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

• Published in: Gene therapy 2015-02, Vol.22 (2), p.138-145
• Main Authors: Kwong, J M K, Gu, L, Nassiri, N, Bekerman, V, Kumar-Singh, R, Rhee, K D, Yang, X-J, Hauswirth, W W, Caprioli, J, Piri, N
• Format: Article
• Language: English
• Subjects: 38/1; 42/109; 631/378/1934; 631/378/2613; 82/80; 96; Animals; Axons - pathology; Benzoquinones - pharmacology; Biomedical and Life Sciences; Biomedicine; Care and treatment; Cell Biology; Cell culture; Cell Survival; Cells; Combined Modality Therapy; Dependovirus - genetics; Dependoviruses; Eye diseases; Gene Expression; Gene Therapy; Genetic Therapy; Health aspects; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; Human Genetics; Humans; Lactams, Macrocyclic - pharmacology; Mice, Inbred C57BL; Nanotechnology; Nerve Crush; Nerve Regeneration; Neurodegenerative diseases; Neurons; Neuroprotection; Optic nerve; Optic Nerve Injuries - therapy; original-article; Pharmacology; Retina; Retina - metabolism; Retina - pathology; Retinal ganglion cells; Retinal Ganglion Cells - physiology; Transcriptional Activation; Transduction, Genetic
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2014.105

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.