Functional correction of neurological and somatic disorders at later stages of disease in MPS IIIA mice by systemic scAAV9-hSGSH gene delivery

Abstract

The reversibility of neuropathic lysosomal storage diseases, including MPS IIIA, is a major goal in therapeutic development, due to typically late diagnoses and a large population of untreated patients. We used self-complementary adeno-associated virus (scAAV) serotype 9 vector expressing human N-sulfoglucosamine sulfohydrolase (SGSH) to test the efficacy of treatment at later stages of the disease. We treated MPS IIIA mice at 1, 2, 3, 6, and 9 months of age with an intravenous injection of scAAV9-U1a-hSGSH vector, leading to restoration of SGSH activity and reduction of glycosaminoglycans (GAG) throughout the central nervous system (CNS) and somatic tissues at a dose of 5E12 vg/kg. Treatment up to 3 months age improved learning ability in the Morris water maze at 7.5 months, and lifespan was normalized. In mice treated at 6 months age, behavioral performance was impaired at 7.5 months, but did not decline further when retested at 12 months, and lifespan was increased, but not normalized. Treatment at 9 months did not increase life-span, though the GAG storage pathology in the CNS was improved. The study suggests that there is potential for gene therapy intervention in MPS IIIA at intermediate stages of the disease, and extends the clinical relevance of our systemic scAAV9-hSGSH gene delivery approach.

Targeting Root Cause by Systemic scAAV9-hIDS Gene Delivery: Functional Correction and Reversal of Severe MPS II in Mice

“…This indicates that a systemic delivery of scAAV9-mCMV-h IDS at an effective dose can mediate the expression of functional rIDS at levels sufficient to effectively clear CNS and somatic GAG storage, regardless of the disease stage to a certain extent, offering extended clinical potential for treating MPS II in humans. Notably, our previous study showed that treating MPS IIIA mice at age 9 months with scAAV9-U1a-h SGSH provided only minimal functional benefit, with no improvement in survival 41 . It is unclear why this scAAV9-h IDS for MPS II is more effective in reversing the disease than scAAV9-h GSH for MPS IIIA.…”

Timing of Gene Therapy Interventions: The Earlier, the Better

“…Fu et al 3 found an age-dependent response to SGSH gene transfer. Importantly, the persistence and level of SGSH expression, as well as the clearance of GAGs, did not appear to be greatly influenced by the age at dosing up to 6 months old, allowing the authors to attribute any differences in efficacy to secondary (presumably irreversible) pathologies in the mice.…”

“…1,2 In a recent issue of Molecular Therapy-Methods & Clinical Development, Fu and colleagues reported the results of a detailed investigation to address the effectiveness of the treatment at different stages of the disease. 3 Specifically, they dosed MPS IIIA mice intravenously with selfcomplementary adeno-associated virus serotype 9 (AAV9) vectors carrying the sulfoglucosamine sulfohydrolase (SGSH) gene at the ages of 1, 2, 3, 6, or 9 months old. At an early stage of the disease the treatment was highly effective, and at the middle stage of the disease the treatment was capable of halting the disease progression, but at the later stage of the disease (9 months) the treatment had minimal benefit to the mice.…”

Gene therapy for Mucopolysaccharidoses

“…Several studies have shown that systemic delivery of rAAV8 or rAAV9 containing the deficient gene cause elevation of lysosomal enzyme activity in CNS lesions and correction of disease progression in mouse models of MPS IIIA [90–93] and MPS IIIB [82,94–96]. Fu et al showed that a single IV administration of a scAAV9 vector encoding human N-sulfoglucosamine sulfohydrolase (hSGSH) (5e 12 vg/kg) in an MPS IIIA model mouse significantly improved behavior performance and survival rate [93] Improvements were best when the vector was administered at an early stage of disease, but these phenotypes were also partially corrected when treatment was delayed until mice showed intermediate progression of disease.…”

“…Fu et al showed that a single IV administration of a scAAV9 vector encoding human N-sulfoglucosamine sulfohydrolase (hSGSH) (5e 12 vg/kg) in an MPS IIIA model mouse significantly improved behavior performance and survival rate [93] Improvements were best when the vector was administered at an early stage of disease, but these phenotypes were also partially corrected when treatment was delayed until mice showed intermediate progression of disease. These results suggest that scAAV9-hSGSH vector may be clinically useful to reverse disease progression in patients with established MPS IIIA.…”