Abstract
A major obstacle to enzyme replacement therapy (ERT) with recombinant human acid-α-glucosidase (rhGAA) for Pompe disease is the development of high titers of anti-rhGAA antibodies in a subset of patients, which often leads to a loss of treatment efficacy. In an effort to induce sustained immune tolerance to rhGAA, we supplemented the rhGAA therapy with a weekly intravenous injection of synthetic vaccine particles carrying rapamycin (SVP-Rapa) during the first 3weeks of a 12-week course of ERT in GAA-KO mice, and compared this with three intraperitoneal injections of methotrexate (MTX) per week for the first 3weeks. Empty nanoparticles (NP) were used as negative control for SVP-Rapa. Co-administration of SVP-Rapa with rhGAA resulted in more durable inhibition of anti-rhGAA antibody responses, higher efficacy in glycogen clearance in skeletal muscles, and greater improvement of motor function than mice treated with empty NP or MTX. Body weight loss was observed during the MTX-treatment but not SVP-Rapa-treatment. Our data suggest that co-administration of SVP-Rapa may be an innovative and safe strategy to induce durable immune tolerance to rhGAA during the ERT in patients with Pompe disease, leading to improved clinical outcomes.
Highlights
Pompe disease is a lysosomal storage disorder caused by a deficiency of lysosomal enzyme acid-α-glucosidase (GAA; acid maltase; EC 3.2.1.20), and characterized by progressive structural disruption and cell dysfunction of muscle tissues due to lysosomal accumulation of glycogen [1]
A broad range of agents have been evaluated for immune tolerance induction, among which rituximab, rapamycin, mycophenolate mofetil, cyclophosphamide, belimumab, Methotrexate (MTX), intravenous immunoglobulin (IVIG), and bortezomib have been shown to be capable of modulating the antirhGAA antibody response [9,10,11,12,13]
We demonstrate that SVP-Rapa can induce immune tolerance to recombinant human acidα-glucosidase (rhGAA) and improve efficacy of enzyme replacement therapy (ERT) in GAA-knockout (KO) mice that is superior to immunosuppression with MTX
Summary
Pompe disease (glycogen storage disease type II, OMIM 232300) is a lysosomal storage disorder caused by a deficiency of lysosomal enzyme acid-α-glucosidase (GAA; acid maltase; EC 3.2.1.20), and characterized by progressive structural disruption and cell dysfunction of muscle tissues due to lysosomal accumulation of glycogen [1]. A broad range of agents have been evaluated for immune tolerance induction, among which rituximab (monoclonal anti-CD 20), rapamycin, mycophenolate mofetil, cyclophosphamide, belimumab (anti-B-cell activating factor; antiBAFF), Methotrexate (MTX), intravenous immunoglobulin (IVIG), and bortezomib have been shown to be capable of modulating the antirhGAA antibody response [9,10,11,12,13] These universal immunosuppressant agents induce systemic immune suppression and may cause side effects such as bone marrow and gastrointestinal toxicities with the possibility of opportunistic infections and tumorigenesis, and chronic administration is often needed in those with an established immune response [10,11,14]
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