title: Protein Delivery of an Artificial Transcription Factor Restores Widespread Ube3a Expression in an Angelman Syndrome Mouse Brain.
abstract: Angelman syndrome (AS) is a neurological genetic disorder caused by loss of expression of the maternal copy of UBE3A in the brain. Due to brain-specific genetic imprinting at this locus, the paternal UBE3A is silenced by a long antisense transcript. Inhibition of the antisense transcript could lead to unsilencing of paternal UBE3A, thus providing a therapeutic approach for AS. However, widespread delivery of gene regulators to the brain remains challenging. Here, we report an engineered zinc finger-based artificial transcription factor (ATF) that, when injected i.p. or s.c., crossed the blood-brain barrier and increased Ube3a expression in the brain of an adult mouse model of AS. The factor displayed widespread distribution throughout the brain. Immunohistochemistry of both the hippocampus and cerebellum revealed an increase in Ube3a upon treatment. An ATF containing an alternative DNA-binding domain did not activate Ube3a. We believe this to be the first report of an injectable engineered zinc finger protein that can cause widespread activation of an endogenous gene in the brain. These observations have important implications for the study and treatment of AS and other neurological disorders.
authors.affiliation: Genome Center, MIND Institute, and Department of Biochemistry and Molecular Medicine, University of California, Davis, California, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Bailus
authors.affiliation: Genome Center, MIND Institute, and Department of Biochemistry and Molecular Medicine, University of California, Davis, California, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Pyles
authors.affiliation: Genome Center, MIND Institute, and Department of Biochemistry and Molecular Medicine, University of California, Davis, California, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: McAlister
authors.affiliation: Genome Center, MIND Institute, and Department of Biochemistry and Molecular Medicine, University of California, Davis, California, USA.
authors.forename: Henriette
authors.initials: H
authors.lastname: O'Geen
authors.affiliation: Genome Center, MIND Institute, and Department of Biochemistry and Molecular Medicine, University of California, Davis, California, USA.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Lockwood
authors.affiliation: Genome Center, MIND Institute, and Department of Biochemistry and Molecular Medicine, University of California, Davis, California, USA.
authors.forename: Alexa N
authors.initials: AN
authors.lastname: Adams
authors.affiliation: Genome Center, MIND Institute, and Department of Biochemistry and Molecular Medicine, University of California, Davis, California, USA.
authors.forename: Jennifer Trang T
authors.initials: JT
authors.lastname: Nguyen
authors.affiliation: Genome Center, MIND Institute, and Department of Biochemistry and Molecular Medicine, University of California, Davis, California, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Yu
authors.affiliation: Department of Neurological Surgery, University of California, Davis, California, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Berman
authors.affiliation: Genome Center, MIND Institute, and Department of Biochemistry and Molecular Medicine, University of California, Davis, California, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Segal
mesh_terms: D017204:Angelman Syndrome / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D056426:Genetic Loci; D051379:Mice; D014157:Transcription Factors / Q000008:administration & dosage / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D016335:Zinc Fingers
chemical_list: D014157:Transcription Factors; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases