Intrathecal enzyme replacement for Hurler syndrome

biomarker association with neurocognitive outcomes

Julie Eisengart, Rene Pierpont, Alexander M. Kaizer, Kyle Rudser, Kelly E King, Marzia Pasquali, Lynda E. Polgreen, Patricia I. Dickson, Steven Q. Le, Weston P. Miller, Jakub Tolar, Paul J Orchard, Troy C Lund

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalGenetics in Medicine
DOIs
StatePublished - Jan 1 2019

Fingerprint

Mucopolysaccharidosis I
Enzyme Replacement Therapy
Biomarkers
Cerebrospinal Fluid
Enzymes
Therapeutics
Cerebrospinal Fluid Pressure
Cell Transplantation
Glycosaminoglycans
Neurodegenerative Diseases
Inflammation
Safety

Keywords

  • biomarkers
  • enzyme replacement therapy
  • intrathecal therapy
  • mucopolysaccharidosis
  • neurocognitive decline

Cite this

Intrathecal enzyme replacement for Hurler syndrome : biomarker association with neurocognitive outcomes. / Eisengart, Julie; Pierpont, Rene; Kaizer, Alexander M.; Rudser, Kyle; King, Kelly E; Pasquali, Marzia; Polgreen, Lynda E.; Dickson, Patricia I.; Le, Steven Q.; Miller, Weston P.; Tolar, Jakub; Orchard, Paul J; Lund, Troy C.

In: Genetics in Medicine, 01.01.2019.

Research output: Contribution to journalArticle

@article{c09b5641767a46e48f3dfde620ba4c6b,
title = "Intrathecal enzyme replacement for Hurler syndrome: biomarker association with neurocognitive outcomes",
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",
author = "Julie Eisengart and Rene Pierpont and Kaizer, {Alexander M.} and Kyle Rudser and King, {Kelly E} and Marzia Pasquali and Polgreen, {Lynda E.} and Dickson, {Patricia I.} and Le, {Steven Q.} and Miller, {Weston P.} and Jakub Tolar and Orchard, {Paul J} and Lund, {Troy C}",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41436-019-0522-1",
language = "English (US)",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Lippincott Williams and Wilkins",

}

TY - JOUR

T1 - Intrathecal enzyme replacement for Hurler syndrome

T2 - biomarker association with neurocognitive outcomes

AU - Eisengart, Julie

AU - Pierpont, Rene

AU - Kaizer, Alexander M.

AU - Rudser, Kyle

AU - King, Kelly E

AU - Pasquali, Marzia

AU - Polgreen, Lynda E.

AU - Dickson, Patricia I.

AU - Le, Steven Q.

AU - Miller, Weston P.

AU - Tolar, Jakub

AU - Orchard, Paul J

AU - Lund, Troy C

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - biomarkers

KW - enzyme replacement therapy

KW - intrathecal therapy

KW - mucopolysaccharidosis

KW - neurocognitive decline

UR - http://www.scopus.com/inward/record.url?scp=85064803728&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064803728&partnerID=8YFLogxK

U2 - 10.1038/s41436-019-0522-1

DO - 10.1038/s41436-019-0522-1

M3 - Article

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

ER -