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.

Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management

“…Lysogene (Neuilly-sur-Seine, France) is currently investigating the use of AAVrh10 (LYS-SAF302) in the treatment of MPS IIIA with the first patients dosed in February of 2019. They recently published data on LYS-SAF302 in large animal models, which confirmed the efficacy of the drug, showing greater than 20% enzyme activity in 78% of dogs and 97% of monkeys [133]. Apart from the AAV-mediated treatment model, Orchard Therapeutics (London, UK) has started a Phase I/II ex vivo gene therapy using autologous CD34 + cells transfected with hSGSH-containing lentiviruses [134].…”

The Challenge of Gene Therapy for Neurological Diseases: Strategies and Tools to Achieve Efficient Delivery to the Central Nervous System

“…69,70 In contrast, AAV6 is axonally transported exclusively in a retrograde direction, 68 whereas AAV9 shows a bidirectional transport and is dose dependent. 71 Recent studies suggest that AAV5 and AAVrh10 have more global transduction with widespread distribution in the brain 11,72,73 and spinal cord. LVs are able to deliver the therapeutic gene in a restricted area.…”

Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches

“…To increase efficacy, multiple intraparenchymal regions should be injected to ensure widespread distribution. To study SGSH distribution in the brain of large animals, the same transducing vector was injected via parenchyma in dogs and cynomolgus monkeys, and SGSH enzyme activity increase was detected [ 115 ].…”