Immunological challenges and approaches to immunomodulation in Pompe disease: a literature review

Ankit K. Desai, Cindy Li, Amy S. Rosenberg, Priya S. Kishnani


Pompe disease is an autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase resulting in intralysosomal glycogen accumulation in multiple tissue types, especially cardiac, skeletal, and smooth muscle. Enzyme replacement therapy (ERT) with alglucosidase alfa has led to improved clinical outcomes and prolonged survival in patients with Pompe disease. While ERT has changed the natural course of Pompe disease, with many long-term survivors, several factors affect the response to ERT. Previous studies in Pompe disease have shown that IgG antibodies to ERT can lead to a decline in muscle strength, pulmonary function, and overall and ventilator-free survival. Additionally, antibody responses to ERT can also cause hypersensitivity reactions. Various strategies to prevent or eliminate the IgG antibody response have been attempted in patients with Pompe disease. A detailed literature search was performed to compile data regarding the consequences of IgG antibodies, clinical approaches to prevent or eliminate IgG antibodies in patients with Pompe disease, and to expand our understanding of new modalities being developed in non-clinical settings. All qualifying articles describing the impact of IgG antibodies on the response to ERT, immunomodulation in patients with Pompe disease, and non-clinical settings identified via a PubMed database search were included in the review. Here, we provide a comprehensive review of combination- and single-agent therapies that have been investigated in the context of immune tolerance induction to ERT in Pompe disease to date. Immunomodulation strategies that successfully induce immune tolerance to ERT have improved overall survival, especially reflected in the decreased number of ventilator-dependent or deceased cross-reactive immunologic material (CRIM)-negative infantile Pompe disease (IPD) patients due to development of IgG antibodies when treated with ERT alone. Immunomodulation in CRIM-positive patients at the time they receive ERT also results in a decrease in the development of IgG antibodies compared to cases treated with ERT alone. Lessons learned from current approaches, alongside results from trials of novel immunomodulation strategies, may provide important insights into the development of next-generation therapies.