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Effect of palmitate treatment on transcriptome in Pompe disease patient fibroblasts

ABSTRACT: Lysosomal storage disorders (LSDs) are rare inherited diseases caused by mutations in lysosomal proteins, leading to substrate accumulation and lysosomal dysfunction. Whether this build-up compromises lysosomal membrane integrity remains an open question. In this study, we aimed to investigate the presence of lysosomal membrane damage in LSD cells and to identify mechanisms that could reveal potential therapeutic strategies for amelioration of cellular physiology. Methods: Primary skin fibroblasts from Pompe disease patients were used to evaluate lysosomal integrity and function. Pharmacologic and metabolite treatments were applied in loss-of-function and rescue analyses, and transcriptomics analysis was done under these conditions. Results: In Pompe disease, caused by mutations in the acid alpha-glucosidase gene, glycogen accumulation, palmitate treatment improved lysosomal function in fibroblasts from patients, with no significant effect at transcriptional level. Conclusions: These findings open to novel therapeutic opportunities for improvement of lysosomal function through development of treatments that target fatty acid metabolism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316968 | GEO | 2026/03/23

REPOSITORIES: GEO

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Project description:Infantile-onset Pompe disease is an inherited disorder that is normally diagnosed within the first months of life. It is caused by lack of or defect in an enzyme (a special protein that carries out normal chemical reactions within the body) called acid alpha-glucosidase (GAA). GAA normally breaks down glycogen (stored sugar) in lysosomes (the part of the cell that digests food and other chemicals). Pompe disease is one of many lysosomal storage diseases (LSDs). LSDs are diseases caused by the malfunction of the lysosome or one of their digestive enzymes. Patients with Pompe disease cannot break down lysosomal glycogen. This causes glycogen to build up and damage cells throughout the body, especially in the heart and muscles. Current treatment for Pompe disease involves enzyme replacement therapy (ERT). In this treatment, the drug alglucosidase alfa (Myozyme) is put into your blood. The drug provides a form of the GAA enzyme to replace the enzyme that is missing or not working properly in the patient's blood. This treatment has allowed babies to live longer and achieve developmental milestones. In this study, researchers will learn about the patient's ability to tolerate ERT. Cross-Reactive Immunological Material (CRIM) is a measurement of natural GAA production. A patient's CRIM status (either positive or negative) is an important factor that affects how he or she responds to ERT with Myozyme. Children who produce some natural GAA are classified as CRIM+, while children who do not produce any natural GAA are classified as CRIM-. Children who are CRIM+ generally tolerate ERT well. But, children who are CRIM-, and some children classified as CRIM+, have a poor response to ERT. Patients who have a poor response to ERT have complications because their body sees Myozyme as "foreign" and triggers an immune response to try to remove it from the body. Treatments are currently being developed to stop this immune response and prevent complications from ERT. We will enroll patients with Infantile Pompe disease in this longitudinal natural history (observational) study. The specific aims of this study are: <ol> <li>To determine and correlate Cross-Reactive Immunological Material (CRIM) status with the GAA gene mutations found on these patients</li> <li>To validate an approach for determining CRIM status from whole blood sample, with the gold standard determination of CRIM status by skin fibroblasts and mutation analysis</li> <li>To explore the clinical treatment response and natural history of CRIM-positive and CRIM-negative Pompe disease patients with and without immune modulation</li> <li>To investigate the role of immune response to treatment</li> </ol>

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Effect of palmitate treatment on transcriptome in Pompe disease patient fibroblasts

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