While the ancient city of Pompeii, buried by volcanic ash, is widely known, few may be familiar with Pompe disease—a rare, life-threatening genetic disorder with an incidence rate ranging from 1 in 40,000 to 1 in 3 million. Characterized by breathing difficulties and movement disorders, its rarity often leads to misdiagnosis. Listed in China’s first national rare disease catalog in 2018, Pompe disease has long posed significant treatment challenges.
Pompe disease, also called glycogen storage disease type II, stems from a deficiency of acid alpha-glucosidase (GAA), causing glycogen to accumulate in lysosomes—particularly in skeletal muscles, heart muscles, and smooth muscles. This autosomal recessive disorder arises from mutations in the GAA gene, impairing glycogen breakdown and leading to progressive organ damage. Infantile Pompe disease, one of its two main forms, affects skeletal and heart muscles, often involving the central nervous system (CNS). Without effective treatment, infants typically die from heart or respiratory failure by age 1.
Enzyme replacement therapy (ERT), introduced in 2006, revolutionized care by reducing mortality and improving quality of life. However, it has critical limitations: it cannot cross the blood-brain barrier to address CNS involvement, requires biweekly injections, incurs high long-term costs, and may trigger antibodies that reduce efficacy or cause allergic reactions. Many long-term ERT patients develop progressive white matter brain damage, leading to intellectual and behavioral issues.
A breakthrough came recently when researchers led by Professor Feng Zhichun from the Seventh Medical Center of the PLA General Hospital published results of an AAV9-mediated gene therapy for infantile Pompe disease in The New England Journal of Medicine. The therapy uses a recombinant adeno-associated virus serotype 9 (AAV9) vector to deliver a codon-optimized human GAA gene, aiming for a “one-shot cure.”
“AAV9 offers excellent tissue penetration and low immunogenicity, ideal for systemic delivery,” explained Feng. The optimized GAA gene enhances enzyme expression and activity. In the study, three of four infants under six months old who received a single IV injection of the therapy (GC301) reached key motor milestones like sitting, standing, and assisted walking within 52 weeks, with improved cardiac function. One patient withdrew and later died.
The journal’s editorial hailed this as a “significant milestone” for treating the complex, disabling disease. It marks China’s shift from following global advancements to leading in gene therapy for rare diseases.
Despite promising results, safety remains a priority. Five serious adverse events occurred but were not linked to GC301. However, potential risks include immune responses to the viral vector and long-term concerns about rare gene integration, which might increase cancer risk. Infants’ immature immune systems also require special safety considerations.
“Gene therapy brings hope, but safety persist,” Feng noted. The team is conducting long-term follow-ups and expanding Phase I-II trials to evaluate durability and safety. If approved, GC301 would be the world’s first gene therapy for infantile Pompe disease, filling a critical treatment gap.
Looking ahead, researchers aim to explore applications for late-onset Pompe disease, optimize vector design to reduce immunogenicity, and develop personalized treatments based on patients’ genotypes. This breakthrough not only offers new hope for Pompe disease patients but also underscores China’s growing role in advancing innovative therapies for rare genetic disorders globally.
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