Project name: Mus musculus

Description: Mucopolysaccharidosis (MPS) IIIA is a neuropathic lysosomal storage disease caused by deficiency in SGSH. Genome-wide gene expression microarrays in MPS IIIA mice detected broad molecular abnormalities (≥2 fold, FDR≤10) in numerous transcripts (314) in the brain and blood (397). Importantly, 22 dysregulated blood transcripts are known to be enriched in the brain and linked to broad neuronal functions. To target the root cause, we used a self-complementary (sc) AAVrh74 vector to deliver the human SGSH gene into 4-6-wk-old MPS IIIA mice by an intravenous injection. The treatment resulted in global CNS and widespread somatic restoration of SGSH activity, clearance of CNS and somatic GAG storage, improved behavior performance, and significantly extended survival. The scAAVrh74-hSGSH treatment also led to the correction of the majority of the transcriptional abnormalities in the brain (95.9%) and blood (97.7%), of which 182 and 290 transcripts were normalized in the brain and blood, respectively. These results demonstrate that a single systemic scAAVrh74-hSGSH delivery mediated efficient restoration of SGSH activity and resulted in a near complete correction of MPS IIIA molecular pathology. This study also demonstrates that blood transcriptional profiles reflect the biopathological status of MPS IIIA, and also respond well to effective treatments.Overall design: To assess the therapeutic impacts of scAAVrh74 gene delivery, we treated 4-6-wk-old MPS IIIA mice with an IV injection of scAAVrh74-U1a-hSGSH (5x1012vg/kg, n=13), using wt and non-treated MPS IIIA littermates (n=15) as controls. The animals were tested for behavioral performance in a hidden task in Morris water maze (n=13) and observed for longevity (n=9). At 7 mo post injection (pi), blood and tissue were collected from groups of male mice (n=4/per group) for analyses to assess therapeutic impact. We focused on males to minimize individual variation in the gene array analysis. Total RNA was isolated from the brain and peripheral blood of individual wt, non-treated MPS IIIA and scAAVrh74-treated mice (all male, n=4/group) and then analyzed separately (n=4/group) using genome-wide gene expression microarrays of >60,000 transcripts, to assess the potential blood-brain molecular association in MPS IIIA and their response to the vector treatment.

Data type: Transcriptome or Gene expression

Sample scope: Multiisolate

Relevance: ModelOrganism

Last updated: 2017-04-13