title: A designed zinc-finger transcriptional repressor of phospholamban improves function of the failing heart.
abstract: Selective inhibition of disease-related proteins underpins the majority of successful drug-target interactions. However, development of effective antagonists is often hampered by targets that are not druggable using conventional approaches. Here, we apply engineered zinc-finger protein transcription factors (ZFP TFs) to the endogenous phospholamban (PLN) gene, which encodes a well validated but recalcitrant drug target in heart failure. We show that potent repression of PLN expression can be achieved with specificity that approaches single-gene regulation. Moreover, ZFP-driven repression of PLN increases calcium reuptake kinetics and improves contractile function of cardiac muscle both in vitro and in an animal model of heart failure. These results support the development of the PLN repressor as therapy for heart failure, and provide evidence that delivery of engineered ZFP TFs to native organs can drive therapeutically relevant levels of gene repression in vivo. Given the adaptability of designed ZFPs for binding diverse DNA sequences and the ubiquity of potential targets (promoter proximal DNA), our findings suggest that engineered ZFP repressors represent a powerful tool for the therapeutic inhibition of disease-related genes, therefore, offering the potential for therapeutic intervention in heart failure and other poorly treated human diseases.
authors: Sangamo BioSciences Inc., Richmond, CA, USA.
authors: H Steve
authors: HS
authors: Zhang
authors: Dingang
authors: D
authors: Liu
authors: Yan
authors: Y
authors: Huang
authors: Stefan
authors: S
authors: Schmidt
authors: Reed
authors: R
authors: Hickey
authors: Dmitry
authors: D
authors: Guschin
authors: Haili
authors: H
authors: Su
authors: Ion S
authors: IS
authors: Jovin
authors: Mike
authors: M
authors: Kunis
authors: Sarah
authors: S
authors: Hinkley
authors: Yuxin
authors: Y
authors: Liang
authors: Linda
authors: L
authors: Hinh
authors: S Kaye
authors: SK
authors: Spratt
authors: Casey C
authors: CC
authors: Case
authors: Edward J
authors: EJ
authors: Rebar
authors: Barbara E
authors: BE
authors: Ehrlich
authors: Barbara
authors: B
authors: Ehrlich
authors: Philip D
authors: PD
authors: Gregory
authors: Frank J
authors: FJ
authors: Giordano
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D006801:Humans; D007700:Kinetics; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers / Q000235:genetics / Q000502:physiology*; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D014157:Transcription Factors; D000099211:Phospholamban