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 J. Tamang, Daniel Neumann, Barbara M. King, Helen Beard, Paul J. Trim, Leanne K. Winner, Adeline A. Lau, Marten F. Snel, Cathy Gomila, Jérôme Ausseil, Xin Mei, Laura Giersch, Mark Plavsic, Ralph Laufer

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)
91 Downloads (Pure)


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.

Original languageEnglish
Pages (from-to)174-187
Number of pages14
JournalMolecular Therapy: Methods and Clinical Development
Publication statusPublished - 12 Jun 2020
Externally publishedYes

Bibliographical note

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).


  • AAV
  • gene therapy
  • lysosomal storage disease
  • mucopolysaccharidosis


Dive into the research topics of 'AAVrh10 Vector Corrects Disease Pathology in MPS IIIA Mice and Achieves Widespread Distribution of SGSH in Large Animal Brains'. Together they form a unique fingerprint.

Cite this