First patient receives prime editing therapy for Wilson's disease

Prime editing – a type of genome editing – has been used to alter DNA directly inside a person's body for the first time.

The first patient has received an experimental prime editing therapy in a clinical trial for Wilson's disease. The treatment is designed to correct a disease-causing mutation in liver cells. Although genome editing therapies have been approved for some conditions (see BioNews 1319, 1275 and 1220), no in vivo genome editing treatment has yet to be approved by the US Food and Drug Administration (FDA). The trial will assess whether the therapy – called PM577a – is safe and tolerable, as well as its preliminary clinical efficacy. Initial clinical data are expected in 2027.

'Dosing the first patient with PM577a is a meaningful step toward our goal of delivering a transformative, one-time treatment for people living with Wilson disease', said Dr Allan Reine, chief executive officer at Prime Medicine, a biotechnology company based in Cambridge, Massachusetts, that developed the treatment. He added, 'We've seen strong interest from patients and physicians that, together with our patient identification and prescreening efforts, positions us well for efficient enrolment.'

Wilson's disease, an autosomal recessive condition affecting one in 30,000 people, is caused by mutations in the ATP7B gene. This gene encodes a protein that helps transport copper into bile, which is then excreted. Mutations cause a build-up of copper, especially in the liver and brain, potentially causing liver disease, neurological disorders and, most notably, copper-coloured rings around the cornea.

Current treatment for Wilson's disease generally involves diet control and lifelong medication to clear accumulated copper. However, these treatments can come with serious side effects, resulting in acute liver failure in five to ten percent of patients who then require liver transplants. PM577a is being investigated as a potential one-time treatment that could address the underlying genetic cause of the disease, rather than managing copper accumulation throughout a person's lifetime.

'I never dreamed that in my lifetime I would see this applied to my rare disease', Rhonda Rowland, president of the Wilson Disease Association in Atlanta, Georgia, said. 'It's going to be an exciting year.'

PM577a is an example of in vivo genome editing, in which genetic material is altered directly inside the body. This differs from ex vivo approaches, in which cells are removed from a patient, genetically modified in a laboratory and then returned to the body.

PM577a uses an advanced genome editing technique called prime editing (see BioNews 1021, 1243 and 1285), which uses an engineered Cas9 protein and a specialised guide RNA to make targeted base changes on a single DNA strand. PM577a is designed to correct the H1069Q mutation in the ATP7B gene, the most prevalent Wilson's disease-causing mutation in North America and Europe.

'PM577a reflects the modularity of our platform', said Dr Reine. However, he added that while this treatment targets a very specific Wilson-causing mutation, the platform itself can be extended to treat other patients, including a variant more common in East Asian populations.