title: Sustained induction of neuronal addition to the adult rat neostriatum by AAV4-delivered noggin and BDNF.
abstract: Intraventricular ependymal infection by adenoviruses expressing brain-derived neurotrophic factor (BDNF) and noggin is sufficient to induce the heterotopic recruitment of new medium spiny neurons to the adult neostriatum, from endogenous subependymal neural progenitor cells. This approach was found to slow disease progression and extend survival in an R6/2 mouse model of Huntington's disease (HD). However, the practical therapeutic value of this strategy is limited by the transient expression and immunogenicity of adenoviral vectors. In addition, it has been unclear whether sustained overexpression of BDNF and noggin would yield similarly sustained neuronal production and striatal recruitment, or whether progenitor depletion or tachyphylaxis might supervene to limit the therapeutic potential of this approach. To address these issues, we used adeno-associated virus serotype 4 (AAV4), an ependymotrophic vector that is neither immunogenic nor neurotoxic, to achieve sustained BDNF and noggin expression. Using AAV4, we found that BDNF and noggin achieved levels sufficient to initiate and maintain, for at least 4 months, ongoing neuronal addition to the neostriatum and olfactory bulb. Over this period, we noted no diminution of treatment-associated neuronal recruitment from resident progenitors. AAV4:BDNF and noggin-induced neuronal addition may thus provide a means to provide longlasting and persistent striatal neuronal replacement in conditions of striatal neuronal loss, such as HD.
authors.affiliation: Department of Neurology, University of Rochester Medical Center, Rochester, NY 14620, USA. Abdellatif_Benraiss@urmc.rochester.edu
authors.forename: A
authors.initials: A
authors.lastname: Benraiss
authors.forename: E
authors.initials: E
authors.lastname: Bruel-Jungerman
authors.forename: G
authors.initials: G
authors.lastname: Lu
authors.forename: A N
authors.initials: AN
authors.lastname: Economides
authors.forename: B
authors.initials: B
authors.lastname: Davidson
authors.forename: S A
authors.initials: SA
authors.lastname: Goldman
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D003342:Corpus Striatum / Q000166:cytology; D000229:Dependovirus / Q000235:genetics; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D017072:Neostriatum / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis; D009830:Olfactory Bulb / Q000378:metabolism; D051381:Rats; D000099176:Noggin Protein
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002352:Carrier Proteins; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D000099176:Noggin Protein