B-Cell Depletion and Immunomodulation before Initiation of Enzyme Replacement Therapy Blocks the Immune Response to Acid Alpha-Glucosidase in Infantile-Onset Pompe Disease

Abstract

Objectives Pompe disease is a progressive neuromuscular disorder due to acid alpha glucosidase (GAA) deficiency. Cross-reacting immunologic material (CRIM)-negative infants with null GAA mutations have the most severe phenotype and develop anti-GAA antibodies following exposure to enzyme replacement therapy (ERT). Antibodies influence bio-distribution, attenuate the beneficial effects of ERT, and are believed to influence infusion-associated reactions (IARs), which occur in nearly all early-onset patients. We evaluated the potential that B-cell depletion prior to ERT initiation would block GAA antibody responses and improve clinical outcome. Study Design Six Pompe subjects (four CRIM-negative) between 2–8 months of age received rituximab and sirolimus or myophenolate prior to ERT. Four subjects continued to receive sirolimus, every 12-week rituximab and monthly intravenous immunoglobulin for the duration of ERT. Sirolimus trough levels, IgG levels, CD3, CD4, CD8, CD19, CD20, NTproBNP, CK, CK-MB, CRP, platelet, alkaline phosphatase, AST, ALT were measured regularly. Results Immunomodulation achieved B-cell depletion without adverse effects. After 17–36 months of rituximab, sirolimus and ERT, all subjects lacked antibodies against GAA, four continued to gain motor milestones, yet two progressed to require invasive ventilation. Absence of infusion associated reactions allowed accelerated infusion rates. No IARs were observed at standard or accelerated infusion rates. Conclusions B-cell depletion and T-cell immunomodulation in infants naïve to ERT was accomplished safely, eliminated immune responses against GAA, thereby optimizing clinical outcome, however this approach did not necessarily influence sustained independent ventilation. Importantly, study outcomes support the concept of initiating immunomodulation prior to beginning ERT since the study regimen allowed for prompt initiation of treatment.

Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease

“…Conversely, growing clinical experience with pharmacological immune modulation in Pompe patients may facilitate development of combination therapies to induce tolerance and prevent antibody production. 8,54,83,84 The cost of manufacturing and release testing of an AAV vector is not inconsequential. 85 In the case of large transgenes that exceed the carrying capacity of AAV, methods have been developed to facilitate packaging and delivery of these longer genes as demonstrated by emerging therapies for Duchenne's muscular dystrophy, dysferlinopathies, hemophilia A, Usher 1B, and Tay-Sachs disease.…”

“…Although clinical management of the immune response is feasible with B-and T-cell modulation using immunosuppressive agents (such as rituximab, sirolimus, or methotrexate), long-term immune tolerance induction established through gene therapy stands as a more attractive means to prevent these responses. 8,20 All recessive conditions face limitations inherent to gene replacement strategies when there is no residual endogenous protein expressed. Pompe disease is a strong candidate for gene therapy given the response to ERT.…”

Sustained immune tolerance induction in enzyme replacement therapy–treated CRIM-negative patients with infantile Pompe disease

“…Various approaches to prevent the development of rhGAA IgG antibody production in patients with Pompe disease in clinical and preclinical settings have been attempted, including a protocol with rituximab and sirolimus or mycophenolate, synthetic vaccine particles that contain only rapamycin, and anti-CD4 antibodies (15)(16)(17)(18)(19)(20). The implementation of immune tolerance induction (ITI) using a combination of rituximab, methotrexate, and/or intravenous immunoglobulin (IVIG) infusions has been safely tolerated and effective in preventing the development of deleterious rhGAA IgG antibodies when administered in the ERT-naive and early ERT setting in patients with CRIM-negative IPD (21)(22)(23).…”

Innovative approach in Pompe disease therapy: Induction of immune tolerance by antigen-encapsulated red blood cells

“…Another prophylactic study involving B cell depletion with rituximab and rapamycin showed satisfactory results in preventing the appearance of GAA-specific antibodies. However, in addition to the potential toxicity of rituximab, these patients were not allowed to receive conventional child vaccines and had to be injected every month with intravenous immunoglobulins to provide passive immunity and avoid infections (Elder et al, 2013). Finally, all of these protocols that are not specific to AGA therapy, require prolonged administration and lead to generalised immune suppression.…”