AAV-mediated and pharmacological induction of Hsp70 expression stimulates survival of retinal ganglion cells following axonal injury

Gene Ther. 2015 Feb;22(2):138-45. doi: 10.1038/gt.2014.105. Epub 2014 Nov 27.

Abstract

We evaluated the effect of AAV2- and 17-AAG (17-N-allylamino-17-demethoxygeldanamycin)-mediated upregulation of Hsp70 expression on the survival of retinal ganglion cells (RGCs) injured by optic nerve crush (ONC). AAV2-Hsp70 expression in the retina was primarily observed in the ganglion cell layer. Approximately 75% of all transfected cells were RGCs. RGC survival in AAV2-Hsp70-injected animals was increased by an average of 110% 2 weeks after the axonal injury compared with the control. The increase in cell numbers was not even across the retinas with a maximum effect of approximately 306% observed in the inferior quadrant. 17-AAG-mediated induction of Hsp70 expression has been associated with cell protection in various models of neurodegenerative diseases. We show here that a single intravitreal injection of 17-AAG (0.2 ug ul(-1)) results in an increased survival of ONC-injured RGCs by approximately 49% compared with the vehicle-treated animals. Expression of Hsp70 in retinas of 17-AAG-treated animals was upregulated approximately by twofold compared with control animals. Our data support the idea that the upregulation of Hsp70 has a beneficial effect on the survival of injured RGCs, and the induction of this protein could be viewed as a potential neuroprotective strategy for optic neuropathies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / pathology
  • Benzoquinones / pharmacology*
  • Cell Survival
  • Combined Modality Therapy
  • Dependovirus / genetics*
  • Genetic Therapy
  • HSP70 Heat-Shock Proteins / genetics*
  • HSP70 Heat-Shock Proteins / metabolism
  • Humans
  • Lactams, Macrocyclic / pharmacology*
  • Mice, Inbred C57BL
  • Nerve Crush
  • Nerve Regeneration
  • Optic Nerve Injuries / therapy*
  • Retina / metabolism
  • Retina / pathology
  • Retinal Ganglion Cells / physiology*
  • Transcriptional Activation
  • Transduction, Genetic

Substances

  • Benzoquinones
  • HSP70 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • tanespimycin