Pompe disease, a rare and potentially fatal genetic disorder, affects the body’s ability to process glycogen, leading to severe motor, respiratory, and cognitive dysfunction. The disease has long been treated with enzyme replacement therapy (ERT), but recent advances in biotechnology are opening new avenues for improved therapies.
Understanding Pompe Disease
Pompe disease is caused by a deficiency in the enzyme α-glucosidase, which is essential for breaking down glycogen, the body’s stored form of sugar. Without proper breakdown, glycogen accumulates in cells, causing damage across various organs. The severity of the disease varies depending on mutations in the α-glucosidase gene, with patients typically categorized into two forms: infantile-onset Pompe disease, which presents severe symptoms early in life, and late-onset Pompe disease, which develops later and is often less severe.
Since 2006, enzyme replacement therapy (ERT) has been the primary treatment for Pompe disease. Patients receive regular intravenous infusions of α-glucosidase to replace the missing enzyme, significantly improving survival rates. However, this treatment is not without risks, such as the need for surgical port placement, which has led to fatalities in some cases.
Challenges of Enzyme Replacement Therapy
While ERT has improved patient outcomes, its efficacy in treating late-onset Pompe disease has been less clear. With the advent of newborn screening, clinicians can now identify whether a patient has infantile- or late-onset Pompe disease, making treatment decisions more targeted. However, measuring the benefits of ERT in late-onset cases remains a challenge due to the subtle nature of symptoms.
Moreover, ERT does not fully address all aspects of the disease. Although the enzyme helps to alleviate motor and respiratory symptoms by reducing glycogen buildup in muscles, it does not cross the blood-brain barrier, leaving neurological symptoms such as hearing loss, neuropathy, and cognitive decline unaddressed.
New Advances in Enzyme Replacement Therapies
To improve treatment, scientists have developed new generations of ERT. In 2021, the FDA approved Nexviazyme, a more efficient version of the enzyme therapy, designed to target muscle cells more effectively than the previous drug, Lumizyme. Additionally, in 2023, Amicus Therapeutics introduced a combination therapy, Pombiliti and Opfolda, which pairs the enzyme with a stabilizer to further enhance its muscle-targeting abilities.
However, while these advancements have shown small clinical improvements, their overall impact on patients’ quality of life remains uncertain. Barry Byrne, a physician-scientist at the University of Florida, cautions that the clinical benefits observed may not be significant enough to justify widespread use.
Exploring Gene Therapy as a Solution
To overcome the limitations of ERT, researchers are increasingly turning to gene therapy. Byrne and his team have made strides in this field, with a 2013 Phase 1/2 clinical trial investigating the use of adeno-associated virus (AAV) vectors to deliver the α-glucosidase gene directly to muscle cells. Results showed some improvement in lung function among ventilator-dependent children, suggesting potential benefits from this approach.
Other biotech companies, including Askbio and GeneCradle, are pursuing similar strategies, using different viral vectors to target the enzyme to muscles and even the central nervous system. These therapies aim to address the root cause of Pompe disease by providing a permanent genetic solution to the enzyme deficiency.
Astellas, another company involved in gene therapy research, is conducting a Phase 1/2 clinical trial of its AAV8-based therapy, AT845, which targets the enzyme directly to muscle cells. “By placing the α-glucosidase gene under the control of a muscle-specific promoter, we can ensure the gene is primarily expressed in muscle cells, where glycogen buildup causes the most harm,” explains Richard Wilson, Senior Vice President and Genetic Regulation Lead at Astellas.
Beyond Gene Therapy: Reducing Glycogen Production
In addition to gene therapy, other innovative approaches aim to reduce the accumulation of glycogen itself. Maze Therapeutics, in partnership with Shionogi, is developing small molecules that inhibit glycogen production. Early trials in Pompe disease mouse models and healthy adults have shown promising results, with the treatment reducing muscle glycogen levels and showing minimal side effects. However, like ERT, these therapies also face the challenge of crossing the blood-brain barrier.
“We’ve seen remarkable progress in developing therapies that can intervene early, with minimal invasiveness and once-daily oral administration,” Byrne says. “But the brain remains a challenge.”
Looking Ahead
While gene therapy and glycogen reduction strategies hold great promise, many of these treatments are still in clinical trials and are not yet widely available. As researchers continue to refine these approaches, the hope is that they will provide more effective and less invasive treatment options for patients with Pompe disease.
“It’s just remarkable how many programs are being run in the clinic and how many benefits we’re seeing patients experience,” says Wilson. “That’s what gives me optimism about the future of Pompe disease treatment.”
As clinical trials progress, families affected by Pompe disease are watching closely, hopeful that these new therapies will lead to better outcomes and improved quality of life.
Related Topics
