Immune tolerance strategies in siblings with infantile Pompe disease - Advantages for a preemptive approach to high-sustained antibody titers

• Type of Material: Article
• Authors: Elizabeth O. Stenger, Emory University; Zoheb Kazi, Duke University School of Medicine; Emily C. Lisi, Emory University; Michael J. Gambello, Emory University; Priya Kishnani, Duke University School of Medicine
• Language: English
• Date: 2015-06-17
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2015 The Authors. Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ymgmr.2015.05.004
• Title of Journal or Parent Work: Molecular Genetics and Metabolism Reports
• ISSN: 2214-4269
• Volume: 4
• Start Page: 30
• End Page: 34
• Grant/Funding Information: This research was also supported in part by a grant from the Genzyme Corporation (PK), a Sanofi Company (Cambridge, MA), and in part by the Lysosomal Disease Network (PK), a part of NIH Rare Diseases Clinical Research Network (RDCRN). The Lysosomal Disease Network (U54NS065768) is a part of NIH RDCRN, supported through collaboration between the NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATAS), the National Institute of Neurological Disorders and Stroke (NINDS), and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).; ZBK is also supported by the University of Minnesota and Lysosomal Disease Network fellowship (NIH U54NS065768).; his research was supported by the ACTSI KL2-Mentored Clinical and Translational Research Program (EOS) and the National Institutes of Health (NIH) Grant KL2TR000455 (EOS).
• Keywords: high sustained antibody titers; bortezomib; Infantile Pompe Disease; immune tolerance induction
• Research Categories: Biology, Genetics; Health Sciences, Human Development

Abstract

Enzyme replacement therapy (ERT) has led to a significant improvement in the clinical course of patients with infantile Pompe disease (IPD), an autosomal recessive glycogen storage disorder characterized by the deficiency in lysosomal acid α-glucosidase. A subset of IPD patients mounts a substantial immune response to ERT developing high sustained anti-rhGAA IgG antibody titers (HSAT) leading to the ineffectiveness of this treatment. HSAT have been challenging to treat, although preemptive approaches have shown success in high-risk patients (those who are cross-reactive immunological material [CRIM]-negative). More recently, the addition of bortezomib, a proteasome inhibitor known to target plasma cells, to immunotherapy with rituximab, methotrexate, and intravenous immunoglobulin has shown success at significantly reducing the anti-rhGAA antibody titers in three patients with HSAT. In this report, we present the successful use of a bortezomib-based approach in a CRIM-positive IPD patient with HSAT and the use of a preemptive approach to prevent immunologic response in an affected younger sibling. We highlight the significant difference in clinical course between the two patients, particularly that a pre-emptive approach was simple and effective in preventing the development of high antibody titers in the younger sibling, thus supporting the role of immune tolerance induction (ITI) in the ERT-naïve high-risk setting.