Targeted approaches to induce immune tolerance for Pompe disease therapy

Abstract

Enzyme and gene replacement strategies have developed into viable therapeutic approaches for the treatment of Pompe disease (acid α-glucosidase (GAA) deficiency). Unfortunately, the introduction of GAA and viral vectors encoding the enzyme can lead to detrimental immune responses that attenuate treatment benefits and can impact patient safety. Preclinical and clinical experience in addressing humoral responses toward enzyme and gene therapy for Pompe disease have provided greater understanding of the immunological consequences of the provided therapy. B- and T-cell modulation has been shown to be effective in preventing infusion-associated reactions during enzyme replacement therapy in patients and has shown similar success in the context of gene therapy. Additional techniques to induce humoral tolerance for Pompe disease have been the targeted expression or delivery of GAA to discrete cell types or tissues such as the gut-associated lymphoid tissues, red blood cells, hematopoietic stem cells, and the liver. Research into overcoming preexisting immunity through immunomodulation and gene transfer are becoming increasingly important to achieve long-term efficacy. This review highlights the advances in therapies as well as the improved understanding of the molecular mechanisms involved in the humoral immune response with emphasis on methods employed to overcome responses associated with enzyme and gene therapies for Pompe disease.

Infantile‐onset Pompe disease: A case series highlighting early clinical features, spectrum of disease severity and treatment response

“…Initiation before the commencement of ERT may also allow the use of less‐toxic regimes that are required to switch off established immune responses. Strategies to better induce immune tolerance are being evaluated, especially in animal studies, and hold promise in the future . Our cases add to the literature of the development of HSAT in both CRIM‐negative and CRIM‐positive patients .…”

Effects of Enzyme Replacement Therapy and Antidrug Antibodies in Patients with Fabry Disease

“…25,90 The humoral response includes crosstalk between antigen-presenting cells, CD4 1 T-helper cells, and B cells (Figure 1). 98 In patients with IgEs, the following general mechanisms might apply: After antigen presentation, an early anaphylactic response includes the formation of IgE antibodies, triggering mast cell activation and histamine release, which could explain the observed severe IARs. With ongoing antigen presentation this process is commonly followed by IgG4 isotype antibody production against similar epitopes.…”

Expression and assembly of largest foreign protein in chloroplasts: oral delivery of human FVIII made in lettuce chloroplasts robustly suppresses inhibitor formation in haemophilia A mice

“…However, there are no prophylactic immune tolerance protocols to prevent inhibitor formation. Similar challenges exist in replacement therapies for other genetic diseases as a result of antidrug antibody formation, such as for the lysosomal storage disorder Pompe disease, prompting the prolonged use of immune‐suppressive drugs (Doerfler et al ., ; Elder et al ., ).…”