Intraventricular delivery of glial cell line-derived neurotrophic factor (GDNF) results in weight loss. We hypothesized that this effect of GDNF was likely mediated via its effects on dopaminergic neurons in the hypothalamus. Continuous rAAV-mediated GDNF expression in the hypothalamus of young and senescent rats resulted in weight loss compared to controls. However, GDNF-induced weight loss was unrelated to alterations in hypothalamic dopamine levels. The weight loss was associated with decreased food intake and increased energy expenditure, but these effects were not mediated by changes in hypothalamic NPY or POMC expression. Moreover, uncoupling protein 1 levels were unchanged in brown adipose tissue (BAT). The reduction in weight and adiposity were as great or greater in the aged rats even though aged rats are generally resistant to weight loss therapies. In summary, central GDNF gene delivery reduces weight and adiposity in young and aged rats through decreased food intake and increased energy expenditure. Our observations in aged rats suggest that GDNF may be especially effective in reducing obesity in aged obese rats.
"With other proteins identified as neurotrophic factors, such as nerve growth factor and glial cell line-derived neurotrophic factor, weight loss in rodents and in human clinical trials has been reported when recombinant protein has been injected (Manfredsson, et al., 2009, Nutt, et al., 2003, Olson, 1993, Pizzo and Thal, 2004, Tumer, et al., 2006). In the case of GDNF, weight loss occurs when GDNF is delivered to the hypothalamus or nigra but not striatum indicating these effects are region specific (Eslamboli, et al., 2003, Manfredsson, et al., 2009, Tumer, et al., 2006). Our results suggest that AAV serotype 7 is suitable for a wide-spread cortical expression of GFP or MANF without altering weight or normal locomotor behavior. "
[Show abstract][Hide abstract] ABSTRACT: Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a secreted protein which reduces endoplasmic reticulum (ER) stress and has neurotrophic effects on dopaminergic neurons. Intracortical delivery of recombinant MANF protein protects tissue from ischemic brain injury in vivo. In this study, we examined the protective effect of adeno-associated virus serotype 7 encoding MANF in a rodent model of stroke. An AAV vector containing human MANF cDNA (AAV-MANF) was constructed and verified for expression of MANF protein. AAV-MANF or an AAV control vector was administered into three sites in the cerebral cortex of adult rats. One week after the vector injections, the right middle cerebral artery (MCA) was ligated for 60min. Behavioral monitoring was conducted using body asymmetry analysis, neurological testing, and locomotor activity. Standard immunohistochemical and western blotting procedures were conducted to study MANF expression. Our data showed that AAV-induced MANF expression is redistributed in neurons and glia in cerebral cortex after ischemia. Pretreatment with AAV-MANF reduced the volume of cerebral infarction and facilitated behavioral recovery in stroke rats. In conclusion, our data suggest that intracortical delivery of AAV-MANF increases MANF protein production and reduces ischemic brain injury. Ischemia also caused redistribution of AAV-mediated MANF protein suggesting an injury-induced release.
"In a study in which GDNF gene therapy was implemented in the rat hypothalamus , injection of an AAV expressing GDNF was able to ameliorate the obesity of 23-month old male Fischer 344 rats. The weight loss, which occurred in both young and old animals, was associated with decreased food intake and increased energy expenditure but not with changes in hypothalamic dopamine or TH protein levels (Tumer et al., 2006). Despite the differences in age, sex and strain, between this study and ours, the findings are in agreement concerning the effect of intrahypothalamic GDNF on body weight in young and old rats. "
[Show abstract][Hide abstract] ABSTRACT: Progressive dysfunction of hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons during normal aging is associated in the female rat with chronic hyperprolactinemia. We assessed the effectiveness of glial cell line-derived neurotrophic factor (GDNF) gene therapy to restore TIDA neuron function in senile female rats and reverse their chronic hyperprolactinemia. Young (2.5 months) and senile (29 months) rats received a bilateral intrahypothalamic injection (10(10) pfu) of either an adenoviral vector expressing the gene for beta-galactosidase; (Y-betagal and S-betagal, respectively) or a vector expressing rat GDNF (Y-GDNF and S-GDNF, respectively). Transgenic GDNF levels in supernatants of GDNF adenovector-transduced N2a neuronal cell cultures were 25+/-4 ng/ml, as determined by bioassay. In the rats, serum prolactin (PRL) was measured at regular intervals. On day 17 animals were sacrificed and neuronal nuclear antigen (NeuN) and tyrosine hydroxylase (TH) immunoreactive cells counted in the arcuate-periventricular hypothalamic region. The S-GDNF but not the S-betagal rats, showed a significant reduction in body weight. The chronic hyperprolactinemia of the senile females was significantly ameliorated in the S-GDNF rats (P<0.05) but not in the S-betagal rats. Neither age nor GDNF induced significant changes in the number of NeuN and TH neurons. We conclude that transgenic GDNF ameliorates chronic hyperprolactinemia in aging female rats, probably by restoring TIDA neuron function.
"The most important adverse finding was that nigral administration of AAV2-GDNF caused significant weight loss and increased GDNF levels in frontal cortical regions. This observation is in accordance with previous reports of weight loss in rats with nigral or hypothalamic delivery of AAV2-GDNF (Tumer et al., 2006; Manfredsson et al., 2009) and with reports describing similar, although transient, weight loss after intracerebroventricular (ICV) infusion of recombinant GDNF protein (Martin et al., 1996; Zhang et al., 1997). In our study, all the aged NHP received the same pattern of both nigral and putaminal injections of either AAV2-GDNF or PBS, indicating that surgery itself is unlikely to have caused weight loss in the SN group. "
[Show abstract][Hide abstract] ABSTRACT: We evaluated neuropathological findings in two studies of AAV2-GDNF efficacy and safety in naive aged (>20 years) or MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned rhesus macaques. In the first study, a total of 17 animals received one of two doses of AAV2-GDNF into either putamen or substantia nigra (SN). To control for surgical variables, all animals received identical putaminal and nigral infusions in which phosphate-buffered saline was substituted for vector as appropriate. All 17 aged monkeys were studied for 6 months before necropsy. In a separate study, 11 MPTP-lesioned rhesus macaques with extensive lesions in the right SN and mild lesions in the left SN received bilateral infusions of AAV2-GDNF (9.9 x 10(11) vector genomes) or PBS into the putamen and were then studied for up to 14 months. In the current analysis, we addressed safety issues regarding AAV2-GDNF administration. An extensive series of assessments of in-life behavioral and clinical parameters was conducted. No overt histopathology or immune responses were detected in any experimental monkey. However, the delivery of AAV2-GDNF to the SN of aged monkeys caused a marked and significant loss of body weight (-19.4%). No weight loss was observed in the MPTP-lesioned monkeys despite bilateral axonal transport of glial cell line-derived neurotrophic factor (GDNF) to the SN from the putamen. These findings indicate that putaminal administration of AAV2-GDNF by convection-enhanced delivery shows therapeutic promise without any apparent side effects. Importantly, nigral administration of AAV2-GDNF caused significant weight loss that raises substantial concern for clinical application of this approach.
Human gene therapy 09/2009; 20(12):1627-40. DOI:10.1089/hum.2009.103 · 3.76 Impact Factor
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