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X-linked inhibitor of apoptosis protein-mediated attenuation of apoptosis, using a novel cardiac-enhanced adeno-associated viral vector.

Publication ,  Journal Article
Piacentino, V; Milano, CA; Bolanos, M; Schroder, J; Messina, E; Cockrell, AS; Jones, E; Krol, A; Bursac, N; Mao, L; Devi, GR; Samulski, RJ; Bowles, DE
Published in: Hum Gene Ther
June 2012

Successful amelioration of cardiac dysfunction and heart failure through gene therapy approaches will require a transgene effective at attenuating myocardial injury, and subsequent remodeling, using an efficient and safe delivery vehicle. Our laboratory has established a well-curated, high-quality repository of human myocardial tissues that we use as a discovery engine to identify putative therapeutic transgene targets, as well as to better understand the molecular basis of human heart failure. By using this rare resource we were able to examine age- and sex-matched left ventricular samples from (1) end-stage failing human hearts and (2) nonfailing human hearts and were able to identify the X-linked inhibitor of apoptosis protein (XIAP) as a novel target for treating cardiac dysfunction. We demonstrate that XIAP is diminished in failing human hearts, indicating that this potent inhibitor of apoptosis may be central in protecting the human heart from cellular injury culminating in heart failure. Efforts to ameliorate heart failure through delivery of XIAP compelled the design of a novel adeno-associated viral (AAV) vector, termed SASTG, that achieves highly efficient transduction in mouse heart and in cultured neonatal rat cardiomyocytes. Increased XIAP expression achieved with the SASTG vector inhibits caspase-3/7 activity in neonatal cardiomyocytes after induction of apoptosis through three common cardiac stresses: protein kinase C-γ inhibition, hypoxia, or β-adrenergic receptor agonist. These studies demonstrate the potential benefit of XIAP to correct heart failure after highly efficient delivery to the heart with the rationally designed SASTG AAV vector.

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Published In

Hum Gene Ther

DOI

EISSN

1557-7422

Publication Date

June 2012

Volume

23

Issue

6

Start / End Page

635 / 646

Location

United States

Related Subject Headings

  • X-Linked Inhibitor of Apoptosis Protein
  • Rats
  • Myocytes, Cardiac
  • Mice
  • Humans
  • Heart Failure
  • Genetic Vectors
  • Dependovirus
  • Biotechnology
  • Apoptosis
 

Citation

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Piacentino, V., Milano, C. A., Bolanos, M., Schroder, J., Messina, E., Cockrell, A. S., … Bowles, D. E. (2012). X-linked inhibitor of apoptosis protein-mediated attenuation of apoptosis, using a novel cardiac-enhanced adeno-associated viral vector. Hum Gene Ther, 23(6), 635–646. https://doi.org/10.1089/hum.2011.186
Piacentino, Valentino, Carmelo A. Milano, Michael Bolanos, Jacob Schroder, Emily Messina, Adam S. Cockrell, Edward Jones, et al. “X-linked inhibitor of apoptosis protein-mediated attenuation of apoptosis, using a novel cardiac-enhanced adeno-associated viral vector.Hum Gene Ther 23, no. 6 (June 2012): 635–46. https://doi.org/10.1089/hum.2011.186.
Piacentino V, Milano CA, Bolanos M, Schroder J, Messina E, Cockrell AS, et al. X-linked inhibitor of apoptosis protein-mediated attenuation of apoptosis, using a novel cardiac-enhanced adeno-associated viral vector. Hum Gene Ther. 2012 Jun;23(6):635–46.
Piacentino, Valentino, et al. “X-linked inhibitor of apoptosis protein-mediated attenuation of apoptosis, using a novel cardiac-enhanced adeno-associated viral vector.Hum Gene Ther, vol. 23, no. 6, June 2012, pp. 635–46. Pubmed, doi:10.1089/hum.2011.186.
Piacentino V, Milano CA, Bolanos M, Schroder J, Messina E, Cockrell AS, Jones E, Krol A, Bursac N, Mao L, Devi GR, Samulski RJ, Bowles DE. X-linked inhibitor of apoptosis protein-mediated attenuation of apoptosis, using a novel cardiac-enhanced adeno-associated viral vector. Hum Gene Ther. 2012 Jun;23(6):635–646.
Journal cover image

Published In

Hum Gene Ther

DOI

EISSN

1557-7422

Publication Date

June 2012

Volume

23

Issue

6

Start / End Page

635 / 646

Location

United States

Related Subject Headings

  • X-Linked Inhibitor of Apoptosis Protein
  • Rats
  • Myocytes, Cardiac
  • Mice
  • Humans
  • Heart Failure
  • Genetic Vectors
  • Dependovirus
  • Biotechnology
  • Apoptosis