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.
| Language | English |
|---|---|
| Pages | 174-187 |
| Number of pages | 14 |
| Journal | Molecular Therapy - Methods and Clinical Development |
| Volume | 17 |
| DOIs | |
| Publication status | Published - 9 Dec 2019 |
Keywords
- AAV
- gene therapy
- lysosomal storage disease
- mucopolysaccharidosis
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
Cite this
}
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 journal › Article
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 -