PACUPod is your trusted source for evidence-based insights tailored to advanced clinical pharmacists and physicians. Each episode dives into the latest primary literature, covering medication-focused studies across pediatric emergency medicine, internal medicine, ambulatory care, critical care, specialty pharmacy, and many more. We break down study designs, highlight key findings, and objectively discuss clinical implications—without the hype—so you stay informed and ready to apply new evidence in practice. Whether you’re preparing for board certification or striving for excellence in patient care, PACUPod helps you make sense of the data, one study at a time.
Britany: Welcome back to PACULit, your source for clinical literature updates. Today, we’re discussing a Phase I trial of AAV9-mediated gene therapy for infantile-onset Pompe disease. Seth, this is a rare but severe condition, right?
Seth: Yes, Britany. Infantile-onset Pompe disease (IOPD) is a lysosomal storage disorder caused by acid alpha-glucosidase (GAA) deficiency. It’s autosomal recessive and leads to severe cardiomyopathy, muscle weakness, and respiratory failure. Without treatment, infant mortality is very high.
Britany: The incidence is about 1 in 40,000 births. Early intervention is critical due to rapid progression. What’s the current standard of care?
Seth: Enzyme replacement therapy (ERT) with recombinant GAA improves survival but has limitations. The enzyme poorly penetrates skeletal muscle and CNS, immune responses reduce efficacy, and cardiac and muscle damage often persist.
Britany: So, there’s a need for durable, systemic enzyme expression that crosses the blood-brain barrier with lower immunogenicity. That’s where gene therapy comes in.
Seth: Exactly. Preclinical studies show AAV9 vectors can cross the blood-brain barrier and target heart, muscle, and CNS. But clinical data in infants with IOPD have been limited until now.
Britany: That’s the rationale behind Ma et al.’s recent New England Journal of Medicine study. They gave a single intravenous dose of an AAV9 vector carrying codon-optimized human GAA cDNA to infants with severe IOPD, assessing safety, tolerability, efficacy, and immune responses.
Seth: They also monitored anti-GAA antibody formation, which could undermine therapy. This first-in-human Phase I trial aims to inform future studies.
Britany: The open-label, single-center trial included four infants with genetically confirmed severe IOPD showing cardiomyopathy and motor impairment. They excluded severe concurrent illnesses and likely screened out pre-existing anti-AAV9 antibodies.
Seth: The intervention was a single IV infusion of AAV9 vector at 1.2 × 10^14 vector genomes/kg, a high dose for robust transduction.
Britany: No comparator was used due to ethical considerations. Primary outcomes were safety and tolerability over 52 weeks, including adverse events and immune monitoring. Secondary outcomes included cardiac and motor function.
Seth: The small sample limits generalizability, but detailed follow-up offers valuable insights. Three of four infants showed improved cardiac function and motor abilities over 52 weeks. One patient withdrew and died; cause and relation to therapy were unclear.
Britany: Importantly, none developed anti-GAA antibodies, suggesting low immunogenicity—a major hurdle in ERT.
Seth: Respiratory infections were the most common adverse events. It’s unclear if related to therapy or disease, highlighting the need for close monitoring.
Britany: AAV9’s ability to target heart, muscle, and CNS likely contributed to improvements, consistent with Smith et al. 2023, who showed AAV9 crosses the blood-brain barrier in Pompe mouse models.
Seth: Johnson et al. 2022 reported improved motor milestones and cardiac function after AAV9-hGAA therapy in a first-in-human case, supporting these findings. Li et al.’s Phase I trial showed similar results.
Britany: Chen et al. 2024 emphasized low immunogenicity post-AAV9-GAA therapy, aligning with Ma et al.’s absence of anti-GAA antibodies.
Seth: Wang et al. 2025 provided preclinical data on sustained enzyme expression with AAV9 vectors, crucial for long-term benefit.
Britany: Colella et al. showed in Pompe mice that an AAV9 vector with a tandem promoter prevented anti-transgene immunity and sustained efficacy, suggesting vector design impacts immune tolerance.
Seth: The codon-optimized human GAA cDNA in Ma et al.’s trial likely enhanced expression and reduced immunogenicity, highlighting the importance of vector engineering.
Britany: Clinicians should be aware of this emerging gene therapy offering hope for improved cardiac and motor outcomes in IOPD, which has poor prognosis despite ERT.
Seth: Monitoring respiratory infections remains important. Coordinating multidisciplinary care to educate caregivers on expectations and adverse events during the first year post-infusion is essential.
Britany: Drug interactions are less concerning here, but immunosuppressive regimens sometimes used in gene therapy could interact with other medications, something to watch in future protocols.
Seth: Special populations like infants with pre-existing anti-AAV9 antibodies or severe comorbidities were excluded. Future studies must address these groups.
Britany: The small sample and one death highlight the need for larger, controlled trials to confirm safety and efficacy. Still, these preliminary data are encouraging.
Seth: This study is a significant advance. Delivering one-time systemic gene therapy that improves cardiac and motor function while avoiding immune responses is a game changer.
Britany: To summarize, Ma et al.’s Phase I trial showed a single IV dose of AAV9-mediated gene therapy in infants with severe IOPD was generally safe and well tolerated over 52 weeks. Three of four patients improved cardiac and motor function; no anti-GAA antibodies were detected.
Seth: Respiratory infections were common but their relation to therapy is unclear. Strengths include innovative vector design and multi-tissue targeting; limitations include small sample size and one patient death with uncertain causality.
Britany: Clinicians should stay informed, monitor patients closely, and collaborate across specialties to optimize outcomes. The future of Pompe disease treatment looks promising with gene therapy.
Seth: Absolutely, Britany. It’s an exciting time in clinical pharmacology and gene therapy. We’ll watch for larger trials and longer-term data to define AAV9-mediated GAA gene therapy’s role.
Britany: Thanks for joining me today, Seth. And thank you to our listeners for tuning in to PACULit. Stay curious, stay informed, and we’ll catch you next time with more clinical updates.
Seth: Thanks, Britany. Looking forward to our next deep dive. Take care, everyone!
Britany: Before we wrap up, Seth, what do you think are the key challenges researchers face in scaling up this therapy for broader clinical use?
Seth: Great question, Britany. One major challenge is manufacturing sufficient quantities of high-quality AAV9 vectors to meet potential demand. The production process is complex and costly. Additionally, ensuring consistent vector potency and purity is critical to maintain safety and efficacy across larger patient populations.
Britany: That makes sense. Also, long-term follow-up will be essential to monitor durability of gene expression and any delayed adverse effects, right?
Seth: Exactly. While 52 weeks is a solid start, Pompe disease is chronic, so we need data on multi-year outcomes. Potential risks like insertional mutagenesis or immune responses developing later must be carefully evaluated.
Britany: And from a clinical perspective, integrating gene therapy into existing treatment algorithms will require education and infrastructure development.
Seth: Absolutely. Multidisciplinary teams including geneticists, cardiologists, neurologists, and immunologists will need to collaborate closely. Plus, patient and family counseling about expectations and potential risks is vital.
Britany: It’s exciting to see how gene therapy is transforming rare genetic diseases like Pompe. Hopefully, ongoing research will address these challenges and expand access.
Seth: I agree. The progress so far is promising, and with continued innovation, we may soon have durable, one-time treatments that dramatically improve quality of life for affected infants.
Britany: Thanks again, Seth, for your insights. And thanks to our listeners for joining us on PACULit. We’ll keep you updated as new data emerge.
Seth: Looking forward to it, Britany. Take care, everyone!