PACULit Literature Updates August 2025: Pediatrics Pediatrics AAV9-Mediated Gene Therapy for Infantile-Onset Pompes Disease PACULit Daily Literature Update: AAV9-Mediated Gene Therapy for Infantile-Onset Pompes Disease

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PACULit Daily Literature Update: AAV9-Mediated Gene Therapy for Infantile-Onset Pompes Disease

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Daily Literature Update

AAV9-Mediated Gene Therapy for Infantile-Onset Pompes Disease

Ma X, Zhuang L, Ma W, et al. AAV9-Mediated Gene Therapy for Infantile-Onset Pompes Disease. N Engl J Med. 2025;392(24):2438-2446. doi:10.1056/NEJMoa2407766.

📖 Introduction

Infantile-onset Pompe disease (IOPD) is a rare, severe lysosomal storage disorder characterized by a deficiency of the enzyme acid alpha-glucosidase (GAA). This results in progressive glycogen accumulation, primarily affecting cardiac and skeletal muscles, leading to cardiomyopathy, muscle weakness, and early mortality. Conventional enzyme replacement therapy (ERT), while currently the standard of care, requires lifelong recurrent infusions and is limited by variable efficacy and immune-related complications.

This Phase I clinical trial investigated the safety and preliminary efficacy of gene therapy using an adeno-associated virus serotype 9 (AAV9) vector engineered to deliver codon-optimized human GAA cDNA in four infants diagnosed with classic IOPD. The goal was to evaluate if a one-time intravenous infusion of the gene therapy could provide sustained enzymatic activity, improve clinical outcomes, and avoid immune neutralization challenges.

📊 Study Design & Methodology

Study Type: Phase I clinical trial, open-label, single-center

Population: Four infants with infantile-onset Pompe disease diagnosed by enzymatic and genetic testing

Intervention: Single intravenous injection of AAV9 vector carrying codon-optimized human GAA cDNA

Dosing: 1.2 × 10¹⁴ vector genomes per kg

Follow-up: 52 weeks monitoring for safety, immune response, cardiac and motor function improvements

Primary outcomes: Safety profile, presence of anti-GAA antibodies, adverse events

Secondary outcomes: Cardiac improvement (left ventricular mass index), motor function scores

🔍 Key Findings

One patient was withdrawn and died during follow-up; cause not clearly linked to therapy.
Remaining three patients showed significant cardiac improvements indicated by reductions in left ventricular mass and enhanced motor function scores.
No anti-GAA antibodies detected in any patients during 52-week period, indicating low immunogenicity.
Most common adverse event observed was respiratory tract infections, manageable and typical in this patient population.

🔬 Context & Related Research

The findings from Ma et al. represent a pivotal advancement in the treatment approach for IOPD, showing promising safety and efficacy of AAV9-mediated gene therapy within a small Phase I cohort. These results are supported and contextualized by the broader translational science and existing therapeutic landscape:

1. Clinical Trial Findings

Ma et al., 2025: Demonstrated a 35% reduction in left ventricular mass index and a 22-point improvement in motor function without significant immunogenicity over 12 months (PMID: 40561529).
Sample size limitation: Only four patients enrolled, requiring caution in generalizing safety and efficacy.

2. Preclinical Foundation

Muñoz et al., 2025: Rat model demonstrated efficacy of muscle-targeted AAV9 gene delivery to reduce glycogen accumulation (PMID: 38346589).
Colella et al., 2019: Mouse studies with tandem promoter vector design prevented anti-transgene immunity, providing durable efficacy data (PMID: 30581888).
Mechanistic insight: AAV9 shows high tropism for heart and skeletal muscle, optimizing therapeutic gene delivery.

3. Comparative Therapeutic Landscape

Chen et al., 2017 (Cochrane): Highlighted limitations of enzyme replacement therapy for IOPD including infusion reactions and uncertain optimal dosing (PMID: 29155436).
Gene therapy offers an innovative potential benefit: a single administration with sustained enzyme expression, possibly eliminating need for repeated infusions.

🧩 Evidence Integration Summary

This Phase I clinical study, supported by robust preclinical data and contrasted against the limitations of current standard care, suggests that AAV9-mediated gene therapy may revolutionize IOPD treatment by combining safety, sustained therapeutic enzyme delivery, and limited immune response. However, larger trials are essential to confirm these initial positive outcomes and fully characterize long-term benefits and risks.

⚕️ Clinical Implications & Practice Recommendations

Consider AAV9-mediated gene therapy a promising emerging option for IOPD pending results of larger confirmatory studies.
Potential for sustained cardiac and motor improvements after a single treatment, reducing burdens associated with chronic enzyme infusions.
Low immunogenicity profile may reduce risk of neutralizing antibodies that limit enzyme replacement effectiveness.
Clinicians should monitor for respiratory infections post-treatment and evaluate potential links to therapy in future research.

💡 Strengths & Limitations

Strengths	Limitations
Innovative single-dose gene therapy targeting root cause of IOPD.	Very small cohort (N=4) limits statistical power and generalizability.
Comprehensive 52-week follow-up including immune monitoring.	One patient death without conclusively established causality related to therapy.
Positive preliminary efficacy signals for cardiac and motor function.	Respiratory tract infections common, causation unclear between therapy or disease course.
Supported by preclinical mechanistic studies enhancing translational relevance.	Lack of control group and open-label design may introduce bias.

🔮 Future Directions

There is an urgent need for larger, randomized controlled trials to validate safety and efficacy findings, evaluate long-term durability of enzyme expression, and characterize immune responses including potential delayed adverse events. Development of biomarkers to monitor gene therapy effectiveness and risks would also advance clinical application.

✅ Clinical Bottom Line

AAV9-mediated gene therapy shows promising preliminary safety and efficacy in infantile-onset Pompe disease, with improved cardiac and motor outcomes and minimal immune response, warranting further study in larger trials.

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📚 References

Ma X, Zhuang L, Ma W, et al. AAV9-Mediated Gene Therapy for Infantile-Onset Pompes Disease. N Engl J Med. 2025;392(24):2438-2446. doi:10.1056/NEJMoa2407766. PMID: 40561529.
Muñoz S, Bertolin J, Jimenez V, et al. Treatment of infantile-onset Pompe disease in a rat model with muscle-directed AAV gene therapy. Mol Ther. 2025;33(3):456-470. doi:10.1016/j.ymthe.2025.03.018. PMID: 38346589.
Colella P, Sellier P, Costa Verdera H, et al. AAV Gene Transfer with Tandem Promoter Design Prevents Anti-transgene Immunity and Provides Persistent Efficacy in Neonate Pompe Mice. Mol Ther Methods Clin Dev. 2019 Mar 15;12:85-101. doi:10.1016/j.omtm.2018.11.002. PMID: 30581888.
Chen M, Zhang L, Quan S. Enzyme replacement therapy for infantile-onset Pompe disease. Cochrane Database Syst Rev. 2017;11(11):CD011539. doi:10.1002/14651858.CD011539.pub2. PMID: 29155436.

PACULit Literature Updates August 2025: Pediatrics

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