Corticostriatopallidal neuroprotection by adenovirus-mediated ciliary neurotrophic factor gene transfer in a rat model of progressive striatal degeneration.
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.
Mittoux
Vincent
V
Unité de Recherche Associée 2210, Commissariat à l'Energie Atomique, Centre National de la Recherche Scientifique, Service Hospitalier Frédéric Joliot, 91401 Orsay Cedex, France.
Ouary
Stephane
S
Monville
Christelle
C
Lisovoski
Fabrice
F
Poyot
Thomas
T
Conde
Francoise
F
Escartin
Carole
C
Robichon
Regine
R
Brouillet
Emmanuel
E
Peschanski
Marc
M
Hantraye
Philippe
P
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D005917:Globus Pallidus / Q000187:drug effects* / Q000473:pathology; D006816:Huntington Disease / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D008297:Male; D008845:Microinjections; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use; D009574:Nitro Compounds; D011422:Propionates; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew
D020934:Ciliary Neurotrophic Factor; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D011422:Propionates; D012333:RNA, Messenger; C015392:3-nitropropionic acid