Recently, the clinical research results of GC301 injection, an AAV gene therapy drug independently developed by Beijing Genecradle Therapeutics Co.,Ltd., for the treatment of infantile-onset Pompe disease (IOPD), were officially published as an original article in eClinicalMedicine, a sub-journal of The Lancet (part of The Lancet Discovery Science series).

This paper is the world's first clinical research report on AAV gene therapy in IOPD patients >1 year of age who had received long-term enzyme replacement therapy (ERT), providing pivotal translational medicine evidence for gene therapy to break through lifelong ERT dependence.

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(26)00334-2/fulltext

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Pompe Disease: An Urgent Rare Disease in Need of Breakthroughs

Infantile-onset Pompe disease (IOPD) is a rare autosomal recessive genetic disorder caused by mutations in the acid alpha-glucosidase (GAA) gene. Due to the lack of GAA enzyme activity, glycogen accumulates abnormally in the myocardium, skeletal muscles, and central nervous system, leading to progressive tissue damage and organ dysfunction. Untreated infants typically die from heart failure or respiratory failure within the first year of life, with a median survival of only 8.7 months.

Since its approval in 2006, conventional enzyme replacement therapy (ERT) has been the standard treatment for IOPD. However, ERT has significant limitations: it requires lifelong intravenous infusion every two weeks; it cannot cross the blood-brain barrier and is therefore ineffective against central nervous system pathology; tissue distribution remains suboptimal even at high doses; and long-term treatment costs are prohibitively high.

GC301: An Innovatively Designed Gene Therapy

GC301 uses recombinant adeno-associated virus serotype 9 (rAAV9) as a vector to deliver a codon-optimized human GAA gene, driven by a modified CA promoter to achieve widespread GAA expression throughout the body.

The key design advantages are: AAV9 can efficiently transduce the myocardium, skeletal muscles, and liver, and can cross the blood-brain barrier to target the central nervous system—overcoming the bottleneck that ERT cannot reach the brain. A single intravenous infusion enables durable expression of the therapeutic gene, offering the potential for "one-time treatment, long-term efficacy."

Research Highlights

This study enrolled 6 IOPD patients aged 12.5 to 50.8 months. All patients had previously received 10–98 ERT infusions (median 30), with a median ERT duration of 19.5 months. Patients received a single intravenous injection of GC301 (1.2×10¹⁴ vg/kg) and were followed for 52 weeks.

1. Favorable and Controllable Safety Profile

• All 6 patients survived to the 52-week follow-up endpoint
• Serious adverse events were mainly upper respiratory tract infections and pneumonia (consistent with the underlying characteristics of IOPD)
• Drug-related adverse events were limited to mild fever and transient transaminase elevation
• Hepatotoxicity was lower than reported levels in similar high-dose AAV gene therapies

2. Freedom from ERT and Ventilator Dependence

• 5/6 patients completed 52-week follow-up completely free from ERT and ventilator support
• One patient resumed ERT on Day 60 due to severe pneumonia but successfully discontinued ERT again after recovery

3. Breakthrough Achievement of Motor Milestones

After treatment, 3 patients achieved motor milestones they had not previously attained:

• Patient 1 (12.5 months old): Achieved assisted standing and crawling (achieved independent standing and walking at Month 13)
• Patient 2 (16.8 months old): Achieved independent standing and walking
• Patient 3 (27.0 months old): Achieved independent walking and sitting

4. Direct Evidence at the Muscle Pathology Level

Paired muscle biopsies performed at baseline and post-treatment (Week 26/39) in 3 patients demonstrated:

• Muscle GAA enzyme activity increased from a baseline median of 1.24 to 24.67 nmol/mg/hr (approximately 20-fold increase)
• Markedly increased GAA protein expression (confirmed by Western blot)
• PAS staining showed significantly reduced glycogen accumulation (Patient 3: 296→51; Patient 5: 270→85; Patient 6: 170→46)
• SDH staining showed improved mitochondrial density and uniformity
• Desmin staining revealed more organized myofiber structure

This is the first time it has been demonstrated in humans that AAV9-GAA gene therapy can restore enzyme activity, clear glycogen, and improve myofiber structure at the muscle tissue level.

5. Controllable Immune Response

• All patients developed anti-AAV9 binding antibodies (expected)
• T-cell responses were mild and transient (only 2 patients responded to AAV9, 3 responded to GAA)
• No liver enzyme elevation or clinical deterioration associated with T-cell responses was observed

International Academic Recognition

eClinicalMedicine is a flagship sub-journal of The Lancet focused on clinical translational research, dedicated to publishing interdisciplinary research spanning "from fundamental discoveries to translational breakthroughs and early clinical progress."

This paper is co-corresponded by Professor Yang Guang from the First Medical Center of the Chinese PLA General Hospital and Dr. Wu Xiaobing from Beijing Genecradle Therapeutics Co.,Ltd., with Liu Xinting (First Medical Center of the Chinese PLA General Hospital), Mao Yingying (Beijing Genecradle Therapeutics Co.,Ltd.), and Hu Linyan (First Medical Center of the Chinese PLA General Hospital) as co-first authors.

Commentary by Professor Yang Guang

From "Lifelong Dependence" to "One-Time Treatment" — A Pediatrician's Original Aspiration

As a pediatrician who has been engaged in the diagnosis and treatment of childhood genetic diseases for more than two decades, I have witnessed firsthand countless Pompe disease families journey from hope to gradual despair. Although enzyme replacement therapy (ERT) can prolong the survival of affected children, the lifelong intravenous infusion every two weeks imposes not only a heavy economic burden on families but also a daily constraint on their lives. Even more distressing is that, despite adherence to treatment, a large number of children still face progressive motor function decline, respiratory muscle weakness, and cognitive impairment—because ERT cannot cross the blood-brain barrier and is powerless against central nervous system pathology.

It is precisely these unmet clinical needs that drove our team and the research team at GeneCradle to come together to explore this entirely new path of gene therapy. The design concept behind GC301 is simple yet extremely challenging: Can we enable patients to produce their own GAA enzyme persistently through a single intravenous injection, thereby freeing them from the plight of lifelong infusions?

This study answers three key clinical questions:

Question One: Can older children who have already received long-term ERT still benefit from gene therapy?

This is the real-world situation faced by the vast majority of Pompe disease patients. Our study provides an affirmative answer: Among 6 children aged 12.5 to 50.8 months who had received a median of 19.5 months of ERT, 5 achieved complete freedom from ERT and ventilator support at 52 weeks after a single GC301 infusion. More importantly, 3 patients achieved milestone motor breakthroughs such as independent standing and walking.

Question Two: Does gene therapy actually "enter" the muscle and exert biological effects?

This may be the most compelling finding of this study. Through paired muscle biopsies, we demonstrated that muscle GAA enzyme activity increased approximately 20-fold, glycogen accumulation was significantly reduced, mitochondrial function improved, and myofiber structure became more organized. This is the first direct proof in humans that AAV9-GAA gene therapy can reverse the muscle pathology of Pompe disease. This evidence is far more convincing than changes in peripheral blood biomarkers.

Question Three: What about safety?

In this study, all 6 children survived to the follow-up endpoint, with no drug-related serious adverse events. Liver enzyme elevations were transient and self-limiting, with hepatotoxicity levels far below those reported in similar high-dose AAV gene therapies. This provides a safety boundary for subsequent dose optimization and indication expansion.

Connection with Previous Research

The earlier-stage study of GC301 published in the New England Journal of Medicine in 2025 (Ma X, Zhuang L, Ma W, et al. AAV9-Mediated Gene Therapy for Infantile-Onset Pompe's Disease. N Engl J Med. 2025;392(24):2438-2446) confirmed the safety and efficacy of GC301 in ERT-naïve IOPD patients <1 year of age, providing important foundational data and experience for the design and implementation of this study.

Building on that study, we further expanded the applicable population boundary of GC301—from "ERT-naïve infants" to "ERT-experienced toddlers." The conclusions of the two studies complement each other, jointly building the chain of evidence for GC301 application across different clinical stages of IOPD.

Outlook for the Future

As a pediatrician and clinical researcher, I have always believed that a good therapy should allow patients to return to a dignified normal life, rather than making the treatment itself the centerpiece of their lives. The interim results of GC301 give us a glimpse of this possibility—gene therapy may indeed enable Pompe disease children to achieve "one treatment, lifelong benefit."

GeneCradle's Versatile Technology Platform

As a platform-type innovative drug development company focused on AAV gene therapy, GeneCradle has established a fully integrated vertical technology platform system covering vector and genetic element design, process scale-up manufacturing, and clinical translation. The successful publication of GC301 is another exemplary case demonstrating the efficient advancement of pipeline R&D through this platform, further validating the platform's reproducibility and scalability in tackling gene therapy challenges across various rare diseases.

Value for the GC301 Product Line
This study addresses the key clinical question of "whether IOPD patients >1 year of age who have received long-term ERT can still benefit from gene therapy," demonstrating that GC301 can bring clinical benefits to a broader IOPD patient population.

Synergistic Value for GC801
During patient screening in this study, 4 patients were excluded due to anti-AAV9 neutralizing antibody titers >1:100—which directly points to the clinical application scenario for GC801. By pre-clearing neutralizing antibodies through GC801, these otherwise excluded patients may gain access to gene therapy.

Value for the Gene Therapy Industry
This study provides key evidence for the clinical pathway of "gene therapy replacing lifelong ERT," offering a replicable paradigm for the application of gene therapy in Pompe disease and other lysosomal storage disorders.