Durable and sustained immune tolerance to ERT in Pompe disease with entrenched immune responses
| Autor: | Renuka Gera, Carrie Bailey, Joyce A. Kobori, Paul McIntosh, Priya S. Kishnani, Amy S. Rosenberg, David W. Stockton, Sean N. Prater, Zoheb B. Kazi, David Viskochil |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities biology business.industry Bortezomib nutritional and metabolic diseases General Medicine Enzyme replacement therapy 3. Good health Immune tolerance 03 medical and health sciences Regimen 030104 developmental biology 0302 clinical medicine Immune system Immunology Proteasome inhibitor medicine biology.protein Rituximab Clinical Medicine Antibody business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | JCI Insight. 1 |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.86821 |
| Popis: | BACKGROUND. Enzyme replacement therapy (ERT) has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD), a rapidly progressive neuromuscular disorder. Yet marked interindividual variability in response to ERT, primarily attributable to the development of antibodies to ERT, remains an ongoing challenge. Immune tolerance to ongoing ERT has yet to be described in the setting of an entrenched immune response. METHODS. Three infantile Pompe patients who developed high and sustained rhGAA IgG antibody titers (HSAT) and received a bortezomib-based immune tolerance induction (ITI) regimen were included in the study and were followed longitudinally to monitor the long-term safety and efficacy. A trial to taper the ITI protocol was attempted to monitor if true immune tolerance was achieved. RESULTS. Bortezomib-based ITI protocol was safely tolerated and led to a significant decline in rhGAA antibody titers with concomitant sustained clinical improvement. Two of the 3 IPD patients were successfully weaned off all ITI protocol medications and continue to maintain low/no antibody titers. ITI protocol was significantly tapered in the third IPD patient. B cell recovery was observed in all 3 IPD patients. CONCLUSION. This is the first report to our knowledge on successful induction of long-term immune tolerance in patients with IPD and HSAT refractory to agents such as cyclophosphamide, rituximab, and methotrexate, based on an approach using the proteasome inhibitor bortezomib. As immune responses limit the efficacy and cost-effectiveness of therapy for many conditions, proteasome inhibitors may have new therapeutic applications. FUNDING. This research was supported by a grant from the Genzyme Corporation, a Sanofi Company (Cambridge, Massachusetts, USA), and in part by the Lysosomal Disease Network, a part of NIH Rare Diseases Clinical Research Network (RDCRN). |
| Databáze: | OpenAIRE |
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