AAVrh10 vector corrects disease pathology in MPS IIIA mice and achieves widespread distribution of SGSH in large animal brains

Michaël Hocquemiller, Kim M. Hemsley, Meghan L. Douglass, Sarah Tamang, Daniel Neumann, Barbara King, Helen Beard, Paul Trim, Leanne Winner, Adeline Bowen, Marten Snel, Cathy Gomila, Jérôme Ausseil, Xin Mei, Laura Giersch, Mark Plavsic, Ralph Laufer

Research output: Contribution to journalArticle

Abstract

Patients with mucopolysaccharidosis type IIIA (MPS IIIA) lack the lysosomal enzyme sulfamidase (SGSH), which is responsible for the degradation of heparan sulfate (HS). Build-up of undegraded HS results in severe progressive neurodegeneration for which there is currently no treatment. The ability of the vector adeno-associated virus (AAV)rh.10-CAG-SGSH (LYS-SAF302) to correct disease pathology was evaluated in a mouse model for MPS IIIA. LYS-SAF302 was administered to 5-week-old MPS IIIA mice at three different doses (8.6E+08, 4.1E+10, and 9.0E+10 vector genomes [vg]/animal) injected into the caudate putamen/striatum and thalamus. LYS-SAF302 was able to dose-dependently correct or significantly reduce HS storage, secondary accumulation of GM2 and GM3 gangliosides, ubiquitin-reactive axonal spheroid lesions, lysosomal expansion, and neuroinflammation at 12 weeks and 25 weeks post-dosing. To study SGSH distribution in the brain of large animals, LYS-SAF302 was injected into the subcortical white matter of dogs (1.0E+12 or 2.0E+12 vg/animal) and cynomolgus monkeys (7.2E+11 vg/animal). Increases of SGSH enzyme activity of at least 20% above endogenous levels were detected in 78% (dogs 4 weeks after injection) and 97% (monkeys 6 weeks after injection) of the total brain volume. Taken together, these data validate intraparenchymal AAV administration as a promising method to achieve widespread enzyme distribution and correction of disease pathology in MPS IIIA.

LanguageEnglish
Pages174-187
Number of pages14
JournalMolecular Therapy - Methods and Clinical Development
Volume17
DOIs
Publication statusPublished - 9 Dec 2019

Keywords

  • AAV
  • gene therapy
  • lysosomal storage disease
  • mucopolysaccharidosis

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Hocquemiller, Michaël ; Hemsley, Kim M. ; Douglass, Meghan L. ; Tamang, Sarah ; Neumann, Daniel ; King, Barbara ; Beard, Helen ; Trim, Paul ; Winner, Leanne ; Bowen, Adeline ; Snel, Marten ; Gomila, Cathy ; Ausseil, Jérôme ; Mei, Xin ; Giersch, Laura ; Plavsic, Mark ; Laufer, Ralph. / AAVrh10 vector corrects disease pathology in MPS IIIA mice and achieves widespread distribution of SGSH in large animal brains. In: Molecular Therapy - Methods and Clinical Development. 2019 ; Vol. 17. pp. 174-187.
@article{08a38d234fef44759cc7349da9cf11e8,
title = "AAVrh10 vector corrects disease pathology in MPS IIIA mice and achieves widespread distribution of SGSH in large animal brains",
abstract = "Patients with mucopolysaccharidosis type IIIA (MPS IIIA) lack the lysosomal enzyme sulfamidase (SGSH), which is responsible for the degradation of heparan sulfate (HS). Build-up of undegraded HS results in severe progressive neurodegeneration for which there is currently no treatment. The ability of the vector adeno-associated virus (AAV)rh.10-CAG-SGSH (LYS-SAF302) to correct disease pathology was evaluated in a mouse model for MPS IIIA. LYS-SAF302 was administered to 5-week-old MPS IIIA mice at three different doses (8.6E+08, 4.1E+10, and 9.0E+10 vector genomes [vg]/animal) injected into the caudate putamen/striatum and thalamus. LYS-SAF302 was able to dose-dependently correct or significantly reduce HS storage, secondary accumulation of GM2 and GM3 gangliosides, ubiquitin-reactive axonal spheroid lesions, lysosomal expansion, and neuroinflammation at 12 weeks and 25 weeks post-dosing. To study SGSH distribution in the brain of large animals, LYS-SAF302 was injected into the subcortical white matter of dogs (1.0E+12 or 2.0E+12 vg/animal) and cynomolgus monkeys (7.2E+11 vg/animal). Increases of SGSH enzyme activity of at least 20{\%} above endogenous levels were detected in 78{\%} (dogs 4 weeks after injection) and 97{\%} (monkeys 6 weeks after injection) of the total brain volume. Taken together, these data validate intraparenchymal AAV administration as a promising method to achieve widespread enzyme distribution and correction of disease pathology in MPS IIIA.",
keywords = "AAV, gene therapy, lysosomal storage disease, mucopolysaccharidosis",
author = "Micha{\"e}l Hocquemiller and Hemsley, {Kim M.} and Douglass, {Meghan L.} and Sarah Tamang and Daniel Neumann and Barbara King and Helen Beard and Paul Trim and Leanne Winner and Adeline Bowen and Marten Snel and Cathy Gomila and J{\'e}r{\^o}me Ausseil and Xin Mei and Laura Giersch and Mark Plavsic and Ralph Laufer",
year = "2019",
month = "12",
day = "9",
doi = "10.1016/j.omtm.2019.12.001",
language = "English",
volume = "17",
pages = "174--187",
journal = "Molecular Therapy - Methods and Clinical Development",
issn = "2329-0501",
publisher = "Cell Press",

}

Hocquemiller, M, Hemsley, KM, Douglass, ML, Tamang, S, Neumann, D, King, B, Beard, H, Trim, P, Winner, L, Bowen, A, Snel, M, Gomila, C, Ausseil, J, Mei, X, Giersch, L, Plavsic, M & Laufer, R 2019, 'AAVrh10 vector corrects disease pathology in MPS IIIA mice and achieves widespread distribution of SGSH in large animal brains', Molecular Therapy - Methods and Clinical Development, vol. 17, pp. 174-187. https://doi.org/10.1016/j.omtm.2019.12.001

AAVrh10 vector corrects disease pathology in MPS IIIA mice and achieves widespread distribution of SGSH in large animal brains. / Hocquemiller, Michaël; Hemsley, Kim M.; Douglass, Meghan L.; Tamang, Sarah; Neumann, Daniel; King, Barbara; Beard, Helen; Trim, Paul; Winner, Leanne; Bowen, Adeline; Snel, Marten; Gomila, Cathy; Ausseil, Jérôme; Mei, Xin; Giersch, Laura; Plavsic, Mark; Laufer, Ralph.

In: Molecular Therapy - Methods and Clinical Development, Vol. 17, 09.12.2019, p. 174-187.

Research output: Contribution to journalArticle

TY - JOUR

T1 - AAVrh10 vector corrects disease pathology in MPS IIIA mice and achieves widespread distribution of SGSH in large animal brains

AU - Hocquemiller, Michaël

AU - Hemsley, Kim M.

AU - Douglass, Meghan L.

AU - Tamang, Sarah

AU - Neumann, Daniel

AU - King, Barbara

AU - Beard, Helen

AU - Trim, Paul

AU - Winner, Leanne

AU - Bowen, Adeline

AU - Snel, Marten

AU - Gomila, Cathy

AU - Ausseil, Jérôme

AU - Mei, Xin

AU - Giersch, Laura

AU - Plavsic, Mark

AU - Laufer, Ralph

PY - 2019/12/9

Y1 - 2019/12/9

N2 - Patients with mucopolysaccharidosis type IIIA (MPS IIIA) lack the lysosomal enzyme sulfamidase (SGSH), which is responsible for the degradation of heparan sulfate (HS). Build-up of undegraded HS results in severe progressive neurodegeneration for which there is currently no treatment. The ability of the vector adeno-associated virus (AAV)rh.10-CAG-SGSH (LYS-SAF302) to correct disease pathology was evaluated in a mouse model for MPS IIIA. LYS-SAF302 was administered to 5-week-old MPS IIIA mice at three different doses (8.6E+08, 4.1E+10, and 9.0E+10 vector genomes [vg]/animal) injected into the caudate putamen/striatum and thalamus. LYS-SAF302 was able to dose-dependently correct or significantly reduce HS storage, secondary accumulation of GM2 and GM3 gangliosides, ubiquitin-reactive axonal spheroid lesions, lysosomal expansion, and neuroinflammation at 12 weeks and 25 weeks post-dosing. To study SGSH distribution in the brain of large animals, LYS-SAF302 was injected into the subcortical white matter of dogs (1.0E+12 or 2.0E+12 vg/animal) and cynomolgus monkeys (7.2E+11 vg/animal). Increases of SGSH enzyme activity of at least 20% above endogenous levels were detected in 78% (dogs 4 weeks after injection) and 97% (monkeys 6 weeks after injection) of the total brain volume. Taken together, these data validate intraparenchymal AAV administration as a promising method to achieve widespread enzyme distribution and correction of disease pathology in MPS IIIA.

AB - Patients with mucopolysaccharidosis type IIIA (MPS IIIA) lack the lysosomal enzyme sulfamidase (SGSH), which is responsible for the degradation of heparan sulfate (HS). Build-up of undegraded HS results in severe progressive neurodegeneration for which there is currently no treatment. The ability of the vector adeno-associated virus (AAV)rh.10-CAG-SGSH (LYS-SAF302) to correct disease pathology was evaluated in a mouse model for MPS IIIA. LYS-SAF302 was administered to 5-week-old MPS IIIA mice at three different doses (8.6E+08, 4.1E+10, and 9.0E+10 vector genomes [vg]/animal) injected into the caudate putamen/striatum and thalamus. LYS-SAF302 was able to dose-dependently correct or significantly reduce HS storage, secondary accumulation of GM2 and GM3 gangliosides, ubiquitin-reactive axonal spheroid lesions, lysosomal expansion, and neuroinflammation at 12 weeks and 25 weeks post-dosing. To study SGSH distribution in the brain of large animals, LYS-SAF302 was injected into the subcortical white matter of dogs (1.0E+12 or 2.0E+12 vg/animal) and cynomolgus monkeys (7.2E+11 vg/animal). Increases of SGSH enzyme activity of at least 20% above endogenous levels were detected in 78% (dogs 4 weeks after injection) and 97% (monkeys 6 weeks after injection) of the total brain volume. Taken together, these data validate intraparenchymal AAV administration as a promising method to achieve widespread enzyme distribution and correction of disease pathology in MPS IIIA.

KW - AAV

KW - gene therapy

KW - lysosomal storage disease

KW - mucopolysaccharidosis

UR - http://www.scopus.com/inward/record.url?scp=85077079982&partnerID=8YFLogxK

U2 - 10.1016/j.omtm.2019.12.001

DO - 10.1016/j.omtm.2019.12.001

M3 - Article

VL - 17

SP - 174

EP - 187

JO - Molecular Therapy - Methods and Clinical Development

T2 - Molecular Therapy - Methods and Clinical Development

JF - Molecular Therapy - Methods and Clinical Development

SN - 2329-0501

ER -