In-body CRISPR therapy holds four-year effect ahead of FDA decision

A pioneering therapy that edits genes inside a recipient's body continues to be effective four years after treatment, its developer Intellia Therapeutics reported, as U.S. regulators weigh whether to grant it a landmark approval.

The therapy, called lonvoguran ziclumeran (lonvo-z), is designed to treat one form of hereditary angioedema, a rare genetic condition that can cause episodes of painful and potentially dangerous swelling in the throat and other parts of the body. It uses the CRISPR-Cas9 gene-editing system to disable the gene that produces prekallikrein, a protein made in the liver that promotes blood-vessel leakage.

If approved, lonvo-z would become the world's first CRISPR medicine delivered directly inside the body, or in vivo. Intellia, based in Cambridge, Massachusetts, has applied for approval by the U.S. Food and Drug Administration, which is expected to issue a decision by 10 March, chief executive John Leonard told investors on 12 November.

A one-day procedure

All CRISPR therapies approved to date are ex vivo. The only such treatment cleared by the FDA is Casgevy, for sickle-cell disease and beta-thalassaemia. To make a dose, physicians first remove blood stem cells from the recipient, send them for editing, then infuse them back. The therapy must be made anew for each person, adding time and cost, and the recipient must undergo harsh chemotherapy to make room for the edited cells.

Lonvo-z aims to sidestep those concerns. It consists of fatty particles that encase mRNA encoding CRISPR-Cas9 components. The particles are infused into the blood and taken up by the liver, where prekallikrein is produced. The procedure takes one day.

For people with the condition, the approach could offer relief from a lifetime of juggling medications to prevent and treat swelling attacks. "It's very reassuring," Jonathan Bernstein, a hereditary-angioedema specialist at the University of Cincinnati in Ohio and an investigator on a lonvo-z trial, said of the four-year data. "That's what you're supposed to see."

Safety questions remain

In vivo editing carries its own concerns. The approach offers no opportunity to screen out cells with unwanted edits elsewhere in the genome, and recipients might have harmful immune responses. Last year the FDA placed a clinical hold on two of Intellia's in vivo trials for a different disorder.

The four-year results were reported by Intellia; the FDA's pending review will determine whether the therapy reaches patients.