Gene Therapy Progress and Prospects – Vectorology: design and production of expression cassettes in AAV vectors

Bec, Christine Le; Douar, Anne

doi:10.1038/sj.gt.3302724

Cited by 38 publications

(11 citation statements)

References 64 publications

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“…Clinical gene transfer should ideally include some regulatory control of therapeutic gene expression particularly when constitutive expression of the transgene may be deleterious 32 . Several pharmacological gene regulation technologies have been developed.…”

Section: Discussionmentioning

confidence: 99%

Molecular therapy of obesity and diabetes by a physiological autoregulatory approach

Cao

Lin

Cahill

et al. 2009

Nat Med

107

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Hypothalamic BDNF is a key element in the regulation of energy balance. Here we investigated gene transfer of BDNF in rodent models of obesity and diabetes. BDNF led to marked weight loss and alleviation of obesity-associated insulin resistance. To facilitate clinical translation and ensure BDNF expression dialed down as weight loss progressed, we developed a molecular autoregulatory system using a single rAAV vector harboring two expression cassettes, one constitutively driving BDNF, the other a specific microRNA targeting the therapeutic gene controlled by a promoter (agouti related peptide) responsive to the BDNF-induced physiological changes. Hence, as body weight declined, microRNA expression was activated inhibiting transgene expression and, in contrast to the progressive weight loss associated with a non-regulated approach, led to a plateau once significant weight loss was achieved. This strategy mimics the body's endogenous physiological feedback mechanisms thereby resetting the hypothalamic set point to reverse obesity and metabolic syndrome.Obesity confers significant risk for diabetes, cardiovascular disease, stroke and some cancers 1,2 . Obesity and the related condition, metabolic syndrome (or syndrome X) are increasing rapidly worldwide with significant morbidity and mortality and socioeconomic burden 3 . Life style modifications such as exercise and diet as well as approved drugs have limited efficacy. Bariatric surgery can lead to weight loss at the cost of significant morbidity, underscoring the need for a safer and more effective approach.To identify potential molecular therapeutic candidates, we used an environmental paradigm. In our previous studies, physically and socially more complex housing leads to increased neurogenesis, improved learning and memory and resistance to insults [4][5][6] . Moreover, although fed ad libitum on identical diets, such enriched animals gain less weight than standard housing controls with an improved metabolic profile and insulin sensitivity. To further characterize this phenotype we focused on potential regulators in the hypothalamic arcuate nucleus (Arc), a brain region critical to energy balance. Amongst a number of genes screened, we observed a consistent upregulation in BDNF expression at 2, 4 and 9 weeks of enrichment.BDNF has previously been identified as an important component of the hypothalamic pathway that controls body weight and energy homeostasis 7 . Obese phenotypes are found in BDNF heterozygous mice 8 , a conditional knockout model 9 and focal hypothalamic deletion in adult mice 10 . This mature onset obesity is associated with hyperphagia, hyperleptinemia, hyperinsulinemia and hyperglycemia. Moreover in humans similar symptoms are associated

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Section: Discussionmentioning

confidence: 99%

Molecular therapy of obesity and diabetes by a physiological autoregulatory approach

Cao

Lin

Cahill

et al. 2009

Nat Med

107

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“…In the presence of the helper virus, the AAV undergoes viral genome replication and productive infection. Adeno-associated viruses are capable of infecting both dividing and quiescent cells, which makes them attractive tools for the delivery of therapeutic genes [ 100 ].…”

Section: Viral-derived Vectorsmentioning

confidence: 99%

Progresses towards safe and efficient gene therapy vectors

et al. 2015

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The emergence of genetic engineering at the beginning of the 1970′s opened the era of biomedical technologies, which aims to improve human health using genetic manipulation techniques in a clinical context. Gene therapy represents an innovating and appealing strategy for treatment of human diseases, which utilizes vehicles or vectors for delivering therapeutic genes into the patients' body. However, a few past unsuccessful events that negatively marked the beginning of gene therapy resulted in the need for further studies regarding the design and biology of gene therapy vectors, so that this innovating treatment approach can successfully move from bench to bedside. In this paper, we review the major gene delivery vectors and recent improvements made in their design meant to overcome the issues that commonly arise with the use of gene therapy vectors. At the end of the manuscript, we summarized the main advantages and disadvantages of common gene therapy vectors and we discuss possible future directions for potential therapeutic vectors.

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“…Several preliminary attempts have relied on different systems ranging from plasmid transfection to viral infection by multiple AAVs (one being the recombinant and one bearing the rep gene) or of hybrid viral systems based on chimeric Ad/AAV vector. These approaches are still in their infancy and have been essentially assessed in vitro (79–81). However, if such a specific integrative system is to be further developed for human application, the following safety and regulatory constraints should be considered.…”

Section: Integration and Life Cycle Of Aavmentioning

confidence: 99%