Correction of Neurological Disease of Mucopolysaccharidosis IIIB in Adult Mice by rAAV9 Trans-Blood–Brain Barrier Gene Delivery

Abstract

The greatest challenge in developing therapies for mucopolysaccharidosis (MPS) IIIB is to achieve efficient central nervous system (CNS) delivery across the blood-brain barrier (BBB). In this study, we used the novel ability of adeno-associated virus serotype 9 (AAV9) to cross the BBB from the vasculature to achieve long-term global CNS, and widespread somatic restoration of α-N-acetylglucosaminidase (NAGLU) activity. A single intravenous (IV) injection of rAAV9-CMV-hNAGLU, without extraneous treatment to disrupt the BBB, restored NAGLU activity to normal or above normal levels in adult MPS IIIB mice, leading to the correction of lysosomal storage pathology in the CNS and periphery, and correction of astrocytosis and neurodegeneration. The IV delivered rAAV9 vector also transduced abundant neurons in the myenteric and submucosal plexus, suggesting peripheral nervous system (PNS) targeting. While CNS entry did not depend on osmotic disruption of the BBB, it was significantly enhanced by pretreatment with an IV infusion of mannitol. Most important, we demonstrate that a single systemic rAAV9-NAGLU gene delivery provides long-term (>18 months) neurological benefits in MPS IIIB mice, resulting in significant improvement in behavioral performance, and extension of survival. These data suggest promising clinical potential using the trans-BBB neurotropic rAAV9 vector for treating MPS IIIB and other neurogenetic diseases.

Viral vectors for therapy of neurologic diseases

“…Numerous preclinical studies with gene replacement by in vivo intracranial AAV administration have shown partial to complete phenotypic correction in animal models of several LSDs. These include MPS I (Hinderer et al, 2014), MPS IIIA (Ruzo et al, 2012), MPS IIIB (Fu et al, 2011), MPS VII (Cearley and Wolfe, 2007), MLD (Miyake et al, 2014; Sevin et al, 2006), multiple sulfatase deficiency (MSD) (Spampanato et al, 2011), Niemann-Pick A disease (Passini et al, 2005), Pompe disease (Falk et al, 2013), GM1-gangliosidosis (Weismann et al, 2015), Tay Sachs disease (Cachón-González et al, 2006) and Sandhoff disease (Sargeant et al, 2011). …”

Catalytic Immunoglobulin Gene Delivery in a Mouse Model of Alzheimer’s Disease: Prophylactic and Therapeutic Applications

“…Self-complementary rAAV vectors can significantly improve the efficacy of transduction as compared with identical vectors in a single-stranded format [59-61] . Widespread and high expression of transgenes in the brain has been reported by systemic intravenous injection of rAAV9 [62], intraparenchymal injection of rAAV9 into nuclei with divergent connections [49], and their combinations [63]. These strategies for improved gene therapy should be exploited in future.…”

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.…”

“…These results suggest that scAAV9-hSGSH vector may be clinically useful to reverse disease progression in patients with established MPS IIIA. This group also showed that IV administration of rAAV9 containing human α- N -acetylglucosaminidase (hNAGLU) corrected GAG accumulation in CNS and somatic tissues and provided long-term (> 18 months) neurological improvement in MPS IIIB model mouse [94]. An investigational new drug (IND)-enabling good laboratory practice (GLP)-compliant toxicology study demonstrated that injection of the rAAV9 did not provide adverse clinical events and chronic toxicity during a 6-month study [95].…”