The Father Who Became a Biotech CEO

In 1998, John Crowley's daughter Megan was 15 months old when she was diagnosed with infantile-onset Pompe disease. His son Patrick, an infant, received the same diagnosis shortly after. The doctors told the Crowleys that their children would not survive to age two.

Pompe disease is a lysosomal storage disorder caused by deficiency of acid alpha-glucosidase (GAA), the enzyme that breaks down glycogen inside cells. Without GAA, glycogen accumulates in muscle tissue throughout the body. In infantile-onset Pompe, the most severe form, glycogen storage in the heart causes massive cardiac enlargement. The heart fails. The skeletal muscles weaken. Breathing becomes impossible. Death follows, usually within the first year of life.

John Crowley quit his job as a marketing executive at a pharmaceutical company and co-founded Novazyme Pharmaceuticals with William Canfield, a glycobiologist at the University of Oklahoma Health Sciences Center who was developing a novel approach to manufacturing recombinant GAA. Crowley was not a scientist. He was a parent with a Harvard MBA and a willingness to do whatever the situation required.

Novazyme was acquired by Genzyme in 2001 for over $100 million. Crowley joined Genzyme to drive the Pompe program forward. The relationship was contentious. Corporate priorities clashed with a father's urgency. The movie "Extraordinary Measures," released in 2010, dramatized the tension between a parent who needed a drug yesterday and a company that operated on corporate timelines.

Megan and Patrick Crowley received their first doses of alglucosidase alfa in January 2003, through an expanded access program before the drug was formally approved. Within months, their enlarged hearts returned to normal size. They gained muscle strength. They survived.

The FDA approved alglucosidase alfa (Myozyme) in April 2006.

What the Drug Does and Does Not Do

Alglucosidase alfa is enzyme replacement therapy (ERT). It provides the GAA enzyme the body cannot produce, delivered through intravenous infusion every two weeks. The infused enzyme is taken up by cells, enters the lysosomes, and breaks down the accumulated glycogen.

The therapy saves lives. Children with infantile-onset Pompe who receive ERT survive into childhood and beyond. Without ERT, most die before their first birthday. With ERT, many reach school age, adolescence, and in the longest-treated cohorts, young adulthood.

The therapy does not cure the disease. The infused enzyme is consumed and must be replenished every two weeks. If infusions stop, glycogen accumulates again and the disease progresses. The underlying genetic defect remains. ERT manages the consequences of the missing enzyme without repairing the gene that fails to produce it.

The distinction between treatment and cure matters practically. A person with Pompe disease on ERT receives biweekly infusions for life, each lasting several hours. The infusions cost approximately $300,000 per year for a child, rising with body weight as the person grows. Insurance coverage battles are routine. Access varies by country, by insurer, and by the willingness of the healthcare system to sustain the cost indefinitely.

The long-term outcomes on ERT are also incomplete. While ERT prevents the cardiac failure that would otherwise kill in infancy, skeletal muscle involvement often progresses despite treatment. Many children and adults on ERT develop respiratory insufficiency requiring ventilatory support. Muscle weakness in the limbs progresses, sometimes requiring wheelchair use. The enzyme reaches the heart and liver efficiently but penetrates skeletal muscle less effectively, especially the diaphragm and limb muscles.

Avalglucosidase alfa (Nexviazyme), a next-generation ERT approved in 2021, was engineered with enhanced mannose-6-phosphate receptor binding to increase cellular uptake by approximately 15-fold compared to the original formulation. It improves enzyme delivery to muscle cells. It is still an infusion, still given every two weeks, still lifelong.

Pompe on the Newborn Screening Panel

Pompe disease was added to the Recommended Uniform Screening Panel in March 2015. By 2025, 46 U.S. states had implemented newborn screening for Pompe. The screening test measures GAA enzyme activity in dried blood spots, the same sample used for other newborn screening conditions.

The screening data has confirmed what the Crowley family's experience demonstrated: early treatment dramatically improves outcomes. In a cohort of 14 infants with infantile-onset Pompe identified through newborn screening and treated at a mean age of 12 days, all showed reduction in cardiac hypertrophy, with 13 of 14 achieving normal heart size. All reached age-appropriate developmental milestones over two years on ERT.

The comparison with children diagnosed after symptom onset is stark. Children who begin ERT after cardiac symptoms have developed still benefit, but their hearts may not fully normalize, their muscle function may not reach age-appropriate milestones, and their overall trajectory is worse. The enzyme cannot undo damage already done. It can only prevent further accumulation.

Screening has also revealed a category of Pompe disease that the clinical system rarely detected: late-onset Pompe. These individuals have partial GAA activity, enough to prevent infantile cardiac failure but not enough to prevent progressive muscle weakness in adulthood. Newborn screening identifies them at birth, decades before symptoms appear. The question of when to begin treatment in late-onset Pompe, whether to treat presymptomatically or wait for symptoms, is unresolved. The data to answer it does not yet exist because the screened population has not been followed long enough.

The Gene Therapy Frontier

Gene therapy for Pompe disease is in clinical development, and the early data suggests it may eventually replace lifelong ERT.

AT845, developed by Astellas (originally Audentes Therapeutics), is in Phase I/II trials for late-onset Pompe disease. The AAV8 vector delivers the GAA gene to the liver, which then produces and secretes GAA into the bloodstream. Preliminary data shows that three participants discontinued ERT after gene therapy while maintaining stable functional outcomes for up to 51 weeks. If the gene continues to express, ERT becomes unnecessary. The biweekly infusions, the insurance battles, the hours in the infusion chair, all of it stops.

GC301, an AAV9-based gene therapy being evaluated for infantile-onset Pompe, has shown improvements in motor milestones and cardiac function in initial dosing. The approach targets muscle directly rather than routing through the liver.

The gene therapy programs for Pompe disease are building on the manufacturing, safety, and regulatory infrastructure established by Zolgensma (AAV9 for SMA), Hemgenix (AAV5 for hemophilia B), and other rare disease gene therapies that preceded them. The AAV vector technology validated through those programs is the platform that makes Pompe gene therapy feasible.

The Crowley Template

John Crowley did not remain at Genzyme. He went on to lead Amicus Therapeutics, another rare disease company, and has spent the past two decades working to advance therapies for Pompe and other lysosomal storage disorders.

Megan and Patrick Crowley are alive. They are in their late twenties. They have lived more than 25 years with a disease that their doctors said would kill them before age two. They have received biweekly enzyme infusions for more than two decades, a treatment that their father helped bring into existence.

The Crowley story established a template that the rare disease community has replicated dozens of times since: a parent receives a devastating diagnosis, learns that no treatment exists, and builds the treatment themselves. Terry Pirovolakis is doing it now for his son's ultra-rare neurological condition, developing the gene therapy Trophos through public fundraising and academic collaboration. Julia Vitarello founded Mila's Miracle Foundation after milasen. The parent-driven drug development model that the Plausible Mechanism Framework now formally enables traces directly to the precedent Crowley set.

The model works because the parent's incentive structure is aligned with the outcome the medical system should want. The pharmaceutical company calculates return on investment. The parent calculates survival. When the two calculations diverge, as they do for diseases affecting hundreds of families rather than millions, the parent fills the gap that the market leaves.

Pompe disease was added to the newborn screening panel nine years after Myozyme's approval. Gene therapy is in clinical trials. The next generation of children born with Pompe disease may receive a single infusion that corrects the genetic error, produces GAA permanently, and makes the biweekly infusions unnecessary.

John Crowley's children were born too early for newborn screening, too early for gene therapy, and too late for any physician to help them without a father who refused to accept the timeline the system offered.