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Clinical Trial
. 2019 Nov;21(11):2552-2560.
doi: 10.1038/s41436-019-0522-1. Epub 2019 Apr 25.

Intrathecal enzyme replacement for Hurler syndrome: biomarker association with neurocognitive outcomes

Julie B Eisengart  1 , Elizabeth I Pierpont  1 , Alexander M Kaizer  2 , Kyle D Rudser  3 , Kelly E King  1 , Marzia Pasquali  4 , Lynda E Polgreen  5 , Patricia I Dickson  5   6 , Steven Q Le  5   6 , Weston P Miller  7   8 , Jakub Tolar  7 , Paul J Orchard  7 , Troy C Lund  9
Affiliations
Clinical Trial

Intrathecal enzyme replacement for Hurler syndrome: biomarker association with neurocognitive outcomes

Julie B Eisengart et al. Genet Med. 2019 Nov.

Abstract

Purpose: Abnormalities in cerebrospinal fluid (CSF) have been reported in Hurler syndrome, a fatal neurodegenerative lysosomal disorder. While no biomarker has predicted neurocognitive response to treatment, one of these abnormalities, glycosaminoglycan nonreducing ends (NREs), holds promise to monitor therapeutic efficacy. A trial of intrathecal enzyme replacement therapy (ERT) added to standard treatment enabled tracking of CSF abnormalities, including NREs. We evaluated safety, biomarker response, and neurocognitive correlates of change.

Methods: In addition to intravenous ERT and hematopoietic cell transplantation, patients (N = 24) received intrathecal ERT at four peritransplant time points; CSF was evaluated at each point. Neurocognitive functioning was quantified at baseline, 1 year, and 2 years posttransplant. Changes in CSF biomarkers and neurocognitive function were evaluated for an association.

Results: Over treatment, there were significant decreases in CSF opening pressure, biomarkers of disease activity, and markers of inflammation. Percent decrease in NRE from pretreatment to final intrathecal dose posttransplant was positively associated with percent change in neurocognitive score from pretreatment to 2 years posttransplant.

Conclusion: Intrathecal ERT was safe and, in combination with standard treatment, was associated with reductions in CSF abnormalities. Critically, we report evidence of a link between a biomarker treatment response and neurocognitive outcome in Hurler syndrome.

Keywords: biomarkers; enzyme replacement therapy; intrathecal therapy; mucopolysaccharidosis; neurocognitive decline.

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Conflict of interest statement

J.B.E. received honoraria, consulting fees, and/or research support from ArmaGen, Gene Spotlight, Inc., Sangamo, and Sanofi Genzyme, and has done contract work for Shapiro Neuropsychology Consulting LLC. K.E.K. is a consultant for Shire Plc; has received research support from Shire, Sanofi Genzyme, and Alexion Pharmaceuticals, Inc.; and has done previous contract work for Shapiro Neuropsychology Consulting. M.P. is a consultant for Moderna Tx, Inc. and BioMarin Pharmaceuticals, Inc. and has received travel support from BioMarin Pharmaceuticals, Inc. L.E.P. has received honoraria, consulting fees, and/or research support from Sanofi Genzyme, Shire, and BioMarin. P.I.D. receives research support from Biomarin and Genzyme. W.P.M. is an employee of Sangamo Therapeutics, Inc.. P.J.O. has received honoraria, consulting fees, and/or research support from Sanofi Genzyme, Bluebird Bio, and Horizon. T.C.L. has received speaker fees and research support from Sanofi Genzyme. The other authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Change in cerebrospinal fluid opening pressure throughout treatment. Cerebrospinal fluid opening pressure on lumbar puncture decreased significantly from time point 1 to 2, i.e., prior to transplant (p = 0.0499). At time point 3, which is 100 days posttransplant, the opening pressure was also significantly lower than time point 1 (p = 0.0004). Opening pressure increased somewhat at time point 4, which is 6 months posttransplant, such that it was no longer significantly different from time point 1 (p = 0.0861).
Fig. 2
Fig. 2
Decrease in biochemical abnormality from pretreatment to last follow-up. Percent change in biochemical abnormalities in the cerebrospinal fluid from time point 1 to 4, i.e., before any treatment to final intrathecal recombinant iduronidase infusion, 6 months posttransplant. All reductions were significant at p < 0.0001. Nonreducing ends (NREs) I0S0 and I0S6 (N = 20, N = 19, respectively) separately showed significant reductions, by more than 80% for I0S0 and 54% for I0S6. Heparan sulfate (HS, N = 20) decreased by 30%, and heparin cofactor II–thrombin complex (HCIIT, N = 19) decreased by more than half. CI confidence interval.
Fig. 3
Fig. 3
Correspondence of biochemical change with IQ outcome. Percent change in IQ from baseline (i.e., pretreatment) to 2-year posttransplant anniversary is plotted against percent reduction in nonreducing end (NRE) I0S6 from time point 1 to 4, i.e., pretreatment through final intrathecal recombinant iduronidase infusion occurring 6 months posttransplant (N = 15). A significant association was found, such that percent decrease in I0S6 was significantly associated with more favorable change in IQ (p = 0.0035). CI confidence interval.
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