Corticostriatopallidal Neuroprotection by Adenovirus-Mediated Ciliary Neurotrophic Factor Gene Transfer in a Rat Model of Progressive Striatal Degeneration

Vincent Mittoux (1, 2) , Stephane Ouary (1, 2) , Christelle Monville (3) , Fabrice Lisovoski (3) , Thomas Poyot (1, 2) , Françoise Condé (2) , Carole Escartin (2) , Regine Robichon (3) , Emmanuel Brouillet (2) , Marc Peschanski (3) , Philippe Hantraye (2, 1)

1 SHFJ - Service Hospitalier Frédéric Joliot
2 LMN - Laboratoire des Maladies Neurodégénératives - UMR 9199
3 Neuroplasticité et thérapeutique

Ciliary neurotrophic factor (CNTF) is a potent protective factor for striatal neurons in animal models of Huntington's disease (HD). Clinical application of this potential therapeutic still requires the design and optimization of delivery systems. In the case of HD, spatial spread in the vast volume occupied by the striatum and long-term delivery of the factor are particular challenges for these systems. We explored the potential of adenovirus-mediated gene transfer to fulfill these requirements by studying the functional and anatomical effects of single-site striatal delivery of CNTF recombinant vectors in a rat model of HD. In an initial series of experiments, unilateral injections of CNTF adenovirus were performed in rats 10, 30, or 90 d before a 5 d neurotoxic treatment with systemic 3-nitropropionic acid (3NP). Preservation of striatal neurons was observed at all time points, demonstrating temporally extended neuroprotective effects of the CNTF adenovirus. In a second series of experiments , bilateral injections of CNTF adenovirus were performed in the medial aspect of the striatum 10 d before starting 3NP intoxication. Despite placement of the CNTF-producing vector outside the lateral striatal area susceptible to lesion, massive protection of corticostriatopallidal circuits was observed, associated with significant behavioral benefits. This spatial spread of neuroprotection is discussed with reference to the retrograde transport of the adenovirus vector and the anterograde transport of the transgenic CNTF. Overall, adenovirus-mediated CNTF gene transfer appears to be a potentially useful delivery system for widespread, long-term circuit neuroprotection in HD patients.

Keywords: adenovirus vector; ciliary neurotrophic factor; 3-nitropropionic acid; corticostriatopallidal degeneration; neu- roprotection; rat; stereology; Huntington's disease

Domains: Neurons and Cognition [q-bio.NC]

Vincent Mittoux, Stephane Ouary, Christelle Monville, Fabrice Lisovoski, Thomas Poyot, et al.. Corticostriatopallidal Neuroprotection by Adenovirus-Mediated Ciliary Neurotrophic Factor Gene Transfer in a Rat Model of Progressive Striatal Degeneration. Journal of Neuroscience, 2002, 22 (11), pp.4478-86. ⟨cea-02290628⟩