Abstract
Objective:Although enzyme replacement therapy (ERT) is a highly effective therapy, CRIM-negative (CN) infantile Pompe disease (IPD) patients typically mount a strong immune response which abrogates the efficacy of ERT, resulting in clinical decline and death. This study was designed to demonstrate that immune tolerance induction (ITI) prevents or diminishes the development of antibody titers, resulting in a better clinical outcome compared to CN IPD patients treated with ERT monotherapy.Methods:We evaluated the safety, efficacy and feasibility of a clinical algorithm designed to accurately identify CN IPD patients and minimize delays between CRIM status determination and initiation of an ITI regimen (combination of rituximab, methotrexate and IVIG) concurrent with ERT. Clinical and laboratory data including measures of efficacy analysis for response to ERT were analyzed and compared to CN IPD patients treated with ERT monotherapy.Results:Seven CN IPD patients were identified and started on the ITI regimen concurrent with ERT. Median time from diagnosis of CN status to commencement of ERT and ITI was 0.5 months (range: 0.1-1.6 months). At baseline, all patients had significant cardiomyopathy and all but one required respiratory support. The ITI regimen was safely tolerated in all seven cases. Four patients never seroconverted and remained antibody-free. One patient died from respiratory failure. Two patients required another course of the ITI regimen. In addition to their clinical improvement, the antibody titers observed in these patients were much lower than those seen in ERT monotherapy treated CN patients.Conclusions:The ITI regimen appears safe and efficacious and holds promise in altering the natural history of CN IPD by increasing ERT efficacy. An algorithm such as this substantiates the benefits of accelerated diagnosis and management of CN IPD patients, thus, further supporting the importance of early identification and treatment initiation with newborn screening for IPD.
| Original language | English (US) |
|---|---|
| Article number | e67052 |
| Journal | PloS one |
| Volume | 8 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 25 2013 |
Funding
SGB, SNP, TTP, CM, KBS, CWR, FL, PC, and ASR have no financial or proprietary interest in the materials presented herein. SMD has received honoraria from Genzyme. DSB reports receiving research and grant support from Genzyme. JAR has received travel support, speaker fees and his department has received unrestricted educational grants from Genzyme. RYW has a material interest in Biomarin Pharmaceuticals, is a member of the Genzyme/Sanofi Aventis North American Board of Advisors for MPS I, and has received research support from Shire plc. He has received travel and lodging support for attendance to scientific meetings from Genzyme/Sanofi Aventis as well as from Shire plc, and is the local study site principal investigator for the Genzyme/Sanofi Aventis Lumizyme phase III extension trial. JC is a member of the Fabry and Gaucher Disease Registry Advisory Board for Genzyme Corporation. He has received honoraria from Genzyme Corporation. PH has received educational grants, travel support to scientific meetings and speaker's honorarium from Genzyme Corporation. PSK reports receiving research and grant support from Genzyme. PSK also receives honoraria and consulting fees from Genzyme and is a member of the Pompe disease and the Gaucher Disease Registry Advisory Boards. Duke University and the inventors of the method of treatment and precursors of the cell lines used to generate the enzyme (rhGAA) used commercially have received royalties pursuant to the University's policy on inventions, patents, and technology transfer. This potential conflict for Duke University has been resolved through monetization. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
ASJC Scopus subject areas
- General
- General Biochemistry, Genetics and Molecular Biology
- General Agricultural and Biological Sciences