Neuroprotective effects of glial cell line-derived neurotrophic factor mediated by an adeno-associated virus vector in a transgenic animal model of amyotrophic lateral sclerosis.
Lijun Wang,Yan-Yan Lu,Shin-ichi Muramatsu,Kunihiko Ikeguchi,Ken-ichi Fujimoto,Takashi Okada,Hiroaki Mizukami,Takashi Matsushita,Yutaka Hanazono,Akihiro Kume,Toshiharu Nagatsu,Keiya Ozawa,Imaharu Nakano +12 more
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TLDR
It is shown here that AAV-GDNF leads to substantial and long-lasting expression of transgenic GDNF in a large number of myofibers with its accumulation at the sites of neuromuscular junctions, indicating that A AV-mediated GDNF delivery to the muscle is a promising means of gene therapy for ALS.Abstract:
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive lethal disease that involves selective annihilation of motoneurons. Glial cell line-derived neurotrophic factor (GDNF) is proposed to be a promising therapeutic agent for ALS and other motor neuron diseases. Because adeno-associated virus (AAV) has been developed as an attractive gene delivery system with proven safety, we explored the therapeutic efficacy of intramuscular delivery of the GDNF gene mediated by an AAV vector (AAV-GDNF) in the G93A mouse model of ALS. We show here that AAV-GDNF leads to substantial and long-lasting expression of transgenic GDNF in a large number of myofibers with its accumulation at the sites of neuromuscular junctions. Detection of GDNF labeled with FLAG in the anterior horn neurons, but not β-galactosidase expressed as a control, indicates that most of the transgenic GDNF observed there is retrogradely transported GDNF protein from the transduced muscles. This transgenic GDNF prevents motoneurons from their degeneration, preserves their axons innervating the muscle, and inhibits the treated-muscle atrophy. Furthermore, four-limb injection of AAV-GDNF postpones the disease onset, delays the progression of the motor dysfunction, and prolongs the life span in the treated ALS mice. Our finding thus indicates that AAV-mediated GDNF delivery to the muscle is a promising means of gene therapy for ALS.read more
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ALS: a disease of motor neurons and their nonneuronal neighbors.
TL;DR: In this paper, a mutant superoxide dismutase (SOD1) was found to induce non-cell-autonomous motor neuron killing by an unknown gain of toxicity.
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Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model.
TL;DR: It is reported that insulin-like growth factor 1 prolongs life and delays disease progression, even when delivered at the time of overt disease symptoms.
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Current hypotheses for the underlying biology of amyotrophic lateral sclerosis
TL;DR: It is demonstrated that mutations and pathology associated with the TDP‐43 gene and protein may be more common than SOD1 mutations in familial and sporadic ALS, and Convergence of these pathways is likely to mediate disease onset and progression.
Journal ArticleDOI
VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model
Mimoun Azzouz,G. Scott Ralph,Erik Storkebaum,Lucy E. Walmsley,Kyriacos A. Mitrophanous,Susan M. Kingsman,Peter Carmeliet,Nicholas D. Mazarakis +7 more
TL;DR: It is reported that a single injection of a VEGF-expressing lentiviral vector into various muscles delayed onset and slowed progression of ALS in mice engineered to overexpress the gene coding for the mutated G93A form of the superoxide dismutase-1 (SOD1G93A).
Journal ArticleDOI
Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS.
TL;DR: mounting evidence from mice with cell restrictive, repressible or chimeric expression of mutant SOD1 transgenes and bone marrow transplants supports non-neuronal origins of neuroprotection in ALS.
References
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An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria
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TL;DR: Glial cell line-derived neurotrophic factor (GDNF), originally identified as a trophic factor specific for dopaminergic neurons, was found to be 75-fold more potent than the neurotrophins in supporting the survival of purified embryonic rat motoneurons in culture and to be a good candidate for treatment of motoneuron disease.
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Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease.
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