Adeno-Associated Virus Serotype 9 Transduction in the Central Nervous System of Nonhuman Primates

Samaranch, Lluı́s; Salegio, Ernesto A.; Sebastián, Waldy San; Kells, Adrian P.; Foust, Kevin D.; Bringas, John; Lamarre, Clementine; Forsayeth, John; Kaspar, Brian K.; Bankiewicz, Krystof S.

doi:10.1089/hum.2011.200

Cited by 264 publications

(307 citation statements)

References 16 publications

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“…AAV vector administration. Despite being detectable, NAb titers in the CSF did not completely block AAV vector transduction in the brain, a result in contrast to previously published results (66) and in agreement with a recent study that explored CNS transduction following intra-CSF delivery in nonhuman primates with low serum NAb titers (64). Altogether, our study demonstrates that CNS gene transfer is possible in the presence of preexisting anticapsid antibodies.…”

Section: Figuresupporting

confidence: 88%

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy

Haurigot¹,

Matarazzo²,

Ribera³

et al. 2013

J. Clin. Invest.

189

246

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Section: Figuresupporting

confidence: 88%

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy

Haurigot¹,

Matarazzo²,

Ribera³

et al. 2013

J. Clin. Invest.

189

246

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“…Evidence of effi cacy has also been demonstrated following CSF administration of AAV vectors (serotypes 1, 2, 5, and 9) in MPS 1, MPS III, and GM1-gangliosidosis mice ( 102,106,107 ). Importantly, the translatability of this route of delivery in the CNS of larger animals such as dogs and primates has been verifi ed ( 49,84,102 ). However, because the ependymal cell lining has a turnover rate of approximately 130 days ( 109 ) and because readministration of the identical AAV serotype vector is currently untenable, it is unclear whether this approach will provide long-term benefi ts.…”

Section: Effi Cacy Of Intracranial Delivery Of Aav Vectors For Neuropmentioning

confidence: 96%

“…An example of an AAV serotype vector that can reportedly cross the blood-brain barrier of mice and nonhuman primates is AAV9 ( 67,84 ). Indeed, systemically delivered recombinant AAV9-based vectors have been demonstrated to successfully treat the CNS disease in mouse models of the LSDs MPS IIIA ( 80 ) and MPS IIIB ( 85 ).…”

Section: Prospects Of Systemically Delivered Aav Vectors To Address Tmentioning

confidence: 99%

Gene therapy for the neurological manifestations in lysosomal storage disorders

Cheng¹

2014

Journal of Lipid Research

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precise mechanistic links between these altered biochemical and cellular states and disease pathophysiology and pathogenesis remain unclear. Typically, disease severity is correlated with the level of residual activity, with individuals harboring lower levels presenting with more aggressive and severe disease manifestations. A large percentage of individuals, particularly those with signifi cantly diminished lysosomal function, also exhibit CNS involvement, the extent of which is dependent on the nature of the specifi c storage metabolites and the differential sensitivity of the resident cell types to the accumulated substrates. Although individually each LSD may be relatively rare, as a group, these disorders have an incidence of approximately 1 per 5,000 live births ( 4, 5 ).Of the approximately 50 LSDs that have been identifi ed thus far, the majority (greater than 70%) exhibit significant CNS involvement ( 6 ). This fi nding is not surprising given that lysosomes and related organelles are ubiquitously present in most cell types and are involved not only in recycling cellular debris but also in maintaining cellular homeostasis ( 7-9 ). Irrespective of the LSD, these CNS diseases are typically characterized by generalized infl ammation and neurodegeneration in multiple brain regions. In a subset of the diseases, altered calcium homeostasis and oxidative stress may also contribute to the overall pathology ( 10 ). Moreover, each specifi c disease may initially present with a unique temporal and spatial alteration that is dictated by the nature of the storage metabolites prior to the development of a more generalized global derangement ( 11 ). In some diseases, the symptoms are evident in neonates, whereas in others, they become apparent only in early childhood. Consequently, some LSDs may require early therapeutic intervention to affect broad and potentially all regions of the CNS. The lysosomal storage disorders (LSDs) are a heterogeneous group of inherited metabolic diseases that result from a defi ciency in one or more of the 80 enzymes or transporters that normally reside within the lysosomal compartment ( 1-3 ). A reduction or loss of one or more of these activities results in the progressive and relentless accumulation of undegraded macromolecules, a consequent derangement of proper lysosomal and autophagosomal functions, and ultimately, cellular demise. However, the

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“…In 2009, Foust et al [21] reported that AAV serotype 9 (AAV9) vectors could cross the intact BBB in neonates and adult mice and yield "widespread" transgene expression in astrocytes, neurons, and endothelial cells. This was followed by reports showing that this finding translated to non-human primates (NHPs) [47,48] and could be achieved with other AAV serotypes [49]. The term "widespread" to describe the transduction pattern of intravenously injected AAV9 may be confusing to those not involved in the field.…”

Section: Virus-based Systemsmentioning

confidence: 99%

“…The field of CNS gene therapy is evolving rapidly with the discovery of new viral vectors, mainly AAV capsids, with remarkable CNS tropism after vascular [21,36,49,[96][97][98], and CSF administration [18,36,47]. A large range of AAV capsids has been investigated for their CNS gene transfer properties by direct intracranial injection [99][100][101][102].…”

Section: Challengesmentioning

confidence: 99%

Gene Therapy for the Nervous System: Challenges and New Strategies

et al. 2014

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Current clinical treatments for central nervous system (CNS) diseases, such as Parkinson's disease and glioblastoma do not halt disease progression and have significant treatment morbidities. Gene therapy has the potential to "permanently" correct disease by bringing in a normal gene to correct a mutant gene deficiency, knocking down mRNA of mutant alleles, and inducing cell-death in cancer cells using transgenes encoding apoptosis-inducing proteins. Promising results in clinical trials of eye disease (Leber's congenital aumorosis) and Parkinson's disease have shown that genebased neurotherapeutics have great potential. The recent development of genome editing technology, such as zinc finger nucleases, TALENS, and CRISPR, has made the ultimate goal of gene correction a step closer. This review summarizes the challenges faced by gene-based neurotherapeutics and the current and recent strategies designed to overcome these barriers. We have chosen the following challenges to focus on in this review: (1) delivery vehicles (both virus and nonviral), (2) use of promoters for vector-mediated gene expression in CNS, and (3) delivery across the blood-brain barrier. The final section (4) focuses on promising pre-clinical/clinical studies of neurotherapeutics.

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Adeno-Associated Virus Serotype 9 Transduction in the Central Nervous System of Nonhuman Primates

Cited by 264 publications

References 16 publications

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy

Gene therapy for the neurological manifestations in lysosomal storage disorders

Gene Therapy for the Nervous System: Challenges and New Strategies

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