Tenenbaum, L. (Lilianne)

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2011 - 20192

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    Development of a liver-specific Tet-on inducible system for AAV vectors and its application in the treatment of liver cancer
    (Nature, 2011) Berraondo, P. (Pedro); González-Aseguinolaza, G. (Gloria); Gil-Fariña, I. (Irene); Baldim, V. (Victor); Pañeda, A. (Astrid); Otano, I. (Itziar); Tenenbaum, L. (Lilianne); Beattie, S.G. (Stuart G.); Prieto, J. (Jesús); Vanrell, L. (Lucía); Chtarto, A. (Abdelwahed); Scala, M. (Marianna) Di; Blanco-Fernández, L. (Laura)
    Recombinant adeno-associated virus (rAAV) are effective gene delivery vehicles that can mediate long-lasting transgene expression. However, tight regulation and tissue-specific transgene expression is required for certain therapeutic applications. For regulatable expression from the liver we designed a hepatospecific bidirectional and autoregulatory tetracycline (Tet)-On system (Tet(bidir)Alb) flanked by AAV inverted terminal repeats (ITRs). We characterized the inducible hepatospecific system in comparison with an inducible ubiquitous expression system (Tet(bidir)CMV) using luciferase (luc). Although the ubiquitous system led to luc expression throughout the mouse, luc expression derived from the hepatospecific system was restricted to the liver. Interestingly, the induction rate of the Tet(bidir)Alb was significantly higher than that of Tet(bidir)CMV, whereas leakage of Tet(bidir)Alb was significantly lower. To evaluate the therapeutic potential of this vector, an AAV-Tet(bidir)-Alb-expressing interleukin-12 (IL-12) was tested in a murine model for hepatic colorectal metastasis. The vector induced dose-dependent levels of IL-12 and interferon-γ (IFN-γ), showing no significant toxicity. AAV-Tet(bidir)-Alb-IL-12 was highly efficient in preventing establishment of metastasis in the liver and induced an efficient T-cell memory response to tumor cells. Thus, we have demonstrated persistent, and inducible in vivo expression of a gene from a liver-specific Tet-On inducible construct delivered via an AAV vector and proved to be an efficient tool for treating liver cancer.
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    Combining Gene Transfer and Nonhuman Primates to Better Understand and Treat Parkinson’s Disease
    (Frontiers Media SA, 2019) Devau, G. (Gina); Kremer, E.J. (Eric J.); Verdier, J.M. (Jean-Michel); Lasbleiz, C. (Christelle); Tenenbaum, L. (Lilianne); Mestre-Francés, N. (Nadine); Luquin, M.R. (María Rosario)
    Parkinson's disease (PD) is a progressive CNS disorder that is primarily associated with impaired movement. PD develops over decades and is linked to the gradual loss of dopamine delivery to the striatum, via the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). While the administration of L-dopa and deep brain stimulation are potent therapies, their costs, side effects and gradual loss of efficacy underlines the need to develop other approaches. Unfortunately, the lack of pertinent animal models that reproduce DA neuron loss and behavior deficits-in a timeline that mimics PD progression-has hindered the identification of alternative therapies. A complementary approach to transgenic animals is the use of nonhuman primates (NHPs) combined with the overexpression of disease-related genes using viral vectors. This approach may induce phenotypes that are not influenced by developmental compensation mechanisms, and that take into account the personality of animals. In this review article, we discuss the combination of gene transfer and NHPs to develop "genetic" models of PD that are suitable for testing therapeutic approaches.