Gene therapy for Pompe disease

Last updated Oct. 24, 2024, by Lindsey Shapiro, PhD
Fact-checked by José Lopes, PhD

Several gene therapies are being developed for Pompe disease, a genetic condition caused by mutations in the GAA gene. All are designed to deliver a healthy copy of the gene to certain cells in the body, with the ultimate goal of easing or eliminating disease symptoms.

Because gene therapy involves altering the genetic makeup of cells, either by replacing a faulty gene with a healthy one, inactivating a malfunctioning gene, or introducing a modified gene into the body, side effects are always a possibility.

Although more Pompe disease gene therapy research is needed to understand the potential risks and benefits of GAA gene therapy for Pompe disease, positive results in preclinical and clinical trials have been reported in recent years.

How could gene therapy work in Pompe disease?

The GAA gene that is mutated in Pompe provides instructions for making an enzyme called acid alpha-glucosidase (GAA), which is involved in breaking down a large complex sugar molecule called glycogen.

Normally, glycogen is stored in muscles and broken down to produce smaller sugars for cells to use as energy. Without enough functional GAA, glycogen builds up to toxic levels in cell compartments called lysosomes, and cannot be used as an energy source. This causes damage to muscles throughout the body, which in turn leads to an array of Pompe disease symptoms.

While there is yet no cure for the disease, the approval of enzyme replacement therapy (ERT) represented a significant Pompe disease treatment advancement. These therapies supply the body with a functioning GAA enzyme that breaks down the excess glycogen in cells, which eases symptoms and slows disease progression.

However, as the body breaks down this enzyme, ERT needs to be frequently re-administered throughout a person’s lifetime. Because the body is not producing its own version of the enzyme, it also might mount an immune response against ERT.

A Pompe disease gene therapy may work to restore the body’s ability to produce a functional GAA enzyme on its own by providing cells with a healthy version of the GAA gene.

Most gene therapies are packaged into a viral vector. These viruses are modified so as not to cause disease, but still use their ability to deliver the healthy gene into the person’s cells. Modifications also can be made to these packaged therapies to deliver them to specific tissues, such as muscle tissue, which is particularly affected in Pompe.

Gene therapies for Pompe disease

Several gene therapies are being tested for Pompe disease. None of these investigational Pompe disease treatments have received regulatory approval so far.

Despite notable gene therapy developments for Pompe disease, these treatments are still in early clinical stages, so it is still not clear if and how they might affect the long-term outcomes and life expectancy of people with Pompe.

AT845

AT845 is being developed by Astellas Gene Therapies. The therapy is packaged into an adeno-associated viral (AAV) carrier called AAV8 and administered via a one-time infusion into the bloodstream. It’s a muscle-targeted gene therapy for Pompe disease that delivers a healthy copy of the GAA gene directly into muscle cells, the cells primarily affected in Pompe.

A Phase 1/2 trial called FORTIS (NCT04174105) is evaluating the safety and efficacy of a single AT845 infusion in up to 18 adults with late-onset Pompe disease (LOPD). Eligible participants were on ERT for at least two years, and at a stable dose for at least six months before enrollment.

Interim results from four participants followed for up to six months after the infusion showed the gene therapy was safe and well tolerated. After up to about 1.5 years, 3 of the 4 patients had discontinued ERT and measures of lung function, endurance, fatigue, and daily activities were all stable.

ACT-101

ACT-101, also called ACTUS-101, is being developed by Asklepios Biopharmaceutical (AskBio), a subsidiary of Bayer. The therapy uses a specially engineered AAV vector called AAV2/AAV8, which directs a healthy version of the GAA gene to cells in the liver, where functional GAA can be produced. From the liver, the functional protein is exported out to the muscle and other tissues.

A Phase 1/2 clinical trial (NCT03533673) is testing the safety and preliminary signs of efficacy of ACT-101 in up to seven adults with LOPD. Participants will receive a single infusion of the gene therapy while continuing on their current ERT. Three different ACT-101 dose levels are being tested.

Early findings from the first three participants, who received a relatively low dose of ACT-101, showed the gene therapy was well tolerated and markedly increased levels of the GAA enzyme in muscle cells. All three patients were on ERT for nearly 10 years, but were able to discontinue ERT about six months after receiving the gene therapy.

However, muscle glycogen levels and measures of fatigue, walking ability, and lung function did not change significantly one year after ACT-101 treatment.

rAAV1-CMV-hGAA

rAAV1-CMV-hGAA is another AAV vector-based gene therapy for Pompe disease. Developed by researchers at the University of Florida (UF), it is designed to deliver a functional version of the GAA gene to cells in the diaphragm, a muscle involved in breathing.

A Phase 1/2 clinical trial (NCT00976352), launched in 2010, evaluated the treatment’s safety in ventilator-dependent children with Pompe disease. Participants received the gene therapy via six injections into the diaphragm, which were done during a surgical procedure under general anesthesia.

Preliminary findings involving five children assessed after six months showed the treatment was safe and led to improved breathing abilities. Some children were able to breathe on their own for short periods of time without needing a ventilator. A later publication indicated the treatment was safe after a year.

That trial concluded in 2015. No additional clinical trials have been announced.

rAAV9-DES-hGAA

The same UF research team also created rAAV9-DES-hGAA, although this gene therapy was then developed by the university’s spin-off company, Lacerta Therapeutics. The gene therapy was later licensed to Sarepta Therapeutics in 2018, but the company dropped out of the agreement in 2023.

A Phase 1 trial (NCT02240407) evaluated the effects of injecting the gene therapy directly into the lower leg muscle called the tibialis anterior in adults with LOPD. Patients initially received one injection in one leg and a control treatment in the other, and treatments were given to the opposite leg four months later.

That trial finished in 2021, but no safety or efficacy results have been reported to date. It’s not clear if this therapy is still being developed for Pompe disease.

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