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

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.

• Authors: Cristhian J Ildefonso, Henrique Jaime, Masmudur M Rahman, Qiuhong Li, Shannon E Boye, William W Hauswirth, Alexandra R Lucas, Grant McFadden, Alfred S Lewin
• Journal: Human gene therapy (Hum Gene Ther) Vol. 26 Issue 1 Pg. 59-68 (Jan 2015) ISSN: 1557-7422 [Electronic] United States
• PMID: 25420215 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cell-Penetrating Peptides
• Gene Products, tat
• Interleukin-1beta
• Recombinant Fusion Proteins
• Viral Proteins
• tat Gene Products, Human Immunodeficiency Virus

Topics

• Animals
• Cell Line, Tumor
• Cell-Penetrating Peptides (genetics, metabolism)
• Dependovirus (genetics)
• Disease Models, Animal
• Gene Expression
• Gene Order
• Gene Products, tat (genetics, metabolism)
• Gene Transfer Techniques
• Genes, Reporter
• Genetic Therapy
• Genetic Vectors (administration & dosage, genetics)
• Humans
• Interleukin-1beta (biosynthesis)
• Mice
• Myxoma virus (genetics)
• Ophthalmoscopes
• Recombinant Fusion Proteins
• Transduction, Genetic
• Transgenes
• Uveitis (pathology, therapy)
• Viral Proteins (genetics, metabolism)
• tat Gene Products, Human Immunodeficiency Virus