Gene delivery of a viral anti-inflammatory protein to combat ocular inflammation

Cristhian J. Ildefonso, Henrique Jaime, Masmudur M. Rahman, Qiuhong Li, Shannon E. Boye, William W. Hauswirth, Alexandra R. Lucas, Grant McFadden, Alfred S. Lewin

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Inflammation of the retina is a contributing factor in ocular diseases such as uveitis, diabetic retinopathy, and age-related macular degeneration (AMD). The M013 immunomodulatory protein from myxoma virus has been shown to interfere with the proinflammatory signaling pathways involving both the NLRP3 inflammasome and NF-κB. We have developed and characterized an adeno-associated viral (AAV) vector that delivers a secretable and cell-penetrating form of the M013 protein (TatM013). The expressed TatM013 protein was secreted and blocked the endotoxin-induced secretion of interleukin (IL)-1β in monocyte-derived cells and the reactive aldehyde-induced secretion of IL-1β in retinal pigment epithelium cells. The local anti-inflammatory effects of AAV-delivered TatM013 were evaluated in an endotoxin-induced uveitis (EIU) mouse model after intravitreal injection of mice with an AAV2-based vector carrying either TatM013 fused to a secreted green fluorescent protein (GFP) tag (sGFP-TatM013) or GFP. Expression of the sGFP-TatM013 transgene was demonstrated by fluorescence funduscopy in living mice. In EIU, the number of infiltrating cells and the concentration of IL-1β in the vitreous body were significantly lower in the eyes injected with AAV-sGFP-TatM013 compared with the eyes injected with control AAV-GFP. These results suggest that a virus-derived inhibitor of the innate immune response, when delivered via AAV, could be a generalized therapy for various inflammatory diseases of the eye.

Original languageEnglish (US)
Pages (from-to)59-68
Number of pages10
JournalHuman Gene Therapy
Volume26
Issue number1
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Ildefonso, C. J., Jaime, H., Rahman, M. M., Li, Q., Boye, S. E., Hauswirth, W. W., Lucas, A. R., McFadden, G., & Lewin, A. S. (2015). Gene delivery of a viral anti-inflammatory protein to combat ocular inflammation. Human Gene Therapy, 26(1), 59-68. https://doi.org/10.1089/hum.2014.089