title: Advancing therapeutic discovery through phenotypic screening of the extracellular proteome using hydrodynamic intravascular injection.
abstract: OBJECTIVE
  Although the human genome encodes ∼ 20,000 protein-coding genes, only a very small fraction of these have been explored as potential targets for therapeutic development. The challenge of identifying and validating new protein targets has contributed to the significant reduction in the productivity of the pharmaceutical industry in the recent decade, highlighting the continued need to find new therapeutic targets.
  
  
  METHODS
  The traditional methods to discover new targets are expensive, low throughput and time consuming, usually taking years to validate or invalidate a target. To address these limitations, as a proof of concept, we explored the hydrodynamic tail vein (HTV) injection as a gene delivery method for direct in vivo phenotypic screening of novel secreted factor targets for Type II diabetes therapeutics.
  
  
  RESULTS
  High levels and sustained expression of target proteins were observed in diabetic mouse models tested, allowing us to identify multiple novel hormones that may regulate glucose metabolism.
  
  
  CONCLUSIONS
  These results suggest that HTV is a low-cost, high-throughput method for direct in vivo phenotypic drug screening in metabolic disorders and could be applicable to many other disease areas as well. This method if combined with other approaches such as human genetic studies could provide a significant value to future drug discovery.
authors.affiliation: Amgen, Inc. , 1120 Veterans Blvd., South San Francisco, CA 94080 , USA +1 650 244 2524 ; yangl@amgen.com.
authors.forename: Helene
authors.initials: H
authors.lastname: Baribault
authors.forename: Jiangwen Z
authors.initials: JZ
authors.lastname: Majeti
authors.forename: Hongfei
authors.initials: H
authors.lastname: Ge
authors.forename: Jinghong
authors.initials: J
authors.lastname: Wang
authors.forename: Yumei
authors.initials: Y
authors.lastname: Xiong
authors.forename: Jonitha
authors.initials: J
authors.lastname: Gardner
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Jamila
authors.initials: J
authors.lastname: Gupte
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: Zheng
authors.initials: Z
authors.lastname: Pan
authors.forename: Gene
authors.initials: G
authors.lastname: Cutler
authors.forename: Paul
authors.initials: P
authors.lastname: Kassner
authors.forename: Hua
authors.initials: H
authors.lastname: Tu
authors.forename: Bei
authors.initials: B
authors.lastname: Shan
authors.forename: Xinle
authors.initials: X
authors.lastname: Wu
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D055808:Drug Discovery / Q000379:methods; D018014:Gene Transfer Techniques; D005947:Glucose / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D057446:Hydrodynamics; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D020543:Proteome; D013623:Tail / Q000098:blood supply
chemical_list: D007004:Hypoglycemic Agents; D020543:Proteome; D005947:Glucose
keywords: diabetes; drug discovery; gene therapy; hydrodynamic tail vein injection; hydrodynamics-based transfection; metabolic disease; naked DNA; phenotypic screening; proteome; secreted factors; transfection