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Durable and sustained immune tolerance to ERT in Pompe disease with entrenched immune responses

机译：庞培病对免疫系统的抵抗力持久且持久

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>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 lowo 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).
机译：>背景。酶替代疗法（ERT）可以延长婴儿Pompe病（IPD）（一种快速发展的神经肌肉疾病）的患者的生存期并改善其临床结局。然而，主要归因于针对ERT的抗体的研发，其对ERT的显着个体差异仍是一项持续的挑战。 >方法。三名婴儿庞培患者出现了高且持续的rhGAA IgG抗体滴度（HSAT），并接受了硼替佐米治疗免疫耐受诱导（ITI）方案包括在研究中，并进行纵向监测以监测长期安全性和有效性。尝试对ITI方案进行锥度试验以监测是否达到了真正的免疫耐受。>结果。基于Bortezomib的ITI方案可以安全耐受，并导致rhGAA抗体滴度显着下降，并伴随持续的临床改善。 3名IPD患者中有2名成功断奶了所有ITI方案药物，并继续维持低/无抗体滴度。在第三位IPD患者中，ITI方案明显变细。在所有3名IPD患者中均观察到B细胞恢复。>结论。这是我们首次成功诱导IPD和HSAT难治性环磷酰胺，HSAT患者长期免疫耐受的知识利妥昔单抗和甲氨蝶呤，基于使用蛋白酶体抑制剂硼替佐米的方法。由于免疫应答限制了许多情况下治疗的有效性和成本效益，蛋白酶体抑制剂可能具有新的治疗应用。>资金。这项研究得到了赛诺菲公司Genzyme公司（剑桥，剑桥）的资助（美国马萨诸塞州），部分由美国国家卫生研究院罕见病临床研究网络（RDCRN）的溶酶体疾病网络（Lysosomal Disease Network）组成。

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