title: Neuroprotection by rAAV-mediated gene transfer of bone morphogenic protein 7.
abstract: BACKGROUND
  Bone morphogenic proteins (BMPs) promote the survival of neurons, suggesting a therapeutic application of BMPs in the treatment of acute and chronic neurodegenerative disorders. However, the application of recombinant BMPs in vivo is limited by their short half-life. To provide a continuous supply for functionally active BMPs, we expressed BMP7, BMP2 and the BMP inhibitor Noggin under the control of rAAV vectors in vivo. For visual control of rAAV-mediated BMP (v-BMP) expression we fused the secreted morphogenic polypeptides and the fluorescent reporter protein Venus via the 'ribosomal skip' promoting 2A peptide-bridge.
  
  
  RESULTS
  In primary cortical neurons, the rAAV-expressed morphogenic polypeptides were efficiently released from the 2A-Venus fusion precursors, were secreted, correctly processed and functionally active as shown by their effects on Smad phosphorylation in HeLa cells and in primary neurons, by the protection of v-BMP7-transduced primary cortical neurons against oxidative stress, and by the activation of BMP responsive GFP in v-BMP2 transduced reporter mice. In the stroke model of middle cerebral artery occlusion rAAV-transduced v-BMP7 reduced the infarct size in mice.
  
  
  CONCLUSIONS
  Polycistronic rAAV vectors encoding secreted polypeptides and 2A-linked reporter proteins are potential novel therapeutic tools for the treatment of neurological and neurodegenerative diseases. Using this technique we documented that rAAV delivery of BMP7 reduced ischemic cell death in mice.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Heinonen
authors.forename: Mahbubur
authors.initials: M
authors.lastname: Rahman
authors.forename: Godwin
authors.initials: G
authors.lastname: Dogbevia
authors.forename: Hannah
authors.initials: H
authors.lastname: Jakobi
authors.forename: Stefan
authors.initials: S
authors.lastname: Wölfl
authors.affiliation: Max Planck Institute for Medical Research, Jahnstrasse 29, Heidelberg D-69120, Germany. rolf.sprengel@mpimf-heidelberg.mpg.de.
authors.forename: Rolf
authors.initials: R
authors.lastname: Sprengel
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaninger
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics* / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000378:metabolism* / Q000517:prevention & control*; D002540:Cerebral Cortex / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D005822:Genetic Vectors / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000627:therapeutic use; D014161:Transduction, Genetic / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D055419:Bone Morphogenetic Protein 7; D018696:Neuroprotective Agents