title: Widespread Central Nervous System Gene Transfer and Silencing After Systemic Delivery of Novel AAV-AS Vector.
abstract: Effective gene delivery to the central nervous system (CNS) is vital for development of novel gene therapies for neurological diseases. Adeno-associated virus (AAV) vectors have emerged as an effective platform for in vivo gene transfer, but overall neuronal transduction efficiency of vectors derived from naturally occurring AAV capsids after systemic administration is relatively low. Here, we investigated the possibility of improving CNS transduction of existing AAV capsids by genetically fusing peptides to the N-terminus of VP2 capsid protein. A novel vector AAV-AS, generated by the insertion of a poly-alanine peptide, is capable of extensive gene transfer throughout the CNS after systemic administration in adult mice. AAV-AS is 6- and 15-fold more efficient than AAV9 in spinal cord and cerebrum, respectively. The neuronal transduction profile varies across brain regions but is particularly high in the striatum where AAV-AS transduces 36% of striatal neurons. Widespread neuronal gene transfer was also documented in cat brain and spinal cord. A single intravenous injection of an AAV-AS vector encoding an artificial microRNA targeting huntingtin (Htt) resulted in 33-50% knockdown of Htt across multiple CNS structures in adult mice. This novel AAV-AS vector is a promising platform to develop new gene therapies for neurodegenerative disorders.
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Sourav R
authors.initials: SR
authors.lastname: Choudhury
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Anne F
authors.initials: AF
authors.lastname: Harris
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Damien J
authors.initials: DJ
authors.lastname: Cabral
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Keeler
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Sapp
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Ferreira
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Gray-Edwards
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA.
authors.forename: Aime K
authors.initials: AK
authors.lastname: Johnson
authors.affiliation: Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Microbiology & Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Su
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Lorelei
authors.initials: L
authors.lastname: Stoica
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Marian
authors.initials: M
authors.lastname: DiFiglia
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Aronin
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA.|Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Martin
authors.affiliation: Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Microbiology & Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Sena-Esteves
mesh_terms: D000818:Animals; D016466:CHO Cells; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism*; D002415:Cats; D002460:Cell Line; D002490:Central Nervous System / Q000378:metabolism*; D003412:Cricetulus; D000229:Dependovirus / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D000071058:Huntingtin Protein / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D036022:Capsid Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D010455:Peptides; D011993:Recombinant Fusion Proteins; C442553:VP2 protein, Dependovirus