Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer

Daly, TM; Ohlemiller, KK; Roberts, Andrea; Vogler, CA; Sands, Mark S.

doi:10.1038/sj.gt.3301420

Cited by 121 publications

(64 citation statements)

References 30 publications

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“…In this respect, the choice of vector is critical. In agreement with other reports, [31][32][33][34] we have shown that an AAV2-based vector can maintain expression of the transgene and hence of the therapeutic protein for 41 year. In addition to the choice of vector, the choice of promoter is also critical for long-term high …”

Section: Durationsupporting

confidence: 93%

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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Section: Durationsupporting

confidence: 93%

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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“…pTR-Pomc encodes the full-length 935-bp murine Pomc cDNA [26] under the control of the hybrid cytomegalovirus immediate early enhancer/chicken β-actin promoter [27]. The woodchuck hepatitis virus post-transcriptional regulatory element is placed downstream of the Pomc transgene to enhance its expression [28] (Fig.…”

Section: Construction Of Raav Vector Plasmidsmentioning

confidence: 99%

Hypothalamic pro-opiomelanocortin gene delivery ameliorates obesity and glucose intolerance in aged rats

Zhang

Wilsey

et al. 2005

Diabetologia

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Aims/hypothesis: Age-related obesity is associated with impaired hypothalamic pro-opiomelanocortin (Pomc) gene expression. We assessed whether overproduction of POMC in the hypothalamus ameliorates age-related obesity in rats. Methods: Recombinant adeno-associated virus (rAAV) encoding Pomc (rAAV-Pomc) or control vector was delivered bilaterally into the basomedial hypothalamus of aged obese rats with coordinates targeting the arcuate nucleus. Energy balance, glucose metabolism, brown adipose tissue thermogenesis and mRNA levels of hypothalamic neuropeptides and melanocortin receptors were assessed. Results: Forty-two days after Pomc gene delivery, hypothalamic Pomc expression increased 12-fold while agouti-related protein and neuropeptide Y mRNA levels remained unchanged. Using a punch technique, we detected the highest Pomc RNA level in the arcuate nucleus. Pomc overexpression reduced food consumption from day 10 after vector injection, but this anorexic effect abated by day 30. In contrast, there was a steady decrease in body weight without apparent attenuation. Pomc gene delivery decreased visceral adiposity and induced uncoupling protein 1 in brown adipose tissue in aged rats. Serum NEFA and triglyceride levels were also diminished by rAAV-Pomc treatment. Improved glucose metabolism and insulin sensitivity were observed on day 36 but not day 20 after Pomc gene delivery. The expression of hypothalamic melanocortin 3 and 4 receptor decreased by 17% and 25%, respectively in rAAV-Pomc rats. Conclusions/ interpretation: This study demonstrates that targeted Pomc gene therapy in the hypothalamus reduces body weight and visceral adiposity, and improves glucose and fat metabolism in aged obese rats. Thus long-term activation of the central melanocortin system may be a viable strategy to combat age-related obesity and diabetes.

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“…The exciting potential of AAV-mediated gene delivery to meet this challenge is substantiated by data generated in over 40 studies in animal models involving at least 15 different LSD phenotypes. The most extensively investigated phenotypes are GSD II [40][41][42][43][44][45][46] and MPS VII [47][48][49][50][51][52][53][54] and distillation of data obtained for these conditions provides representative insights across the spectrum of LSDs.…”

Section: Lysosomal Storage Diseasesmentioning

confidence: 99%

“…Intravenous delivery resulted in measurable enzyme levels in a number of tissues, most notably the liver in which glycosaminoglycan levels were normalized with an associated dramatic drop in storage granules. Other and more recent studies have focused on CNS and ocular manifestations [49][50][51]53,54 and systemic delivery has not yet been revisited with newer capsid serotypes. It is highly likely that studies with muscle and liver tropic capsids, such as 6 and 8 in the mouse, respectively, would give more robust systemic correction, although strategies to improve the cross-complementation properties of GUSB may also be required.…”

Section: Lysosomal Storage Diseasesmentioning

confidence: 99%

Potential of AAV vectors in the treatment of metabolic disease

et al. 2008

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Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer

Cited by 121 publications

References 30 publications

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

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

Hypothalamic pro-opiomelanocortin gene delivery ameliorates obesity and glucose intolerance in aged rats

Potential of AAV vectors in the treatment of metabolic disease

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