Researchers have fixed a genetic mutation that causes disease with a single injection carrying treatments that accurately target the false gene.
This was the first time a mutant gene had successfully recovered.
A small study of nine patients, published Monday by Beam Therapeutics in Cambridge, Massachusetts, involved correcting spelling errors involving four base sequences in DNA (G, A, C, T). The effect was to change the incorrect DNA letter to the right letter. The results were normal genes, which are normal genes that could potentially stop liver and lung damage in patients with rare disorders.
“This is the beginning of a new era of medicine,” said Dr. Kiran Musnoor, a gene therapy researcher at the University of Pennsylvania Perelman School of Medicine.
He added that the method provides hope for accurately treating other genetic diseases by modifying mutations. This is an alternative to current gene therapy, in which new gene therapy is added to compensate for mutated genes, or in which genes are sliced to slice genes.
Dr. Musunuru is a co-founder and equity holder of the gene therapy company Verve Therapeutics and receives funding from Beam Therapeutics for the study, but this study does not.
Dr. Richard P. Liton, president of Rockefeller University and head of its human genetics and genomics lab, said something like a gene editing beam would rewrite the gene “the Holy Grail” and “have the promise that it is the only treatment.”
Dr. Lifton is the director of Roche Pharmaceuticals and its subsidiary Genentech.
Despite the small size of the study, he said the results were “a very impressive progress and very promising.”
This study involved patients with alpha-1 antitrypsin deficiency, or genetic diseases affecting an estimated 100,000 Americans, primarily from their European ancestors. This is just as common as sickle cells in this country. It is progressive and incurable.
The alpha-1 antitrypsin protein is produced in the liver and usually goes to the lungs and protects against inflammation from inhaled irritants such as smoke and dust. However, in people with this disease, a single change in the DNA letters of the gene results in altered non-functional proteins. The result is often emphysema or chronic obstructive pulmonary disease in the unprotected lung.
However, many abnormal alpha-1 antitrypsin proteins do not reach the lungs and instead accumulate in the patient's liver, often causing cirrhosis.
Gene editing was easy for patients. They sat in the chair for several hours, but the lipid nanoparticles were injected into the blood, similar to those used in the covid vaccine. However, the nanoparticles did not carry the vaccine. Instead, they wrapped up a microscope gene editor. The lipid casing protected the editor on a journey to the liver.
When the nanoparticles reach the liver, the lipid layer is peeled off and the editor is released. It acted like a genome GPS, and the enzyme acted like an enzyme that corrects mutations. The CRISPR molecule was raw along the patient's DNA until one incorrect letter was found that needed to be repaired between the 3 billion DNA letters in the genome. The editing enzyme then replaced the letter with the correct one.
In this study, patients were divided into three groups and tested three different doses of the gene editor. Those who obtained the highest doses have made regular alpha-1 antitrypsin enough to reach the range where no further damage occurs. According to Beam CEO John Evans, there were no serious side effects.
Beam provides high doses for patients who get lower doses in company research. Beam also studies treatments in more patients and tests higher doses of its gene editor.
“And we have to think about how to approve this right away,” Evans said.
Dr. Noel McKelvanney, professor of Royal Surgeons in Ireland and investigator at Beam Research, said there is a real need for effective treatment to stop damage caused by mutant genes. He said he was looking at patients in their 30s and 40s with severe emphysema and “really bad liver disease.” And he said, “By the time we see them, there's already a fair amount of damage.”
For those suffering from the worst effects of AATD, he said the new gene therapy is a “major major breakthrough.”
“Big Pro,” a new treatment, said “it theoretical treatment of liver and lung diseases at once.”
But Dr. McElvaney added, “Like all genetic interventions, we need to follow up for a long time to make sure it's as good as we think.”
However, patients are now renewing their hopes, says Andrew Wilson, PhD, director of science at the advocacy group Alpha-1 Foundation.
“We've dreamed of gene therapy as a treatment for this disease,” he said.
