title: Immune Tolerance Strategies in Siblings with Infantile Pompe Disease-Advantages for a Preemptive Approach to High-Sustained Antibody Titers.
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 mount 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.
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, United States.
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Stenger
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States.
authors.forename: Zoheb
authors.initials: Z
authors.lastname: Kazi
authors.affiliation: Division of Medical Genetics, Department of Human Genetics, Emory University, Atlanta, GA, United States.
authors.forename: Emily
authors.initials: E
authors.lastname: Lisi
authors.affiliation: Division of Medical Genetics, Department of Human Genetics, Emory University, Atlanta, GA, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gambello
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States.
authors.forename: Priya
authors.initials: P
authors.lastname: Kishnani
keywords: Infantile Pompe Disease; bortezomib; high sustained antibody titers; immune tolerance induction