Treating the Most Vulnerable: What a New Pompe disease Trial Tells Us About Global Standards

We are proud to acknowledge that our researchers, Prof. Giancarlo Parenti and Prof. Nicola Brunetti-Pierri, were invited by The New England Journal of Medicine to write a commentary on the recent article by Ma et al., describing the results of a gene therapy trial in infants with Pompe disease. Their involvement is a testament to the international recognition of their contributions to the field of lysosomal storage diseases and metabolic disorders.

Since its approval in 2006, enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase (rhGAA) has been the standard of care for Pompe disease, offering clear benefits in terms of cardiac function and survival, particularly when initiated early. However, ERT has important limitations: it requires lifelong biweekly infusions, poses a significant treatment burden on patients and families, and does not effectively reach all affected tissues, especially skeletal muscle and the central nervous system. Immune responses to the exogenous enzyme can further limit its efficacy, and long-term outcomes remain suboptimal, especially in infantile-onset Pompe disease (IOPD). These challenges have fueled the search for more durable and systemic treatment approaches. Gene therapy, which aims to restore continuous endogenous production of the deficient enzyme following a single administration, offers the potential to overcome many of these limitations and transform the therapeutic landscape for Pompe disease.

The study by Ma et al. represents a significant step forward in the quest for transformative therapies in infantile-onset Pompe disease (IOPD), a devastating genetic disorder characterized by early and rapidly progressive cardiomyopathy, respiratory failure, and early death if left untreated. The authors treated four semi-naïve infants with an AAV9-based gene therapy approach, reporting improvements in cardiac and neurodevelopmental outcomes in three of the patients.

However, this study is not exempt from ethical and regulatory questions, particularly when considered in a global context.

Designing Trials for Rapidly Progressing Pediatric Diseases

Designing a clinical trial for IOPD presents profound scientific and ethical challenges. The disease progresses rapidly, and effective intervention must occur early to prevent irreversible damage. Trial designs must therefore carefully weigh the urgency of immediate therapeutic intervention against the need to rigorously evaluate novel approaches. In this context, the decision to recruit patients who had limited prior exposure to ERT may have facilitated clearer efficacy signals for the investigational gene therapy. However, it also limits direct comparison with the current standard of care, which—in many countries—requires immediate initiation of ERT.

Given the heterogeneity of clinical trajectories and treatment responses, particularly in infants, small patient cohorts can make data interpretation difficult. Future studies might benefit from adaptive trial designs, use of external or historical controls, and clearly defined primary endpoints that are clinically meaningful for patients and caregivers. Importantly, longer follow-up periods are needed to assess the durability of response, especially when gene therapy is administered during early developmental stages.

Regulatory Landscape and Standard of Care Discrepancy

First and foremost, it is unlikely that a trial like this would have received regulatory approval in Europe or the United States. In these regions, enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase (rhGAA) has been the established standard of care since its approval in 2006. ERT remains the only approved treatment that can offer stabilization of cardiac and motor symptoms during the critical early stages of disease. Withholding this treatment — or minimizing its administration prior to an experimental intervention — would be considered ethically questionable, especially in such a vulnerable pediatric population.

In contrast, the regulatory environment in China appears to have permitted the administration of gene therapy in infants who had received only minimal ERT exposure. This choice raises ethical concerns: the infants enrolled in the study were not given the full benefit of the current best-available therapy. While it is understandable that the goal was to assess the efficacy of gene therapy without the confounding effects of prolonged ERT, this approach potentially exposed the children to potential risks.

Global Access and Availability of ERT

ERT is not universally available or affordable. While in the United States and Europe ERT is generally reimbursed and integrated into national healthcare systems, in many low- and middle-income countries access remains limited or inconsistent. . China's healthcare system is characterized by urban–rural and regional disparities: access to advanced therapies like ERT for rare diseases is often concentrated in major urban centers (e.g., Beijing, Shanghai, Guangzhou), while rural and less developed areas may lack specialized facilities and trained personnel. In recent years, alglucosidase alfa (Myozyme) was added to the National Reimbursement Drug List (NRDL), but regional implementation still varies, and out-of-pocket costs remain significant in many areas (Chen M., 2021).

Thus, the ethical acceptability of enrolling infants in a gene therapy trial without proper ERT pre-treatment must also be weighed against the local standard of care and realistic therapeutic options.

However, the regulatory flexibility that allowed Ma et al. to proceed with this trial also enabled a first-in-human assessment of gene therapy efficacy in a real clinical scenario, opening a door that might otherwise have remained closed for years under stricter regulatory regimes. This raises the question: Is there a global ethical double standard when access to standard treatments is itself unequal? And how should this inequality shape our expectations of trial design and patient protections?

Patient Safety vs. Innovation

The trial also brings to light broader issues around patient safety in the era of high-dose systemic AAV gene therapy. While a one-time gene therapy is an attractive alternative to biweekly ERT, particularly for infants, the safety of systemic AAV administration in patients with underlying cardiac disease remains a significant concern. Experiences from spinal muscular atrophy and Duchenne muscular dystrophy trials have shown that systemic AAV at high doses can trigger severe immune responses, liver toxicity, and even fatalities. It remains unclear whether the high-dose approach used by Ma et al. will be sustainable or safe in larger trials, especially if administered before stabilizing cardiac function through ERT.

Furthermore, many questions remain open regarding the durability of response, the immunological consequences of transgene expression, and the risk of loss of efficacy over time due to vector dilution in dividing muscle cells or immune rejection of GAA.

Conclusion: Caution, Equity, and Scientific Responsibility

While gene therapy holds tremendous promise — especially for diseases like Pompe where the limitations of ERT are well documented — we must proceed with caution. Studies like the one by Ma et al. are undeniably important for the field, but they must be scrutinized carefully within a framework that prioritizes patient safety, informed consent, regulatory consistency, and equitable access to care.

Prof. Parenti and Dr. Brunetti-Pierri’s commentary in NEJM highlights the complexity of translating innovative therapies into clinical practice, particularly when conducted across different regulatory, ethical, and economic environments. Their perspective urges the scientific and medical communities to ensure that the drive for innovation never compromises the foundational principles of medical ethics — especially when the lives of vulnerable children are at stake.