title: Fiber-modified adenovirus for central nervous system Parkinson's disease gene therapy.
abstract: Gene-based therapies for neurological diseases continue to develop briskly. As disease mechanisms are elucidated, flexible gene delivery platforms incorporating transcriptional regulatory elements, therapeutic genes and targeted delivery are required for the safety and efficacy of these approaches. Adenovirus serotype 5 (Ad5)-based vectors can carry large genetic payloads to provide this flexibility, but do not transduce neuronal cells efficiently. To address this, we have developed a tropism-modified Ad5 vector with neuron-selective targeting properties for evaluation in models of Parkinson disease therapy. A panel of tropism-modified Ad5 vectors was screened for enhanced gene delivery in a neuroblastoma cell line model system. We used these observations to design and construct an unbiased Ad vector platform, consisting of an unmodified Ad5 and a tropism-modified Ad5 vector containing the fiber knob domain from canine Ad serotype 2 (Ad5-CGW-CK2). Delivery to the substantia nigra or striatum showed that this vector produced a neuronally-restricted pattern of gene expression. Many of the transduced neurons were from regions with afferent projections to the injection site, implicating that the vector binds the presynaptic terminal resulting in presynaptic transduction. We show that Ad5-CGW-CK2 can selectively transduce neurons in the brain and hypothesize that this modular platform is potentially adaptable to clinical use.
authors.affiliation: Department of Cell Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA. travis.lewis@uphs.upenn.edu.
authors.forename: Travis B
authors.initials: TB
authors.lastname: Lewis
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. jng@uab.edu.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Glasgow
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA. anharms@uab.edu.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Harms
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA. dstandaert@uab.edu.
authors.forename: David G
authors.initials: DG
authors.lastname: Standaert
authors.affiliation: Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63108, USA. dcuriel@radonc.wustl.edu.
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000821:virology; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015316:Genetic Therapy / Q000379:methods*; D051379:Mice; D009474:Neurons / Q000821:virology; D030781:Organisms, Genetically Modified / Q000235:genetics / Q000502:physiology*; D010300:Parkinson Disease / Q000628:therapy*; D014161:Transduction, Genetic; D056189:Viral Tropism
chemical_list: D036022:Capsid Proteins; C018315:hexon capsid protein, Adenovirus