Mannitol-facilitated CNS entry of rAAV2 vector significantly delayed the neurological disease progression in MPS IIIB mice

McCarty, Douglas M.; DiRosario, Julianne; Gulaid, K; Muenzer, Joseph; Fu, Huiling

doi:10.1038/gt.2009.85

Cited by 93 publications

(78 citation statements)

References 58 publications

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“…Similarly, Burger et al [67] demonstrated its impact on the total number of transduced cells and on vector striatal distribution, showing a 400% and 200% increase, respectively.Moreover, according to a subsequent study by McCarty et al[68] the effect of mannitol in rAAV CNS entry potentiates its therapeutic action in neurological diseases after IV injection. However, it is important to state that this method generates an…”

mentioning

confidence: 92%

Gene therapy for the CNS using AAVs: The impact of systemic delivery by AAV9

Rajão‐Saraiva

Nobre

Almeida

2016

Journal of Controlled Release

153

127

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mentioning

confidence: 92%

Gene therapy for the CNS using AAVs: The impact of systemic delivery by AAV9

Rajão‐Saraiva

Nobre

Almeida

2016

Journal of Controlled Release

153

127

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“…The adeno-associated virus (AAV) vector system offers important advantages as a gene delivery tool for treating a great variety of diseases, including a broad tissue tropism and absence of known pathogenesis in humans (Berns and Linden, 1995). Recombinant AAV (rAAV) vectors based on AAV serotype 2 (AAV2) have been shown to transduce both neuronal and nonneuronal cells in the CNS in numerous gene therapy studies, with demonstrated therapeutic benefits in treating neurological diseases (Daya and Berns, 2008), including MPS and other LSDs, in animal models (Fu et al, 2002(Fu et al, , 2003(Fu et al, , 2007(Fu et al, , 2011Heuer et al, 2002;Desmaris et al, 2004;Liu et al, 2005;Fraldi et al, 2007;Sands and Haskins, 2008;McCarty et al, 2009;Baek et al, 2010;Heldermon et al, 2010;Ruzo et al, 2012). Multiple phase I clinical trials have been completed using rAAV gene delivery approaches in patients with neurological disorders (McPhee et al, 2006;Kaplitt et al, 2007;Worgall et al, 2008;Marks et al, 2010;Mittermeyer et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Feasibility and Safety of Systemic rAAV9-hNAGLU Delivery for Treating Mucopolysaccharidosis IIIB: Toxicology, Biodistribution, and Immunological Assessments in Primates

Murrey

Naughton²,

Duncan³

et al. 2014

Human Gene Therapy Clinical Development

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No treatment is currently available for mucopolysaccharidosis (MPS) IIIB, a neuropathic lysosomal storage disease caused by autosomal recessive defect in a-N-acetylglucosaminidase (NAGLU). In anticipation of a clinical gene therapy treatment for MPS IIIB in humans, we tested the rAAV9-CMV-hNAGLU vector administration to cynomolgus monkeys (n = 8) at 1E13 vg/kg or 2E13 vg/kg via intravenous injection. No adverse events or detectable toxicity occurred over a 6-month period. Gene delivery resulted in persistent global central nervous system and broad somatic transduction, with NAGLU activity detected at 2.9-12-fold above endogenous levels in somatic tissues and 1.3-3-fold above endogenous levels in the brain. Secreted rNAGLU was detected in serum. Low levels of preexisting anti-AAV9 antibodies (Abs) did not diminish vector transduction. Importantly, high-level preexisting anti-AAV9 Abs lead to reduced transduction in liver and other somatic tissues, but had no detectable impact on transgene expression in the brain. Enzyme-linked immunoabsorbent assay showed Ab responses to both AAV9 and rNAGLU in treated animals. Serum anti-hNAGLU Abs, but not anti-AAV9 Abs, correlated with the loss of circulating rNAGLU enzyme. However, serum Abs did not affect tissue rNAGLU activity levels. Weekly or monthly peripheral blood interferon-c enzyme-linked immunospot assays detected a CD4 + T-cell (Th-1) response to rNAGLU only at 4 weeks postinjection in one treated subject, without observable correlation to tissue transduction levels. The treatment did not result in detectable CTL responses to either AAV9 or rNAGLU. Our data demonstrate an effective and safe profile for systemic rAAV9-hNAGLU vector delivery in nonhuman primates, supporting its clinical potential in humans.

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“…Motor changes are also observed, including gaitwidth abnormalities (Hemsley and Hopwood 2005;Crawley et al 2006) and swim speed (Hemsley et al unpublished data), albeit at later stages in the disease process. The knockout mouse model of MPS IIIB also exhibits both cognitive and motor deficits (Fu et al 2007;McCarty et al 2009). Unlike MPS III dogs, the mice have not been reported to exhibit either cerebellar Purkinje cell loss or gross cerebellar cortex degeneration, at least in mice aged 6 months or less-a period in which deficits in motor function are readily observable.…”

Section: Do Animal Models Adequately Mimic Disease In Humans?mentioning

confidence: 98%

Lessons learnt from animal models: pathophysiology of neuropathic lysosomal storage disorders

Hemsley

Hopwood

2010

J of Inher Metab Disea

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Approximately 50 inborn errors of metabolism known as lysosomal storage disorders have been discovered to date, most of which are due to a single mutation in a gene encoding a soluble lysosomal enzyme. Consequently, inadequate enzyme activity results in the accumulation of substrates for that enzyme, invariably accompanied by a wide variety of secondary pathological changes. Many of these conditions remain untreatable, and therefore, research into pathogenic processes and potential treatment strategies is intense. A key tool for researchers in this area is the availability of clinically relevant animal models in which to study disease manifestation and evaluate therapeutic outcomes. Large numbers of both naturally occurring and genetically modified animal models of neurodegenerative lysosomal storage disorders are in existence, with spontaneous models occurring in both large domestic (e.g., cat, dog, sheep) and small (e.g., mouse) animal species. Many have undergone rigorous phenotypic characterization and are now providing us with insights into neurological disease processes. The purpose of this review is to highlight some of the major lessons learnt from these studies.

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Mannitol-facilitated CNS entry of rAAV2 vector significantly delayed the neurological disease progression in MPS IIIB mice

Cited by 93 publications

References 58 publications

Gene therapy for the CNS using AAVs: The impact of systemic delivery by AAV9

Gene therapy for the CNS using AAVs: The impact of systemic delivery by AAV9

Feasibility and Safety of Systemic rAAV9-hNAGLU Delivery for Treating Mucopolysaccharidosis IIIB: Toxicology, Biodistribution, and Immunological Assessments in Primates

Lessons learnt from animal models: pathophysiology of neuropathic lysosomal storage disorders

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