Intellia’s first CRISPR gene editing therapy shows promise in small study

A single infusion of the treatment kept levels of a disease-causing protein low for up to a year in people with a rare disorder.

Intellia Therapeutics headquarters in CambridgeIntellia Therapeutics

Intellia Therapeutics has moved one step closer to its ambition of creating one-and-done gene editing treatments for people with genetic diseases.

Last August, the Cambridge company and its partner, Regeneron Pharmaceuticals, published a landmark study showing that even low doses of their one-time treatment based on CRISPR-Cas9 technology could dramatically reduce levels of a disease-causing protein made in the liver of people with a rare condition called transthyretin amyloidosis.

“The takeaway on that day was this stuff can work,” said Intellia chief executive John Leonard. But questions remained, including how consistent the treatment is from person to person, and how long its effect lasts, he added.

Since August, Intellia has expanded its small clinical trial from 6 to 15 people and tested a total of four doses of its treatment. New data releasedMonday suggest the highest dose of the treatment worked even better than the initial doses tested last year, and that the treatments were durable. “Thus far, we have not seen any loss of effect,” Leonard said.

Dr. Vaishali Sanchorawala, director of the Amyloidosis Center at Boston University School of Medicine and Boston Medical Center, said that longer-term follow up of the patients will be needed to see if the treatment can eventually reverse organ damage caused by the disease, but she is encouraged by the results so far. ”CRISPR gene editing for transthyretin amyloidosis is going to be the revolutionary treatment for this rare disease,” she said. “This is truly an epic moment.”

It’s hard to predict how long the effect will last, but the tests of the treatment in monkeys lead the company to believe it “will be long-lasting, potentially lifelong,” said Intellia’s chief scientific officer Laura Sepp-Lorenzino.

Intellia is one of several Boston-area companies developing CRISPR therapies for an array of genetic diseases. For instance, CRISPR Therapeutics and Vertex Pharmaceuticals are using gene editing to treat sickle cell disease, although their approach involves removing a patient’s blood cells, editing them in a lab, and then reinfusing them.

To treat transthyretin amyloidosis, Intellia must infuse its therapy directly into the bloodstream, where it travels to the liver and deactivates a gene that produces a toxic protein. In November 2020, Intellia became the first biotech to infuse a CRISPR therapy directly into the body when its transthyretin amyloidosis clinical trial began.

The inherited form of transthyretin amyloidosis Intellia hopes to treat is rare, affecting only about 50,000 people worldwide. The disease is caused by a genetic mutation that disrupts the shape of the protein transthyretin. The misshapen protein accumulates in and damages parts of the body, especially the heart and nerves. Although there are approved treatments for the disease that can reduce the protein, they must be taken regularly. Intellia hopes that a single CRISPR treatment could reduce transthyretin permanently.

Intellia’s therapy uses Cas9, a CRISPR enzyme that scientists often liken to a pair of molecular scissors. It essentially breaks the gene for transthyretin, and reduces the production and buildup of the protein.

In August, Intellia showed that its lowest dose cut transthyretin levels in half a month after infusion. A medium dose went even further, causing transthyretin in the blood to drop by 87 percent. The new data shows the largest dose tested cuts the toxic protein by 93 percent.

“You want to remove as many molecules of it as you can,” Leonard said. The goal is to get to the point where the amount of transthyretin protein removed from tissues exceeds the amount that is stored. “That is when you not only halt progression of disease, but you have prospects to actually have patients improve over time.”

“This clinical work is a clear advance in the treatment of transthyretin amyloidosis,” said Lorena Saelices Gomez, who studies the disease at the University of Texas Southwestern Medical Center.Existing gene silencing treatments for the disease are promising when administered early but have “limited effects” at advanced stages of the disease, she added. “If CRISPR-based technologies could bypass this problem, and since this disease is often diagnosed late, gene therapy could represent a powerful alternative for advanced [transthyretin] amyloidosis cases.”

Intellia’s initial focus has been on making sure its therapy is safe, and finding the optimal dose to study in a larger group of people. So far, the treatment seems mostly safe. One person who got the highest dose experienced serious vomiting, although the patient had a history of gastroparesis, a stomach condition in which nausea and vomiting are common. The company will need to track its patients’ progress to ensure that problems don’t arise over the long term.

The study is not equipped to determine how just how big of a difference the transthyretin reduction actually makes in a person’s life. “That will take longer” to determine, Leonard said. “But we know from prior work that clinical benefits, when they come, are a function of the transthyretin reduction.”