Therapeutic ultrasound: Increased HDL-Cholesterol following infusions of acoustic microspheres and apolipoprotein A-I plasmids
| Autor: | Jason William Castle, Jeannette Christine Roberts, Hae W. Lim, Ying Fan, Anthony N. DeMaria, Kevin P. Kent, Steven B. Feinstein, Eric Coles, Kai Erik Thomenius, Michael Ernest Marino, Cynthia Elizabeth Landberg Davis, Michael H. Davidson, Kirk D. Wallace |
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| Rok vydání: | 2015 |
| Předmět: |
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medicine.medical_specialty Time Factors Apolipoprotein B Transcription Genetic medicine.medical_treatment Article Rats Sprague-Dawley chemistry.chemical_compound Plasmid Internal medicine medicine Animals Humans Ultrasonics RNA Messenger Risk factor Therapeutic ultrasound biology Apolipoprotein A-I business.industry Cholesterol Immunogenicity Cholesterol HDL Gene Transfer Techniques nutritional and metabolic diseases Genetic Therapy Microspheres Up-Regulation Clinical trial Endocrinology chemistry Liver Drug delivery Injections Intravenous Models Animal biology.protein Feasibility Studies lipids (amino acids peptides and proteins) Cardiology and Cardiovascular Medicine business Biomarkers Plasmids |
| Zdroj: | Atherosclerosis. 241(1) |
| ISSN: | 1879-1484 |
| Popis: | 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.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.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.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).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. |
| Databáze: | OpenAIRE |
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