First gene-editing treatment injected into the blood reduces toxic protein for up to 1 year | Science

The first team to disable a disease gene directly in a person through an infusion of the genome editor CRISPR reported yesterday that levels of the toxic protein made by the gene dropped as much as 93% for up to 1 year. The researchers hope the long-term reduction means patients in the clinical trial will soon show clear improvement in their nerve symptoms and that these benefits will persist for an extended period.

“It is quite remarkable that this first [intravenous] CRISPR-based gene-editing effort has been so successful,” says gene therapy researcher Terence Flotte of the University of Massachusetts Medical School, who was not involved with the study. “This demonstrates great potential for the power of this platform clinically.”

People who have inherited a gene mutation responsible for a condition known as transthyretin (TTR) amyloidosis can develop nerve pain, numbness, and heart failure as adults. The genetic defect results in buildup in nerves and organs of a misfolded version of TTR, a protein made by the liver. Last year, the companies Intellia Therapeutics and Regeneron Pharmaceuticals began to inject TTR patients with a fat particle carrying messenger RNA coding for CRISPR’s DNA-cutting enzyme, Cas9, and an RNA strand that guides it to snip the TTR gene in the liver; cells then repair the break imperfectly, disabling the gene’s production of the protein.

In June 2021, the companies reported that 1 month after six patients received an injection of this in vivo CRISPR treatment, their blood levels of TTR fell sharply. Although there wasn’t yet documented improvement in the patients’ symptoms, Science named those results, along with early data from a study using in vivo CRISPR to treat inherited blindness, one of the runners-up for its 2021 Breakthrough of the Year.

In a trial update yesterday the companies reported in a press release and data slides that the treatment has still led to no major safety problems. And the blood levels of TTR—on average just 7% to 59% of their pretreatment levels, depending on which of four CRISPR doses people received—remained stable in a total of 15 people treated between 2 and 12 months ago.

The durable reduction was what the companies expected based on earlier tests in mice and monkeys. Still, there remained a chance that as a person’s edited liver cells turn over, which happens over 200 to 300 days, TTR levels would rebound, if young cells arose that the editing did not reach. “We’ve been waiting for the definitive answer,” says Intellia President and CEO John Leonard.

The researchers don’t yet know whether the patients, who already have nerve pain and numbness throughout their body, will improve on neurological tests or whether the treatment may just stabilize the disease. Because peripheral nerves involved in pain and sensation take time to recover from the buildup of TTR, those tests are usually done 1 year after treatment, says Intellia Chief Medical Officer David Lebwohl.

Approved drugs that knock down TTR levels by 80% lead to symptom improvements, spurring optimism that CRISPR will do the same with a one-time treatment. “I think people are generally assuming that the clinical outcomes will follow,” says gene-editing researcher and cardiologist Kiran Musunuru of the University of Pennsylvania, who works on CRISPR treatments for heart disease that are also infused directly in a patient.

The companies continue to enroll TTR amyloidosis patients with widespread nerve pain or numbness as well as people with a cardiac form of the disease. Intellia is also using a similar CRISPR treatment to edit a liver gene in people with hereditary angioedema, which causes severe swelling of limbs and airways.

Despite its progress in the clinic, the company faced a potential business setback yesterday when the University of California (UC), Berkeley, lost a legal battle over the patent rights to using CRISPR for medicines to the Broad Institute. Intellia had licensed the UC Berkeley technology and will now need to negotiate rights with the Broad Institute of MIT and Harvard.