First Clinical Proof of Genetic Mutation Correction for Rare Lung Disease

A groundbreaking clinical trial has achieved what researchers call a landmark moment in medicine: the first-ever precise correction of a disease-causing genetic mutation in patients with alpha-1 antitrypsin deficiency (AATD), a rare inherited disorder that can lead to early-onset emphysema and liver disease.

Beam Therapeutics reported initial data from its phase 1/2 trial of BEAM-302, a novel gene-editing therapy that shows promise in treating this genetic condition.

AAT is a protein made in the liver to help protect the lungs. A deficiency in this protein can lead to chronic obstructive pulmonary disease and may also cause the liver disease cirrhosis.

The study demonstrated that a single intravenous infusion could potentially transform treatment for patients with the most severe form of AATD. The research focused on patients with the PiZZ genotype who have two copies of a mutated gene that causes alpha-1 antitrypsin to misfold and accumulate in the liver, leaving the lungs unprotected from damage.

BEAM-302 is a liver-targeting lipid nanoparticle (LNP) formulation designed to correct the PiZZ mutation, which is the genotype that accounts for the severe AATD population. Company officials said in a presentation that there are about 100,000 patients in the United States who have this mutation, but only about 10% are diagnosed. About 30% of patients have liver disease, including fibrosis and cirrhosis. About 80% of patients have lung disease, including early-onset emphysema, chronic cough, and shortness of breath.

In the trial, patients received varying doses of the experimental therapy, with the highest dose group showing dramatic improvements. At the 60 mg dose level, patients saw a nearly threefold increase in total alpha-1 antitrypsin protein and a 78% reduction in circulating mutant protein. In addition, the treatment achieved levels of functional protein above the protective therapeutic threshold, a key milestone for potential treatment success.

"This landmark result represents the first clinical evidence of precise correction of a disease-causing mutation by rewriting the genetic code," said John Evans, chief executive officer of Beam Therapeutics, in a news release.

Beam’s approach differs from existing treatments by potentially offering a one-time therapy that could address both liver and lung manifestations of the disease. Currently, only about 10% of AATD patients have been diagnosed, and there are no curative treatments approved in the United States. The existing intravenous protein replacement therapy has not been shown to prevent ongoing lung function decline.

In the trial, all adverse events were classified as mild to moderate, with no serious complications reported. The company plans to continue dose escalation and expects to report additional data in the second half of 2025, with potential expansion to patients with mild-to-moderate liver disease.