International Pompe Disease Day: Advancing a Systemic Approach to a Systemic Disease

A central element in understanding Pompe disease lies in deciphering lysosomal biology—an area in which TIGEM has made pivotal contributions. Under the direction of Professor Andrea Ballabio, several TIGEM scientists have helped reshape the world’s view of lysosomes from inert “garbage disposals” into key regulators of cellular metabolism. Professor Ballabio’s discovery of the the CLEAR gene network and the master regulator TFEB unveiled how the cell controls lysosome formation and function at the genetic level.

A multisystem disease like Pompe calls for sophisticated tools that can track its course and gauge the effectiveness of emerging treatments. A research leaded by Antonietta Tarallo is also developing prognostic biomarkers to better predict how the disease might progress and to reveal, in real time, whether a therapy is achieving its intended effects. By applying large-scale genomic, proteomic, and metabolomic techniques, they aim to capture subtle molecular changes that take place as treatments are administered. Such biomarkers could guide decision-making at every stage of patient care, from determining the right time to initiate therapy to fine-tuning individual treatment plans based on measurable biological responses.

While enzyme replacement therapy (ERT) has markedly improved outcomes for many individuals with Pompe disease, first-generation enzymes are far from perfect. They often lack sufficient stability, struggle with limited biodistribution, and come at a high cost—challenges common to other lysosomal storage disorders (LSDs) as well. In a pioneering series of studies, Giancarlo Parenti’s research provided a crucial proof of principle demonstrating that pharmacological chaperones can help recombinant acid alpha-glucosidase (GAA) survive longer in circulation and reach target tissues more effectively.
The study revealed that co-administration significantly enhanced the stability of recombinant GAA in blood, leading to improved enzymatic activity and more efficient tissue targeting. These compelling results were subsequently translated into a clinical trial, supported by Fondazione Telethon, which assessed the combination therapy in Pompe patients. The clinical data confirmed that the chaperone improved the pharmacokinetic profile of GAA, supporting its therapeutic benefit. This line of research has directly informed the design of next-generation ERTs, several of which are now advancing through clinical development. Beyond Pompe, pharmacological chaperone therapy (PCT) is also being explored in clinical settings for Fabry and Gaucher diseases, underscoring its promise as a broadly applicable therapeutic strategy for LSDs. 

Several gene therapy approaches are now in clinical trials. Some target the liver (e.g., ACTUS-101) to produce a systemic enzyme source. Others aim directly at muscle (e.g., AT845), or the CNS via intrathecal delivery. While each offers hope, they are largely tissue-specific—and that’s a problem. Many of these approaches are designed to address either the CNS or the muscle phenotype, limiting their therapeutic scope. Therapies targeting the brain do not potentially alleviate cardiac or respiratory issues, while muscle-directed vectors do not aim to prevent also the neurocognitive decline or autonomic dysfunction. This fragmented vision doesn’t reflect the complexity of Pompe disease, which is multisystemic by nature. What’s needed is a strategy that reaches every affected tissue.