Journal article
Immunosuppression Decreases Inflammation and Increases AAV6-hSERCA2a-Mediated SERCA2a Expression
Human gene therapy, Vol.23(7), pp.722-732
07/01/2012
DOI: 10.1089/hum.2011.108
PMCID: PMC3404422
PMID: 22482463
Abstract
The calcium pump SERCA2a (sarcoplasmic reticulum calcium ATPase 2a), which plays a central role in cardiac contraction, shows decreased expression in heart failure (HF). Increasing SERCA2a expression in HF models improves cardiac function. We used direct cardiac delivery of adeno-associated virus encoding human SERCA2a (AAV6-hSERCA2a) in HF and normal canine models to study safety, efficacy, and the effects of immunosuppression. Tachycardic-paced dogs received left ventricle (LV) wall injection of AAV6-hSERCA2a or solvent. Pacing continued postinjection for 2 or 6 weeks, until euthanasia. Tissue/serum samples were analyzed for hSERCA2a expression (Western blot) and immune responses (histology and AAV6-neutralizing antibodies). Nonpaced dogs received AAV6-hSERCA2a and were analyzed at 12 weeks; a parallel cohort received AAV-hSERCA2a and immunosuppression. AAV-mediated cardiac expression of hSERCA2a peaked at 2 weeks and then declined (to ∼50%;
p
<0.03, 6 vs. 2 weeks). LV end diastolic and end systolic diameters decreased in 6-week dogs treated with AAV6-hSERCA2a (
p
<0.05) whereas LV diameters increased in control dogs. Dogs receiving AAV6-hSERCA2a developed neutralizing antibodies (titer ≥1:120) and cardiac cellular infiltration. Immunosuppression dramatically reduced immune responses (reduced inflammation and neutralizing antibody titers <1:20), and maintained hSERCA2a expression. Thus cardiac injection of AAV6-hSERCA2a promotes local hSERCA2a expression and improves cardiac function. However, the hSERCA2a protein level is reduced by host immune responses. Immunosuppression alleviates immune responses and sustains transgene expression, and may be an important adjuvant for clinical gene therapy trials.
Zhu and colleagues employ direct cardiac delivery of adeno-associated virus encoding the human calcium pump SERCA2a (AAV6-hSERCA2a) in heart failure and normal canine models in order to study the safety and efficacy of the approach as well as the effects of concomitant immunosuppressant treatment. Tachycardic-paced dogs injected with AAV6-hSERCA2a via the left ventricle wall displayed hSERCA2a expression and improved cardiac function, although hSERCA2a protein levels were reduced by host immune responses. Immunosuppression dramatically reduced inflammation and neutralizing antibody titers while maintaining hSERCA2a expression.
Details
- Title: Subtitle
- Immunosuppression Decreases Inflammation and Increases AAV6-hSERCA2a-Mediated SERCA2a Expression
- Creators
- Xiaodong Zhu - 1Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213Charles F McTiernan - 1Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213Navin Rajagopalan - 1Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213Hemal Shah - 1Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213David Fischer - 1Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213Yoshiya Toyoda - 2Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213Dustin Letts - 1Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213Jonathan Bortinger - 1Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213Gregory Gibson - 1Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213Wenyu Xiang - 1Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213Kenneth McCurry - 2Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213Michael Mathier - 1Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213Joseph C Glorioso - 3Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA 15213Barry London - 1Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213
- Resource Type
- Journal article
- Publication Details
- Human gene therapy, Vol.23(7), pp.722-732
- DOI
- 10.1089/hum.2011.108
- PMID
- 22482463
- PMCID
- PMC3404422
- NLM abbreviation
- Hum Gene Ther
- ISSN
- 1043-0342
- eISSN
- 1557-7422
- Publisher
- Mary Ann Liebert, Inc
- Language
- English
- Date published
- 07/01/2012
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984025321002771
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