are now trying to apply the technology, such as heart disease.
On Saturday, Intellia became the first to pull it off. Doudna hailed it as a proof-of-concept for the entire field.
“While these are early data, they show us that we can overcome one of the biggest challenges with applying CRISPR clinically so far, which is being able to deliver it systemically and get it to the right place,” Doudna said in an email. “It’s a critical first step in being able to inactivate, repair or replace any gene that causes disease, anywhere in the body. This opens up the possibility to treat a wide range of diseases that we haven’t been able to address so far.”
Intellia began working on the ATTR program not long after it was founded in 2014, said CEO John Leonard. They tinkered for years, after the first versions edited less than 2% of targeted cells in mice. Eventually, they devised two RNA strands, one that codes for the DNA-cutting enzyme Cas9 and another, the guide RNA, that tells Cas9 which gene to cut.
They encased the RNA in a lipid nanoparticle, the microscopic bubbles of fat that have now been used around the world to deliver mRNA Covid-19 vaccines. After the LNPs are administered to patients, they go to the liver, express Cas9, which slices the DNAs and flush out within hours, said CSO Laura Sepp Lorenzino.
“Part of our design criteria was rapid elimination,” Lorenzino told Endpoints.
The first three ATTR patients, who received a low dose of the therapy, saw their production of TTR protein fall by an average of 57%. When they escalated for the next three patients, they saw an average reduction of 87%.
The latter figure closely rivals the data from Alnylam’s RNAi drug Onpattro, one of three drugs recently approved for the disease. But Intellia’s approach only has to be dosed once in a lifetime, as opposed to once every three weeks.
“The level of TTR protein reduction is impressive,” Harvard biochemist David Liu, who co-founded CRISPR companies Beam and Prime, said in an email. The data “serve as a compelling reminder that the era of in vivo therapeutic human gene editing is already upon us.”
Liu noted Intellia got results despite using less than 1/10th the dose they used in monkeys. The company plans to up the dosage further to try to completely eliminate protein production — a benchmark they hope will not only stop the disease’s progression but potentially reverse it, giving the body time to clean up that misshapen protein that accumulated in the years prior to therapy.
Outside experts took particular note of the safety data. It was not clear what would happen when researchers first administered Cas9, a protein derived from bacteria, throughout the body. Some feared that the immune system would recognize it as foreign and go into dangerous overdrive.
“The safety data look really good,” Alexis Komor, who runs a gene editing lab at UC San Diego, told Endpoints. “There’s no crazy immune response. That was a question that everybody’s had for a while.”
Still, there are key safety questions that can only be answered with time. Over the last decade, CRISPR researchers have documented in numerous lab studies that, by breaking the DNA in two, Cas9 can inflict unintended damage on the genome.
So far those have not born out in patients and experts say there’s no red flags in Intellia’s data. But it will be harder for Intellia to monitor than for previous companies who edited blood cells; they were able to check in the lab how the cells responded initially and take subsequent samples from patients to monitor.
By contrast, doctors can’t just remove a patient’s liver to monitor for early signs of cancer. “There’s just a fundamental question of how we do long-term followup,” Urnov said.
The company will now look to apply the same strategy they used for ATTR to another genetic disease, hereditary angioedema, swapping out the guide RNA for TTR and replacing it with one for a gene called KLB1.
Urnov said the technology will work like mRNA vaccines: Once proven, the platform can be redeployed for another disease by swapping out one set of genetic instructions for another. It provides a proof of principal for Verve Therapeutics, which is trying to prevent heart disease by knocking out a gene in the liver that strongly affects cholesterol levels.
For these companies, he said, “the ball is in your court,” he said, “to do it and just not drop the ball.”
But that only applies to a subset of therapies and diseases. Intellia effectively went after the lowest hanging fruit for systemic CRISPR treatments. They directed the treatment against the liver, the body’s internal filter and the easiest organ to direct genetic therapies. And they only tried to cripple a gene, rather than repair one.
To tackle most of the diseases scientists envisioned curing when CRISPR was first pioneered a decade ago, researchers will have to prove they can deliver throughout the body and, once there, turn a mutant gene into a healthy one — a pair of significantly higher hurdles.
Early tests for those hurdles will arrive in the coming years, as therapies for Duchenne and HIV, among others, enter the clinic.
“It’s an exciting day, it’s an exciting milestone,” Rodolphe Barrangou, an early CRISPR researcher and a co-founder of Intellia, told Endpoints. “But we have a ways to go.”