title: Therapeutic ultrasound: Increased HDL-Cholesterol following infusions of acoustic microspheres and apolipoprotein A-I plasmids.
abstract: BACKGROUND
  Low levels of HDL-C are an independent cardiovascular risk factor associated with increased premature cardiovascular death. However, HDL-C therapies historically have been limited by issues relating to immunogenicity, hepatotoxicity and scalability, and have been ineffective in clinical trials.
  
  
  OBJECTIVE
  We examined the feasibility of using injectable acoustic microspheres to locally deliver human ApoA-I DNA plasmids in a pre-clinical model and quantify increased production of HDL-C in vivo.
  
  
  METHODS
  Our novel site-specific gene delivery system was examined in naïve rat model and comprised the following steps: (1) intravenous co-administration of a solution containing acoustically active microspheres (Optison™, GE Healthcare, Princeton, New Jersey) and human ApoA-I plasmids; (2) ultrasound verification of the presence of the microspheres within the liver vasculature; (3) External application of locally-directed acoustic energy, (4) induction of microsphere disruption and in situ sonoporation; (4) ApoA-I plasmid hepatic uptake; (5) transcription and expression of human ApoA-I protein; and (6) elevation of serum HDL-C.
  
  
  RESULTS
  Co-administration of ApoA-I plasmids and acoustic microspheres, activated by external ultrasound energy, resulted in transcription and production of human ApoA-I protein and elevated serum HDL-C in rats (up to 61%; p-value < 0.05).
  
  
  CONCLUSIONS
  HDL-C was increased in rats following ultrasound directed delivery of human ApoA-I plasmids by microsphere sonoporation. The present method provides a novel approach to promote ApoA-I synthesis and nascent HDL-C elevation, potentially permitting the use of a minimally-invasive ultrasound-based, gene delivery system for treating individuals with low HDL-C.
authors.affiliation: General Electric Global Research, Niskayuna, NY, USA. Electronic address: castle@ge.com.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Castle
authors.affiliation: Formerly GE Global Research, Niskayuna, NY, USA.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Kent
authors.affiliation: General Electric Global Research, Niskayuna, NY, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Fan
authors.affiliation: General Electric Global Research, Niskayuna, NY, USA.
authors.forename: Kirk D
authors.initials: KD
authors.lastname: Wallace
authors.affiliation: General Electric Global Research, Niskayuna, NY, USA.
authors.forename: Cynthia E L
authors.initials: CE
authors.lastname: Davis
authors.affiliation: General Electric Global Research, Niskayuna, NY, USA.
authors.forename: Jeannette C
authors.initials: JC
authors.lastname: Roberts
authors.affiliation: General Electric Global Research, Niskayuna, NY, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Marino
authors.affiliation: General Electric Global Research, Niskayuna, NY, USA.
authors.forename: Kai E
authors.initials: KE
authors.lastname: Thomenius
authors.affiliation: Formerly GE Global Research, Niskayuna, NY, USA.
authors.forename: Hae W
authors.initials: HW
authors.lastname: Lim
authors.affiliation: SonoGene LLC, Glen Ellyn, IL, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Coles
authors.affiliation: SonoGene LLC, Glen Ellyn, IL, USA; University of Chicago, Pritzker School of Medicine, Chicago, IL, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Davidson
authors.affiliation: SonoGene LLC, Glen Ellyn, IL, USA; Rush University Medical Center, Chicago, IL, USA.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Feinstein
authors.affiliation: Sulpizio Cardiovascular Center, University of California, San Diego, CA, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: DeMaria
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood*; D005240:Feasibility Studies; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism*; D008297:Male; D008863:Microspheres; D023421:Models, Animal; D010957:Plasmids / Q000008:administration & dosage; D012333:RNA, Messenger / Q000096:biosynthesis; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014158:Transcription, Genetic; D014465:Ultrasonics / Q000379:methods*; D015854:Up-Regulation
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D015415:Biomarkers; D008076:Cholesterol, HDL; D012333:RNA, Messenger
keywords: Acoustic microspheres; ApoA-I; Drug delivery; HDL-C; Hypo-alphalipoproteinemia; Optison™; Ultrasound