Myeloid/Microglial driven autologous hematopoietic stem cell gene therapy corrects a neuronopathic lysosomal disease

Ana Sergijenko, Alexander Langford-Smith, Ai Y Liao, Claire E Pickford, John McDermott, Gabriel Nowinski, Kia J Langford-Smith, Catherine L R Merry, Simon A Jones, J Edmond Wraith, Robert F Wynn, Fiona L Wilkinson, Brian W Bigger

Research output: Contribution to journalArticle

49 Citations (Scopus)
3 Downloads (Pure)

Abstract

Mucopolysaccharidosis type IIIA (MPSIIIA) is a lysosomal storage disorder caused by mutations in N-sulfoglucosamine sulfohydrolase (SGSH), resulting in heparan sulfate (HS) accumulation and progressive neurodegeneration. There are no treatments. We previously demonstrated improved neuropathology in MPSIIIA mice using lentiviral vectors (LVs) overexpressing SGSH in wild-type (WT) hematopoietic stem cell (HSC) transplants (HSCTs), achieved via donor monocyte/microglial engraftment in the brain. However, neurological disease was not corrected using LVs in autologous MPSIIIA HSCTs. To improve brain expression via monocyte/microglial specificity, LVs expressing enhanced green fluorescent protein (eGFP) under ubiquitous phosphoglycerate kinase (PGK) or myeloid-specific promoters were compared in transplanted HSCs. LV-CD11b-GFP gave significantly higher monocyte/B-cell eGFP expression than LV-PGK-GFP or LV-CD18-GFP after 6 months. Subsequently, autologous MPSIIIA HSCs were transduced with either LV-PGK-coSGSH or LV-CD11b-coSGSH vectors expressing codon-optimized SGSH and transplanted into MPSIIIA mice. Eight months after HSCT, LV-PGK-coSGSH vectors produced bone marrow SGSH (576% normal activity) similar to LV-CD11b-coSGSH (473%), but LV-CD11b-coSGSH had significantly higher brain expression (11 versus 7%), demonstrating improved brain specificity. LV-CD11b-coSGSH normalized MPSIIIA behavior, brain HS, GM2 ganglioside, and neuroinflammation to WT levels, whereas LV-PGK-coSGSH partly corrected neuropathology but not behavior. We demonstrate compelling evidence of neurological disease correction using autologous myeloid driven lentiviral-HSC gene therapy in MPSIIIA mice.

Original languageEnglish
Pages (from-to)1938-49
Number of pages12
JournalMolecular therapy : the journal of the American Society of Gene Therapy
Volume21
Issue number10
Early online date16 Jul 2013
DOIs
Publication statusPublished - Oct 2013

Fingerprint

Mucopolysaccharidosis III
Cell- and Tissue-Based Therapy
Hematopoietic Stem Cells
Phosphoglycerate Kinase
Genetic Therapy
Brain
Monocytes
Heparitin Sulfate
Transplants
G(M2) Ganglioside
Mucopolysaccharidosis I
Codon
B-Lymphocytes
Bone Marrow
Mutation

Keywords

  • Animals
  • Antigens, CD11b
  • Brain
  • Cell Line
  • Disease Models, Animal
  • Female
  • Genetic Therapy
  • Genetic Vectors
  • Green Fluorescent Proteins
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells
  • Heparitin Sulfate
  • Humans
  • Hydrolases
  • Lentivirus
  • Leukocytes
  • Lysosomes
  • Mice
  • Mice, Inbred C57BL
  • Microglia
  • Mucopolysaccharidosis III
  • Myeloid Cells
  • Organ Specificity
  • Promoter Regions, Genetic

Cite this

Myeloid/Microglial driven autologous hematopoietic stem cell gene therapy corrects a neuronopathic lysosomal disease. / Sergijenko, Ana; Langford-Smith, Alexander; Liao, Ai Y; Pickford, Claire E; McDermott, John; Nowinski, Gabriel; Langford-Smith, Kia J; Merry, Catherine L R; Jones, Simon A; Wraith, J Edmond; Wynn, Robert F; Wilkinson, Fiona L; Bigger, Brian W.

In: Molecular therapy : the journal of the American Society of Gene Therapy, Vol. 21, No. 10, 10.2013, p. 1938-49.

Research output: Contribution to journalArticle

Sergijenko, A, Langford-Smith, A, Liao, AY, Pickford, CE, McDermott, J, Nowinski, G, Langford-Smith, KJ, Merry, CLR, Jones, SA, Wraith, JE, Wynn, RF, Wilkinson, FL & Bigger, BW 2013, 'Myeloid/Microglial driven autologous hematopoietic stem cell gene therapy corrects a neuronopathic lysosomal disease', Molecular therapy : the journal of the American Society of Gene Therapy, vol. 21, no. 10, pp. 1938-49. https://doi.org/10.1038/mt.2013.141
Sergijenko, Ana ; Langford-Smith, Alexander ; Liao, Ai Y ; Pickford, Claire E ; McDermott, John ; Nowinski, Gabriel ; Langford-Smith, Kia J ; Merry, Catherine L R ; Jones, Simon A ; Wraith, J Edmond ; Wynn, Robert F ; Wilkinson, Fiona L ; Bigger, Brian W. / Myeloid/Microglial driven autologous hematopoietic stem cell gene therapy corrects a neuronopathic lysosomal disease. In: Molecular therapy : the journal of the American Society of Gene Therapy. 2013 ; Vol. 21, No. 10. pp. 1938-49.
@article{291d7692990b4de68711f0a15e934592,
title = "Myeloid/Microglial driven autologous hematopoietic stem cell gene therapy corrects a neuronopathic lysosomal disease",
abstract = "Mucopolysaccharidosis type IIIA (MPSIIIA) is a lysosomal storage disorder caused by mutations in N-sulfoglucosamine sulfohydrolase (SGSH), resulting in heparan sulfate (HS) accumulation and progressive neurodegeneration. There are no treatments. We previously demonstrated improved neuropathology in MPSIIIA mice using lentiviral vectors (LVs) overexpressing SGSH in wild-type (WT) hematopoietic stem cell (HSC) transplants (HSCTs), achieved via donor monocyte/microglial engraftment in the brain. However, neurological disease was not corrected using LVs in autologous MPSIIIA HSCTs. To improve brain expression via monocyte/microglial specificity, LVs expressing enhanced green fluorescent protein (eGFP) under ubiquitous phosphoglycerate kinase (PGK) or myeloid-specific promoters were compared in transplanted HSCs. LV-CD11b-GFP gave significantly higher monocyte/B-cell eGFP expression than LV-PGK-GFP or LV-CD18-GFP after 6 months. Subsequently, autologous MPSIIIA HSCs were transduced with either LV-PGK-coSGSH or LV-CD11b-coSGSH vectors expressing codon-optimized SGSH and transplanted into MPSIIIA mice. Eight months after HSCT, LV-PGK-coSGSH vectors produced bone marrow SGSH (576{\%} normal activity) similar to LV-CD11b-coSGSH (473{\%}), but LV-CD11b-coSGSH had significantly higher brain expression (11 versus 7{\%}), demonstrating improved brain specificity. LV-CD11b-coSGSH normalized MPSIIIA behavior, brain HS, GM2 ganglioside, and neuroinflammation to WT levels, whereas LV-PGK-coSGSH partly corrected neuropathology but not behavior. We demonstrate compelling evidence of neurological disease correction using autologous myeloid driven lentiviral-HSC gene therapy in MPSIIIA mice.",
keywords = "Animals, Antigens, CD11b, Brain, Cell Line, Disease Models, Animal, Female, Genetic Therapy, Genetic Vectors, Green Fluorescent Proteins, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Heparitin Sulfate, Humans, Hydrolases, Lentivirus, Leukocytes, Lysosomes, Mice, Mice, Inbred C57BL, Microglia, Mucopolysaccharidosis III, Myeloid Cells, Organ Specificity, Promoter Regions, Genetic",
author = "Ana Sergijenko and Alexander Langford-Smith and Liao, {Ai Y} and Pickford, {Claire E} and John McDermott and Gabriel Nowinski and Langford-Smith, {Kia J} and Merry, {Catherine L R} and Jones, {Simon A} and Wraith, {J Edmond} and Wynn, {Robert F} and Wilkinson, {Fiona L} and Bigger, {Brian W}",
year = "2013",
month = "10",
doi = "10.1038/mt.2013.141",
language = "English",
volume = "21",
pages = "1938--49",
journal = "Molecular therapy : the journal of the American Society of Gene Therapy",
issn = "1525-0024",
publisher = "Cell Press",
number = "10",

}

TY - JOUR

T1 - Myeloid/Microglial driven autologous hematopoietic stem cell gene therapy corrects a neuronopathic lysosomal disease

AU - Sergijenko, Ana

AU - Langford-Smith, Alexander

AU - Liao, Ai Y

AU - Pickford, Claire E

AU - McDermott, John

AU - Nowinski, Gabriel

AU - Langford-Smith, Kia J

AU - Merry, Catherine L R

AU - Jones, Simon A

AU - Wraith, J Edmond

AU - Wynn, Robert F

AU - Wilkinson, Fiona L

AU - Bigger, Brian W

PY - 2013/10

Y1 - 2013/10

N2 - Mucopolysaccharidosis type IIIA (MPSIIIA) is a lysosomal storage disorder caused by mutations in N-sulfoglucosamine sulfohydrolase (SGSH), resulting in heparan sulfate (HS) accumulation and progressive neurodegeneration. There are no treatments. We previously demonstrated improved neuropathology in MPSIIIA mice using lentiviral vectors (LVs) overexpressing SGSH in wild-type (WT) hematopoietic stem cell (HSC) transplants (HSCTs), achieved via donor monocyte/microglial engraftment in the brain. However, neurological disease was not corrected using LVs in autologous MPSIIIA HSCTs. To improve brain expression via monocyte/microglial specificity, LVs expressing enhanced green fluorescent protein (eGFP) under ubiquitous phosphoglycerate kinase (PGK) or myeloid-specific promoters were compared in transplanted HSCs. LV-CD11b-GFP gave significantly higher monocyte/B-cell eGFP expression than LV-PGK-GFP or LV-CD18-GFP after 6 months. Subsequently, autologous MPSIIIA HSCs were transduced with either LV-PGK-coSGSH or LV-CD11b-coSGSH vectors expressing codon-optimized SGSH and transplanted into MPSIIIA mice. Eight months after HSCT, LV-PGK-coSGSH vectors produced bone marrow SGSH (576% normal activity) similar to LV-CD11b-coSGSH (473%), but LV-CD11b-coSGSH had significantly higher brain expression (11 versus 7%), demonstrating improved brain specificity. LV-CD11b-coSGSH normalized MPSIIIA behavior, brain HS, GM2 ganglioside, and neuroinflammation to WT levels, whereas LV-PGK-coSGSH partly corrected neuropathology but not behavior. We demonstrate compelling evidence of neurological disease correction using autologous myeloid driven lentiviral-HSC gene therapy in MPSIIIA mice.

AB - Mucopolysaccharidosis type IIIA (MPSIIIA) is a lysosomal storage disorder caused by mutations in N-sulfoglucosamine sulfohydrolase (SGSH), resulting in heparan sulfate (HS) accumulation and progressive neurodegeneration. There are no treatments. We previously demonstrated improved neuropathology in MPSIIIA mice using lentiviral vectors (LVs) overexpressing SGSH in wild-type (WT) hematopoietic stem cell (HSC) transplants (HSCTs), achieved via donor monocyte/microglial engraftment in the brain. However, neurological disease was not corrected using LVs in autologous MPSIIIA HSCTs. To improve brain expression via monocyte/microglial specificity, LVs expressing enhanced green fluorescent protein (eGFP) under ubiquitous phosphoglycerate kinase (PGK) or myeloid-specific promoters were compared in transplanted HSCs. LV-CD11b-GFP gave significantly higher monocyte/B-cell eGFP expression than LV-PGK-GFP or LV-CD18-GFP after 6 months. Subsequently, autologous MPSIIIA HSCs were transduced with either LV-PGK-coSGSH or LV-CD11b-coSGSH vectors expressing codon-optimized SGSH and transplanted into MPSIIIA mice. Eight months after HSCT, LV-PGK-coSGSH vectors produced bone marrow SGSH (576% normal activity) similar to LV-CD11b-coSGSH (473%), but LV-CD11b-coSGSH had significantly higher brain expression (11 versus 7%), demonstrating improved brain specificity. LV-CD11b-coSGSH normalized MPSIIIA behavior, brain HS, GM2 ganglioside, and neuroinflammation to WT levels, whereas LV-PGK-coSGSH partly corrected neuropathology but not behavior. We demonstrate compelling evidence of neurological disease correction using autologous myeloid driven lentiviral-HSC gene therapy in MPSIIIA mice.

KW - Animals

KW - Antigens, CD11b

KW - Brain

KW - Cell Line

KW - Disease Models, Animal

KW - Female

KW - Genetic Therapy

KW - Genetic Vectors

KW - Green Fluorescent Proteins

KW - Hematopoietic Stem Cell Transplantation

KW - Hematopoietic Stem Cells

KW - Heparitin Sulfate

KW - Humans

KW - Hydrolases

KW - Lentivirus

KW - Leukocytes

KW - Lysosomes

KW - Mice

KW - Mice, Inbred C57BL

KW - Microglia

KW - Mucopolysaccharidosis III

KW - Myeloid Cells

KW - Organ Specificity

KW - Promoter Regions, Genetic

U2 - 10.1038/mt.2013.141

DO - 10.1038/mt.2013.141

M3 - Article

C2 - 23748415

VL - 21

SP - 1938

EP - 1949

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 - 10

ER -