The human body cannot run without the sugar glucose. To ensure that people don’t have to constantly eat sugary foods, humans have developed a way to store sugar in the form of glycogen. Normally, the body can break down glycogen to mobilize it for energy. But in Pompe disease, the enzyme that usually does this — called α-glucosidase — is defunct, and glycogen accumulates in the body, wreaking havoc across all organs (1). 

Different mutations in the α-glucosidase gene can have varying effects on the enzyme’s function, leading to a range of disease severities. As a result, patients often fall into two disease categories: infantile-onset Pompe disease, where the enzyme is either almost or completely gone, or late-onset Pompe disease, where there is some residual enzyme (2). 

But in all cases, the treatment has been the same since 2006: enzyme replacement therapy, where patients receive a biweekly intravenous infusion of the α-glucosidase enzyme. “It’s not without risk to undergo treatment because it requires a fusion port to be placed surgically,” said Barry Byrne, a physician-scientist at the University of Florida who studies Pompe disease. “Children have actually died during that procedure.” 

Now, several research groups and biotechnology companies are exploring new ways to treat Pompe disease. These techniques include second-generation enzyme replacement therapies, gene therapies, and even small molecules that inhibit glycogen formation. While the approaches might be different, the goals are similar — reduce the pileup of glycogen in the body, which will hopefully resolve patients’ symptoms. 

Enzyme replacement therapy 

The introduction of enzyme replacement therapy in 2006 quickly became a mainstay for Pompe disease treatment, largely because it helped people survive much longer. Without treatment, patients with the infantile-onset form of disease often developed critical cardiac and respiratory dysfunction along with severe muscle weakness that led to death within the first year of life. 

The trickier part was figuring out if this therapy would be similarly useful in those with late-onset Pompe disease. With the advent of newborn screening, physicians could then pick up exactly which infants had the infantile versus the late-onset disease forms by looking at their genetic mutations. “You have to ask, what would I measure if I treated an infant who has late-onset disease? How would we determine that they benefited in any way?” said Byrne. “That is always a challenge when there is a huge gray zone of what is normal and what is not.”

Along with these challenges, physicians quickly realized that enzyme replacement therapy wasn’t a cure-all. While glycogen pileup in the muscle is a huge contributor to the major motor and respiratory dysfunction experienced by patients, they also could develop neurological complications including hearing loss, neuropathy, and even cognitive decline (3). And because the enzyme couldn’t cross the blood-brain barrier, infusing the patients with the enzyme didn’t make a dent in solving their neurological problems. 

You have to ask, what would I measure if I treated an infant who has late-onset disease? How would we determine that they benefited in any way?
- Barry Byrne, University of Florida

That being said, scientists are pushing forward new and improved enzyme replacement therapies. One from Sanofi, called Nexviazyme and approved by the Food and Drug Administration in 2021, was designed to deliver the α-glucosidase enzyme to muscle cells more efficiently than its previous counterpart, Lumizyme. Another, a combination therapy called Pombiliti and Opfolda from Amicus Therapeutics, was approved in 2023 as a muscle-targeted α-glucosidase enzyme along with an enzyme stabilizer. 

Both new therapies target patients with late-onset Pompe disease. For Byrne, it remains to be seen whether they stick as viable treatments. “They have a very small and hard-to-measure clinical benefit, and some may say that these changes are statistically significant but not clinically meaningful,” he said. 

Emerging gene therapies 

To overcome some of the drawbacks associated with enzyme replacement therapy, Byrne and others have moved toward creating new gene therapies. Byrne, who published the initial findings of a Phase 1/2 clinical trial in 2013, used the adeno-associated virus (AAV) 1 capsid to deliver the α-glucosidase enzyme into the diaphragms of five ventilator-dependent children with Pompe disease (4). 

When Byrne’s group measured the participants’ capability to breathe over the course of 180 days, they found that the patients had significantly larger unassisted tidal volume and had longer periods of unventilated breathing — all indicating a potential increase in lung function. 

Other groups have taken different approaches to this idea of delivering the α-glucosidase gene into patients. The biotechnology company Askbio is running a Phase 1/2 clinical trial of a liver-targeted gene therapy, with initial results from 2023 showing a significant increase in the enzyme’s activity in muscle over the course of 52 weeks (5). And the company GeneCradle is looking at the efficacy of an AAV9-based gene therapy for delivering the enzyme into muscle and the central nervous system. 

Another company, Astellas, is currently running a Phase 1/2 clinical trial with its candidate AT845, which is an AAV8-based treatment that similarly contains the α-glucosidase gene. The goal is to target the therapy into muscle, where the buildup of glycogen can lead to severe motor impairment. 

“We know that there’s a certain tropism for muscle that we see with AAV8,” said Richard Wilson, the Senior Vice President and Genetic Regulation Lead at Astellas. By placing the α-glucosidase gene under the control of a muscle-specific promoter, the scientists can ensure that expression of the gene generally only occurs inside muscle cells. 

Wilson noted that because their therapy is muscle-targeted, they wouldn’t expect to see much expression in the central nervous system. “We’re still interested to see what we can learn from the clinical program,” he added. “To what extent does the ability to process glycogen peripherally help reduce the burden?”

Trying to reduce glycogen

It’s just remarkable how many programs are being run in the clinic and how many benefits we’re seeing patients experience.
- Richard Wilson, Astellas 

Beyond gene therapies, other strategies to reduce glycogen include selectively inhibiting glycogen production in places like the skeletal muscle. This approach, developed by Maze Therapeutics and recently licensed to Shionogi, showed efficacy in reducing glycogen burden when applied to a Pompe disease mouse model (6). In addition, the company ran a trial in healthy adults, showing that the drug was well-tolerated and did reduce muscle glycogen in a manner like that of enzyme replacement therapy (7). 

“It’s been a very good strategy for minimally-invasive, early intervention with a once-a-day oral drug without major side effects,” said Byrne. “Only one problem — it doesn’t cross the blood-brain barrier.” 

The tricky problem of getting the α-glucosidase enzyme into the brain is something that persists even among all of these new therapies. But by leveraging a brain-specific delivery vehicle, tweaking the viral capsid, or even adding a promoter that is active in both muscle and brain tissue, scientists may eventually develop a treatment that can go everywhere that it needs to go. 

For now, scientists are curious to see how these most recent new approaches hold up over time as the clinical trials begin wrapping up their endpoints. “It’s just remarkable how many programs are being run in the clinic and how many benefits we’re seeing patients experience,” said Wilson. “That’s what gives me optimism.”

References

1. George, K.A. et al. Pompe disease: Unmet needs and emerging therapies. Mol Genet Metab  143, 108590 (2024).
2. Stevens, D. et al. Pompe Disease: a Clinical, Diagnostic, and Therapeutic Overview. Curr Treat Options Neurol  24, 573–588 (2022).
3. Korlimarla, A. et al. An emerging phenotype of central nervous system involvement in Pompe disease: from bench to bedside and beyond. Ann Transl Med  7, 289 (2019).
4. Smith, B.K. et al. Phase I/II Trial of Adeno-Associated Virus–Mediated Alpha-Glucosidase Gene Therapy to the Diaphragm for Chronic Respiratory Failure in Pompe Disease: Initial Safety and Ventilatory Outcomes. Hum Gene Ther  24, 630-640 (2013).
5. Smith, E.C. et al. Phase I study of liver depot gene therapy in late-onset Pompe disease. Mol Ther 31, 1994-2004 (2023).
6. Ullman, J.C. et al. Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders. Sci Transl Med  16, eadf1691 (2024).
7. Ullman, J.C. et al. First-in-Human Evaluation of Safety, Pharmacokinetics and Muscle Glycogen Lowering of a Novel Glycogen Synthase 1 Inhibitor for the Treatment of Pompe Disease. Clin Pharmacol Ther  116, 1580–1592 (2024).