CRISPR base editing corrects mutation that causes lung disease

A genome editing approach has been used to correct a disease-causing genetic variation in people, for the first time.

Researchers from Beam Therapeutics, Cambridge, Massachusetts, reported the initial results of their ongoing clinical trial, which seeks to treat the underlying cause of alpha-1 antitrypsin deficiency (AATD). In this early trial, patients receive a single dose of a DNA 'base editor', an approach in which CRISPR enzymes have been modified to not cut the DNA as usual, but instead convert one specific nucleotide (or 'letter') in a person's genome to another. After one month, the total amount of alpha-1 antitrypsin in these patients' blood increased, while the amount of the harmful 'mutant' form decreased, without evidence of serious side-effects.

'These data represent a major breakthrough in the area of AATD, offering, for the first time ever, an opportunity to simultaneously treat the lung and liver disease associated with the condition by targeting the root cause and the potential for a cure from a single therapeutic administration, something which we have never seen before in a genetic lung disease,' said Professor Noel McElvaney from the Royal College of Surgeons in Ireland, an investigator on the trial.

AATD is caused by both copies of the gene which encodes alpha-1 antitrypsin having a particular sequence (or 'mutation') that makes a toxic version of the protein, which can then cause disease in the lungs or liver. AATD, which occurs in about one in 2500 people, is currently incurable, with treatments only aiming to reduce symptoms.

As this experimental treatment changes the patients' DNA, it is hoped that it will lead to both a long-term reduction of the toxic protein while providing physiological amounts of the regular healthy version, neither of which would be easily achieved by providing synthetic alpha-1 antitrypsin.

This approach differs from previous genetic therapies, in that it is not just either inactivating a harmful gene, or providing a beneficial one, but doing both simultaneously.

The treatment is delivered in a lipid nanoparticle containing RNA, similar to COVID vaccines. Unlike those vaccines, however, these are delivered intravenously and modified to target the liver, which is where alpha-1 antitrypsin is produced. The RNA within includes a mRNA encoding the base editor – a modified CRISPR/Cas enzyme that converts adenine to guanine – and a guide RNA, which directs the base editor to the location of the gene encoding alpha-1 antitrypsin in the genome.

This is only a preliminary report of a small, early-stage trial on nine patients, covering the first part of the trial, which tests the lowest doses in AATD patients with lung disease. As the trial continues it will test delivery both of higher doses and into patients with liver disease.

'…like all genetic interventions, we have to follow up for a long time to make sure it's as good as we think it is,' Professor McElvaney told the New York Times.