Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in mucopolysaccharidosis IIIA mice

Alexander Langford-Smith, Fiona L Wilkinson, Kia J Langford-Smith, Rebecca J Holley, Ana Sergijenko, Steven J Howe, William R Bennett, Simon A Jones, Je Wraith, Catherine Lr Merry, Robert F Wynn, Brian W Bigger

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo disease) is a neurodegenerative disorder caused by a deficiency in the lysosomal enzyme sulfamidase (SGSH), catabolizing heparan sulfate (HS). Affected children present with severe behavioral abnormalities, sleep disturbances, and progressive neurodegeneration, leading to death in their second decade. MPS I, a similar neurodegenerative disease accumulating HS, is treated successfully with hematopoietic stem cell transplantation (HSCT) but this treatment is ineffectual for MPS IIIA. We compared HSCT in MPS IIIA mice using wild-type donor cells transduced ex vivo with lentiviral vector-expressing SGSH (LV-WT-HSCT) versus wild-type donor cell transplant (WT-HSCT) or lentiviral-SGSH transduced MPS IIIA cells (LV-IIIA-HSCT). LV-WT-HSCT results in 10% of normal brain enzyme activity, near normalization of brain HS and GM2 gangliosides, significant improvements in neuroinflammation and behavioral correction. Both WT-HSCT and LV-IIIA-HSCT mediated improvements in GM2 gangliosides and neuroinflammation but were less effective at reducing HS or in ameliorating abnormal HS sulfation and had no significant effect on behavior. This suggests that HS may have a more significant role in neuropathology than neuroinflammation or GM2 gangliosides. These data provide compelling evidence for the efficacy of gene therapy in conjunction with WT-HSCT for neurological correction of MPS IIIA where conventional transplant is ineffectual.

Original languageEnglish
Pages (from-to)1610-1621
Number of pages12
JournalMolecular therapy : the journal of the American Society of Gene Therapy
Volume20
Issue number8
Early online date1 May 2012
DOIs
Publication statusPublished - Aug 2012

Fingerprint

Mucopolysaccharidoses
Hematopoietic Stem Cell Transplantation
Cell- and Tissue-Based Therapy
Hematopoietic Stem Cells
Genetic Therapy
Mucopolysaccharidosis III
Heparitin Sulfate
G(M2) Ganglioside
Neurodegenerative Diseases
Tissue Donors
Transplants
Neuropathology
Brain
Enzymes
Sleep

Keywords

  • animals
  • female
  • flow cytometry
  • genetic therapy
  • hematopoietic stem cells
  • immunohistochemistry
  • mice
  • mucopolysaccharidoses

Cite this

Langford-Smith, A., Wilkinson, F. L., Langford-Smith, K. J., Holley, R. J., Sergijenko, A., Howe, S. J., ... Bigger, B. W. (2012). Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in mucopolysaccharidosis IIIA mice. Molecular therapy : the journal of the American Society of Gene Therapy, 20(8), 1610-1621. https://doi.org/10.1038/mt.2012.82

Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in mucopolysaccharidosis IIIA mice. / Langford-Smith, Alexander; Wilkinson, Fiona L; Langford-Smith, Kia J; Holley, Rebecca J; Sergijenko, Ana; Howe, Steven J; Bennett, William R; Jones, Simon A; Wraith, Je; Merry, Catherine Lr; Wynn, Robert F; Bigger, Brian W.

In: Molecular therapy : the journal of the American Society of Gene Therapy, Vol. 20, No. 8, 08.2012, p. 1610-1621.

Research output: Contribution to journalArticle

Langford-Smith, A, Wilkinson, FL, Langford-Smith, KJ, Holley, RJ, Sergijenko, A, Howe, SJ, Bennett, WR, Jones, SA, Wraith, J, Merry, CL, Wynn, RF & Bigger, BW 2012, 'Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in mucopolysaccharidosis IIIA mice', Molecular therapy : the journal of the American Society of Gene Therapy, vol. 20, no. 8, pp. 1610-1621. https://doi.org/10.1038/mt.2012.82
Langford-Smith, Alexander ; Wilkinson, Fiona L ; Langford-Smith, Kia J ; Holley, Rebecca J ; Sergijenko, Ana ; Howe, Steven J ; Bennett, William R ; Jones, Simon A ; Wraith, Je ; Merry, Catherine Lr ; Wynn, Robert F ; Bigger, Brian W. / Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in mucopolysaccharidosis IIIA mice. In: Molecular therapy : the journal of the American Society of Gene Therapy. 2012 ; Vol. 20, No. 8. pp. 1610-1621.
@article{6c8cdba50f3e4ffbaa79f16160023020,
title = "Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in mucopolysaccharidosis IIIA mice",
abstract = "Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo disease) is a neurodegenerative disorder caused by a deficiency in the lysosomal enzyme sulfamidase (SGSH), catabolizing heparan sulfate (HS). Affected children present with severe behavioral abnormalities, sleep disturbances, and progressive neurodegeneration, leading to death in their second decade. MPS I, a similar neurodegenerative disease accumulating HS, is treated successfully with hematopoietic stem cell transplantation (HSCT) but this treatment is ineffectual for MPS IIIA. We compared HSCT in MPS IIIA mice using wild-type donor cells transduced ex vivo with lentiviral vector-expressing SGSH (LV-WT-HSCT) versus wild-type donor cell transplant (WT-HSCT) or lentiviral-SGSH transduced MPS IIIA cells (LV-IIIA-HSCT). LV-WT-HSCT results in 10{\%} of normal brain enzyme activity, near normalization of brain HS and GM2 gangliosides, significant improvements in neuroinflammation and behavioral correction. Both WT-HSCT and LV-IIIA-HSCT mediated improvements in GM2 gangliosides and neuroinflammation but were less effective at reducing HS or in ameliorating abnormal HS sulfation and had no significant effect on behavior. This suggests that HS may have a more significant role in neuropathology than neuroinflammation or GM2 gangliosides. These data provide compelling evidence for the efficacy of gene therapy in conjunction with WT-HSCT for neurological correction of MPS IIIA where conventional transplant is ineffectual.",
keywords = "animals, female, flow cytometry, genetic therapy, hematopoietic stem cells, immunohistochemistry, mice, mucopolysaccharidoses",
author = "Alexander Langford-Smith and Wilkinson, {Fiona L} and Langford-Smith, {Kia J} and Holley, {Rebecca J} and Ana Sergijenko and Howe, {Steven J} and Bennett, {William R} and Jones, {Simon A} and Je Wraith and Merry, {Catherine Lr} and Wynn, {Robert F} and Bigger, {Brian W}",
year = "2012",
month = "8",
doi = "10.1038/mt.2012.82",
language = "English",
volume = "20",
pages = "1610--1621",
journal = "Molecular therapy : the journal of the American Society of Gene Therapy",
issn = "1525-0024",
publisher = "Cell Press",
number = "8",

}

TY - JOUR

T1 - Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in mucopolysaccharidosis IIIA mice

AU - Langford-Smith, Alexander

AU - Wilkinson, Fiona L

AU - Langford-Smith, Kia J

AU - Holley, Rebecca J

AU - Sergijenko, Ana

AU - Howe, Steven J

AU - Bennett, William R

AU - Jones, Simon A

AU - Wraith, Je

AU - Merry, Catherine Lr

AU - Wynn, Robert F

AU - Bigger, Brian W

PY - 2012/8

Y1 - 2012/8

N2 - Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo disease) is a neurodegenerative disorder caused by a deficiency in the lysosomal enzyme sulfamidase (SGSH), catabolizing heparan sulfate (HS). Affected children present with severe behavioral abnormalities, sleep disturbances, and progressive neurodegeneration, leading to death in their second decade. MPS I, a similar neurodegenerative disease accumulating HS, is treated successfully with hematopoietic stem cell transplantation (HSCT) but this treatment is ineffectual for MPS IIIA. We compared HSCT in MPS IIIA mice using wild-type donor cells transduced ex vivo with lentiviral vector-expressing SGSH (LV-WT-HSCT) versus wild-type donor cell transplant (WT-HSCT) or lentiviral-SGSH transduced MPS IIIA cells (LV-IIIA-HSCT). LV-WT-HSCT results in 10% of normal brain enzyme activity, near normalization of brain HS and GM2 gangliosides, significant improvements in neuroinflammation and behavioral correction. Both WT-HSCT and LV-IIIA-HSCT mediated improvements in GM2 gangliosides and neuroinflammation but were less effective at reducing HS or in ameliorating abnormal HS sulfation and had no significant effect on behavior. This suggests that HS may have a more significant role in neuropathology than neuroinflammation or GM2 gangliosides. These data provide compelling evidence for the efficacy of gene therapy in conjunction with WT-HSCT for neurological correction of MPS IIIA where conventional transplant is ineffectual.

AB - Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo disease) is a neurodegenerative disorder caused by a deficiency in the lysosomal enzyme sulfamidase (SGSH), catabolizing heparan sulfate (HS). Affected children present with severe behavioral abnormalities, sleep disturbances, and progressive neurodegeneration, leading to death in their second decade. MPS I, a similar neurodegenerative disease accumulating HS, is treated successfully with hematopoietic stem cell transplantation (HSCT) but this treatment is ineffectual for MPS IIIA. We compared HSCT in MPS IIIA mice using wild-type donor cells transduced ex vivo with lentiviral vector-expressing SGSH (LV-WT-HSCT) versus wild-type donor cell transplant (WT-HSCT) or lentiviral-SGSH transduced MPS IIIA cells (LV-IIIA-HSCT). LV-WT-HSCT results in 10% of normal brain enzyme activity, near normalization of brain HS and GM2 gangliosides, significant improvements in neuroinflammation and behavioral correction. Both WT-HSCT and LV-IIIA-HSCT mediated improvements in GM2 gangliosides and neuroinflammation but were less effective at reducing HS or in ameliorating abnormal HS sulfation and had no significant effect on behavior. This suggests that HS may have a more significant role in neuropathology than neuroinflammation or GM2 gangliosides. These data provide compelling evidence for the efficacy of gene therapy in conjunction with WT-HSCT for neurological correction of MPS IIIA where conventional transplant is ineffectual.

KW - animals

KW - female

KW - flow cytometry

KW - genetic therapy

KW - hematopoietic stem cells

KW - immunohistochemistry

KW - mice

KW - mucopolysaccharidoses

U2 - 10.1038/mt.2012.82

DO - 10.1038/mt.2012.82

M3 - Article

C2 - 22547151

VL - 20

SP - 1610

EP - 1621

JO - Molecular therapy : the journal of the American Society of Gene Therapy

JF - Molecular therapy : the journal of the American Society of Gene Therapy

SN - 1525-0024

IS - 8

ER -