In vivo expression of therapeutic human genes for dopamine production in the caudates of MPTP-treated monkeys using an AAV vector

During, MJ; Samulski, R. Jude; Elsworth, J. D.; Mg, Kaplitt; Leone, Paola; Xiao, Xianmin; Li, J; Freese, Andrew; Taylor, J. R.; Rh, Roth; Sladek, J. R.; Kl, O'Malley; Redmond, D. Eugene

doi:10.1038/sj.gt.3300650

Cited by 160 publications

(77 citation statements)

References 18 publications

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“…However, since a variety of promoters, transgenes, ITRs, and brain regions have been used, a direct comparison between species is not possible. [36][37][38][39][40][41] A comparison of AAV2 and AAV5 injection into the rat striatum indicated that AAV5 transduction was less predictable in the direction of spread and in the volume of transduction than AAV2. 41 There have been no studies examining the ability of AAV1 to transduce the brain in the adult of any species.…”

Section: Discussionmentioning

confidence: 99%

Adeno-associated virus vector-mediated transduction in the cat brain

et al. 2003

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Adeno-associated virus (AAV) vectors are capable of delivering a therapeutic gene to the mouse brain that can result in long-term and widespread protein production. However, the human infant brain is more than 1000 times larger than the mouse brain, which will make the treatment of global neurometabolic disorders in children more difficult. In this study, we evaluated the ability of three AAV serotypes (1,2, and 5) to transduce cells in the cat brain as a model of a large mammalian brain. The human lysosomal enzyme bglucuronidase (GUSB) was used as a reporter gene, because it can be distinguished from feline GUSB by heat stability. The vectors were injected into the cerebral cortex, caudate nucleus, thalamus, corona radiata, internal capsule, and centrum semiovale of 8-week-old cats. The brains were evaluated for gene expression using in situ hybridization and enzyme histochemistry 10 weeks after surgery. The AAV2 vector was capable of transducing cells in the gray matter, while the AAV1 vector resulted in greater transduction of the gray matter than AAV2 as well as transduction of the white matter. AAV5 did not result in detectable transduction in the cat brain.

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Section: Discussionmentioning

confidence: 99%

Adeno-associated virus vector-mediated transduction in the cat brain

et al. 2003

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“…First, AAV gene transfer vectors are capable of mediating transfer and persistence of expression of a variety of genes in the CNS. [11][12][13][14][15][16][17] Second, mucopolysaccharidosis VII, a related lysosomal storage disease, has been successfully reversed in a knockout mouse model by recombinant AAV2-mediated intracranial gene transfer. 16,[18][19][20] Third, a significant fraction of newly synthesized TPP-I protein is secreted as pro-TPP-I, a 563 amino-acid inactive form which can crosscorrect nearby nontransduced cells through mannose 6-phosphate receptor-mediated uptake and subsequent activation in lysosomes to the 367 amino-acid mature form.…”

Section: Introductionmentioning

confidence: 99%

AAV2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for LINCL

et al. 2005

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“…42 Furthermore, in nonhuman primates that were rendered parkinsonian by MPTP administration, TH and AADC delivery in the striatum resulted in TH-positive cells and biochemical improvement, but no consistent behavioral improvement. 43 Some reports, however, also suggest a detrimental effect of AADC on dopamine production, perhaps due to end-product inhibition of TH. 44 This effect might be cell-type-specific, perhaps seen in nonneuronal cells such as fibroblasts that cannot sequester dopamine into synaptic vesicles, thus allowing it to interact with and inhibit cytoplasmic TH.…”

Section: Gene Therapy For Parkinson's Disease (Pd)mentioning

confidence: 99%

Advances in Gene Therapy for Movement Disorders

Mochizuki

Yasuda

Mouradian³

2008

Neurotherapeutics

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Summary:After nearly 20 years of preclinical experimentation with various gene delivery approaches in animal models of Parkinson's disease (PD), clinical trials are finally underway. The risk/benefit ratio for these procedures is now generally considered acceptable under approved protocols. The current vehicle for gene delivery to the human brain is recombinant adeno-associated viral vector, which is nonpathogenic and non-self-amplifying. Candidate genes tested in PD patients encode 1) glutamic acid decarboxylase, which is injected into the subthalamic nucleus to catalyze biosynthesis of the inhibitory neurotransmitter ␥-aminobutyric acid and so essentially mimic deep brain stimulation of this nucleus; 2) aromatic Lamino acid decarboxylase, which converts L-dopa to dopamine; and 3) neurturin, a member of the glial cell line-derived neurotrophic factor family. Unraveling the genetic underpinnings of PD could allow gene therapy to go beyond modulating neurotransmission or providing trophic effects to dopaminergic neurons by delivering a specific missing or defective gene. For example, the parkin gene (PARK2) is linked to recessively inherited PD due to loss of function mutations; it prevents ␣-synuclein-induced degeneration of nigral dopaminergic neurons in rats and nonhuman primates. On the other hand, for dominantly inherited Huntington's disease (HD), in which an expanded polyglutamine tract imparts to the protein huntingtin a toxic gain of function, repressing expression of the mutant allele in the striatum using RNA interference technology mitigates pathology and delays the phenotype in a mouse model. Here we review the current state of preclinical and clinical gene therapy studies conducted in PD and HD.

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In vivo expression of therapeutic human genes for dopamine production in the caudates of MPTP-treated monkeys using an AAV vector

Cited by 160 publications

References 18 publications

Adeno-associated virus vector-mediated transduction in the cat brain

Adeno-associated virus vector-mediated transduction in the cat brain

AAV2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for LINCL

Advances in Gene Therapy for Movement Disorders

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