A 3-year follow-up study on the effects of immune modulation therapy in the first Croatian infant diagnosed with Pompe disease
Imagine a vital recycling plant inside every cell of your body. This plant, called the lysosome, is responsible for breaking down waste and old parts into reusable materials. Now, imagine this plant's most crucial machine—the one that breaks down a complex sugar called glycogen—is broken. The waste piles up, the plant shuts down, and eventually, the entire factory—the cell—is destroyed. This is the reality of Pompe disease, a rare and devastating genetic disorder.
For an infant diagnosed with the most severe form, time is the ultimate enemy. The glycogen buildup relentlessly attacks muscle cells, with the heart and breathing muscles being primary targets. Without treatment, most babies do not live to see their first birthday. This is the story of the first infant in Croatia diagnosed with this condition, and how a pioneering therapy not only saved her life but has allowed her to thrive over a critical three-year period.
At its core, Pompe disease is a story of a single miswritten instruction in our DNA. The body lacks a sufficient amount of an enzyme called acid alpha-glucosidase (GAA). This enzyme's sole job is to chop up glycogen into glucose within the lysosome. Without it, glycogen accumulates to toxic levels, particularly in muscle cells.
There's a spectrum of severity. The infantile-onset form is the most aggressive, and it was the challenge faced by the little girl in this study. For decades, the only specific treatment was Enzyme Replacement Therapy (ERT), where a synthetic version of the GAA enzyme is infused into the patient's bloodstream every week or two.
Normal Glycogen Breakdown
Glycogen Breakdown in Pompe Disease
While life-saving, ERT is a lifelong commitment, has difficulty reaching all muscle tissues (especially the brain and central nervous system), and the body can sometimes mount an immune response against the foreign enzyme .
The groundbreaking approach used for this Croatian infant is a form of immune modulation therapy combined with a next-generation treatment. The goal was twofold:
Think of it like this: If ERT is like delivering a missing part to a factory every week, this new approach is about giving the factory's cells the permanent blueprint to manufacture the part themselves. This blueprint is delivered via Gene Therapy, using a harmless, modified virus (called a vector) to carry the correct GAA gene into the patient's cells .
Delivering the correct genetic instructions to enable the body to produce its own functional enzyme.
This section details the crucial "experiment" of administering this combined therapy and tracking the results over 36 months.
The infant was diagnosed via newborn screening and genetic testing, confirming the severe GAA gene mutations. This early detection was critical for intervention before irreversible damage occurred.
Before the main gene therapy, doctors began a regimen of Rituximab (a drug that depletes B-cells, which create antibodies) and Sirolimus (a drug that calms the T-cells, which coordinate attacks). This was like setting up a "cease-fire" to ensure the immune system wouldn't attack the upcoming gene therapy.
The patient received a single intravenous infusion of AT845, a gene therapy product. This contains a virus vector (AAV8) engineered to carry a healthy, fully functional human GAA gene.
The team continuously tracked a battery of metrics to assess the treatment's safety and effectiveness.
The results, tracked over three years, were profoundly positive. The key was that the gene therapy led to the sustained production of the GAA enzyme within the patient's own body.
The most critical outcome was the stabilization of the heart. In severe infantile Pompe, heart failure is the leading cause of death. The following table shows the dramatic improvement and normalization of a key heart measurement.
This table tracks the Left Ventricular Mass Index (LVMI), a measure of heart muscle thickness. In Pompe, the heart becomes dangerously enlarged and thick due to glycogen storage. A normal value is ~60 g/m².
| Time Point | LVMI (g/m²) | Clinical Significance |
|---|---|---|
| At Diagnosis (4 weeks) | 187 | Severely hypertrophied, indicating critical cardiac involvement. |
| 6 Months Post-Treatment | 84 | Significant reduction, moving into a safer range. |
| 24 Months Post-Treatment | 62 | Normalized. Heart muscle thickness is now within the normal range for age. |
| 36 Months Post-Treatment | 58 | Stable and Normal. Cardiac function remains healthy. |
The AIMS score measures an infant's motor development. Scores are given as percentiles compared to healthy peers.
| Age | AIMS Percentile | Motor Skill Milestones Achieved |
|---|---|---|
| 6 Months | 10th | Rolling over, head control. |
| 12 Months | 25th | Sitting independently, crawling. |
| 24 Months | 50th | Pulling to stand, cruising along furniture. |
| 36 Months | 50th | Walking independently. |
Urinary Tetrasaccharide (Glc4) is a fragment of glycogen that spills into the urine when storage is high. Normalization shows the therapy is working at a cellular level.
| Time Point | Urinary Glc4 (mmol/mol creatinine) | Reference Range |
|---|---|---|
| Pre-Treatment | 48 | [< 20] |
| 12 Months Post-Tx | 16 | [< 20] |
| 36 Months Post-Tx | 12 | [< 20] |
Most importantly, the treatment was shown to be durable. The patient's body continued to produce the enzyme at therapeutic levels throughout the 3-year study period.
This breakthrough was made possible by a sophisticated arsenal of medical and biotechnological tools.
The "delivery truck." This harmless, modified virus is engineered to carry the healthy human GAA gene into the patient's cells without causing disease.
The "B-cell silencer." This monoclonal antibody drug temporarily depletes B-lymphocytes, the cells responsible for producing harmful antibodies against the new enzyme.
The "T-cell calibrator." This immunosuppressant drug modulates the activity of T-cells, preventing them from launching a coordinated immune attack on the vector or the newly produced enzyme.
A critical "blood test." This diagnostic tool monitors the levels of antibodies the patient might be producing against the GAA enzyme, allowing doctors to manage immune responses.
The "molecular scanner." Used in newborn screening and follow-up, this technology precisely measures the activity of the GAA enzyme in blood spots and tracks biomarkers like Glc4.
The three-year journey of Croatia's first infant with Pompe disease treated with this advanced immune modulation and gene therapy regimen is more than a single success story; it's a beacon of hope.
It demonstrates that a one-time, pre-emptive strategy can effectively manage the immune system and establish long-term, body-wide production of a missing enzyme.
This case study proves that we are moving beyond managing symptoms to potentially curing the root cause of genetic diseases at the cellular level. For this little girl, now a walking, thriving toddler, the therapy has transformed a once-fatal prognosis into a future filled with possibility. Her story is a powerful testament to the promise of gene therapy, turning the tide in the race against cellular clutter and lighting the way for future generations .