Recombinant Adeno-Associated Virus Vector Expressing Glial Cell Line-Derived Neurotrophic Factor Reduces Ischemia-Induced Damage

Tsai, Tung Han; Chen, Show Li; Chiang, Yung Hsiao; Lin, Shinn Zong; Hsin, I.; Kuo, Shi‐Wen; Tsao, Yeou‐Ping

doi:10.1006/exnr.2000.7505

Cited by 61 publications

(36 citation statements)

References 45 publications

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“…Consistently, an rAAV-NSE-BDNF vector injected in the SNc after intrastriatal injection of 6-hydroxydopamine prevented rotational behavior, presumably by increasing dopamine metabolism and release by the remaining dopaminergic fibers still innervating the striatum [41]. AAV-mediated GDNF gene delivery has also been shown to be effective for protection of striatal neurons in a model for Huntington disease [20], cortical neurons in a model of brain ischemia [23], as well as spinal cord motoneurons in a mouse model for amyotrophic lateral sclerosis [21,73]. Recombinant AAV-mediated delivery of BDNF ameliorates chronic pain after partial injury of the spinal cord nerves [74].…”

Section: Neuroprotectionmentioning

confidence: 87%

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Recombinant AAV-mediated gene delivery to the central nervous system

et al. 2004

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Various regions of the brain have been successfully transduced by recombinant adeno-associated virus (rAAV) vectors with no detected toxicity. When using the cytomegalovirus immediate early (CMV) promoter, a gradual decline in the number of transduced cells has been described. In contrast, the use of cellular promoters such as the neuron-specific enolase promoter or hybrid promoters such as the chicken beta-actin/CMV promoter resulted in sustained transgene expression. The cellular tropism of rAAV-mediated gene transfer in the central nervous system (CNS) varies depending on the serotype used. Serotype 2 vectors preferentially transduce neurons whereas rAAV5 and rAAV1 transduce both neurons and glial cells. Recombinant AAV4-mediated gene transfer was inefficient in neurons and glial cells of the striatum (the only structure tested so far) but efficient in ependymal cells. No inflammatory response has been described following rAAV2 administration to the brain. In contrast, antibodies to AAV2 capsid and transgene product were elicited but no reduction of transgene expression was observed and readministration of vector without loss of efficiency was possible from 3 months after the first injection. Based on the success of pioneer work performed with marker genes, various strategies for therapeutic gene delivery were designed. These include enzyme replacement in lysosomal storage diseases, Canavan disease and Parkinson's disease; delivery of neuroprotective factors in Parkinson's disease, Huntington disease, Alzheimer's disease, amyotrophic lateral sclerosis, ischemia and spinal cord injury; as well as modulation of neurotransmission in epilepsy and Parkinson's disease. Several of these strategies have demonstrated promising results in relevant animal models. However, their implementation in the clinics will probably require a tight regulation and a specific targeting of therapeutic gene expression which still demands further developments of the vectors.

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Section: Neuroprotectionmentioning

confidence: 87%

“…These could be envisaged in all the situations in which neurons gradually die, such as neurodegenerative diseases [19][20][21][22] or ischemia [23], as well as in situations in which regrowth of neuron fibers is expected such as spinal cord repair [24].…”

Section: Introductionmentioning

confidence: 99%

Recombinant AAV-mediated gene delivery to the central nervous system

et al. 2004

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“…The neuroprotective effect is mediated by GDNF binding to the GFRα-1 receptor [132]. Several mechanisms of neuroprotection have been proposed for GDNF, including reduction of NMDA-induced calcium influx, reduction of iNOS activity and NO production and release, and down-regulation of caspase-dependent apoptotic pathways [132,133,134,135]. …”

Section: Trophic Factors and Neuroprotection In Strokementioning

confidence: 99%

Apoptosis: Future Targets for Neuroprotective Strategies

Ferrer

2006

Cerebrovasc Dis

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Focal permanent or transient cerebral artery occlusion produces massive cell death in the central core of the infarction, whereas in the peripheral zone (penumbra) nerve cells are subjected to various determining survival and death signals. Cell death in the core of the infarction and in the adult brain is usually considered a passive phenomenon, although events largely depend on the partial or complete disruption of crucial metabolic pathways. Cell death in the penumbra is currently considered an active process largely dependent on the activation of cell death programs leading to apoptosis. Yet cell death in the penumbra includes apoptosis, necrosis, intermediate and other forms of cell death. A rather simplistic view implies poor prospects regarding cell survival in the core of the infarction and therapeutic expectations in the control of cell death and cell survival in the penumbra. However, the capacity for neuroprotection depends on multiple factors, primarily the use of the appropriate agent, at the appropriate time and during the appropriate interval. Understanding the mechanisms commanding cell death and survival area is as important as delimiting the therapeutic time window and the facility of a drug to effectively impact on specific targets. Moreover, the detrimental effects of homeostasis and the activation of multiple pathways with opposing signals following ischemic stroke indicate that better outcome probably does not depend on a single compound but on several drugs acting in combination at the optimal time in a particular patient.

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“…Administration of VEGF is neuroprotective through inhibition of apoptosis (Hayashi et al, 1998;Jin et al, 2001;Manoonkitiwongsa et al, 2004). Gene therapy strategies for GDNF are also promising (Harvey et al, 2005;Shirakura et al, 2003;Tsai et al, 2000). Other neurotrophins are similarly able to exert protective actions by inhibiting death or triggering protective mechanisms.…”

Section: Protective Effects Of Exogenous Growth Factorsmentioning

confidence: 99%