Molecular Therapy: Methods & Clinical Development (Jun 2020)

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

Journal volume & issue
Vol. 17
pp. 174 – 187

Abstract

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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.

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