Post-transplant laronidase augmentation for children with Hurler syndrome: biochemical outcomes

Troy C Lund,Jakub Tolar,Brian W Bigger,Ryan Shanley,Ai Yin Liao,Weston P Miller,Lynda E Polgreen,Nicole Sando,Paul J Orchard,Marzia Pasquali

doi:10.1038/s41598-019-50595-1

Abstract

Allogeneic hematopoietic cell transplantation (HCT) benefits children with Hurler syndrome (MPS-IH). However, survivors remain burdened by substantial MPS-IH related residual disease. We studied the feasibility, safety and biochemical impact of augmentative recombinant intravenous enzyme replacement therapy (IV-ERT) post transplantation. Ten children with MPS-IH and ≥2 years from successful HCT underwent IV-ERT for 2 years’ duration. Patients were monitored for anti-drug antibody (ADA) development, including inhibitory capacity and changes in urinary excretion of glycosaminoglycans (uGAG). Three patients demonstrated low-level ADA at baseline, though all children tolerated IV-ERT well. Eight patients developed ADA over the 2-year study, with 3 (38%) meeting criteria for an inhibitory ADA response. The aggregate cohort experienced a reduction in uGAG from baseline to study end, which was enhanced in children with low or no ADA response. Conversely, children with inhibitory ADA showed increase in uGAG over time. IV-ERT in previously transplanted children with MPS-IH appears safe and can reduce uGAG, although this is reversed by the presence of inhibitory ADA. These data show a biochemical change after initiation of post-HCT IV-ERT, but the occurrence of ADA and inhibitory antibodies are a concern and should be monitored in future efficacy trials. This trial was registered at www.clinicaltrials.gov, NCT01173016, 07/30/2010.

Highlights

Severe mucopolysaccharidosis type I, or Hurler syndrome (MPS-IH), is a rare, autosomal recessive disorder of glycosaminoglycan (GAG) catabolism
When comparing the patients with and without baseline anti-drug antibodies (ADA), there were no significant differences in pre-treatment urinary excretion of heparan sulfate (HS), I0S0, or I0S6; patients without baseline ADA had slightly higher donor hematopoietic chimerism at enrollment (91% versus 86%; p < 0.01)
Based on clinical studies documenting the benefit of full engraftment and higher enzyme levels positively influencing long term outcomes[6], and animal data suggesting a dose-response effect of enzyme delivery[9], we hypothesized that there may be better biochemical correction with the addition of intravenous enzyme replacement therapy (IV-ERT) after transplant

Summary

Introduction

Severe mucopolysaccharidosis type I, or Hurler syndrome (MPS-IH), is a rare, autosomal recessive disorder of glycosaminoglycan (GAG) catabolism. Over the past 3 decades, engrafted survival outcomes have improved following HCT for children with MPS-IH4,5 As these patients live longer, it has become evident that transplant does not fully ameliorate the disorder. Retrospective, multi-center study of 217 patients with MPS-IH surviving HCT, investigators catalogued high incidences of substantial and morbid residual Hurler-related disease. They correlated increased disease burden with lower post-transplant circulating leukocyte α-L-iduronidase activity, a finding begging the clinical question of whether augmentative enzyme sources might be beneficial[6]. We describe the incidence and impact of ADA, including inhibitory capacity, on donor hematopoietic chimerism and urinary GAG excretion (uGAG) over two years’ duration of laronidase treatment

Methods

Results

Conclusion