Oral Delivery of ACE2/Ang-(1–7) Bioencapsulated in Plant Cells Protects against Experimental Uveitis and Autoimmune Uveoretinitis

• Published in: Molecular therapy Vol. 22; no. 12; pp. 2069 - 2082
• Main Authors: Shil, Pollob K, Kwon, Kwang-Chul, Zhu, Ping, Verma, Amrisha, Daniell, Henry, Li, Qiuhong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2014; Elsevier Limited; Nature Publishing Group
• Subjects: Administration, Oral; Angiotensin I - administration & dosage; Angiotensin-Converting Enzyme 2; Animals; Bacteria; Chloroplasts; Chloroplasts - genetics; Chloroplasts - metabolism; Cholera; Disease Models, Animal; Endocrine system; Enzymes; Genetic engineering; Humans; Hypotheses; Mice; Mice, Inbred C57BL; Ophthalmology; Oral administration; Original; Peptide Fragments - administration & dosage; Peptidyl-Dipeptidase A - administration & dosage; Physiology; Plants, Genetically Modified - genetics; Plants, Genetically Modified - metabolism; Proteins; Retina; Retinal Vasculitis; Retinitis - chemically induced; Retinitis - immunology; Retinitis - therapy; Uveitis - chemically induced; Uveitis - immunology; Uveitis - therapy; Florida; United States > US; Pennsylvania
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2014.179

Hyperactivity of the renin-angiotensin system (RAS) resulting in elevated Angiotensin II (Ang II) contributes to all stages of inflammatory responses including ocular inflammation. The discovery of angiotensin-converting enzyme 2 (ACE2) has established a protective axis of RAS involving ACE2/Ang-(1–7)/Mas that counteracts the proinflammatory and hypertrophic effects of the deleterious ACE/AngII/AT1R axis. Here we investigated the hypothesis that enhancing the systemic and local activity of the protective axis of the RAS by oral delivery of ACE2 and Ang-(1–7) bioencapsulated in plant cells would confer protection against ocular inflammation. Both ACE2 and Ang-(1–7), fused with the non-toxic cholera toxin subunit B (CTB) were expressed in plant chloroplasts. Increased levels of ACE2 and Ang-(1–7) were observed in circulation and retina after oral administration of CTB-ACE2 and Ang-(1–7) expressing plant cells. Oral feeding of mice with bioencapsulated ACE2/Ang-(1–7) significantly reduced endotoxin-induced uveitis (EIU) in mice. Treatment with bioencapsulated ACE2/Ang-(1–7) also dramatically decreased cellular infiltration, retinal vasculitis, damage and folding in experimental autoimmune uveoretinitis (EAU). Thus, enhancing the protective axis of RAS by oral delivery of ACE2/Ang-(1–7) bioencapsulated in plant cells provide an innovative, highly efficient and cost-effective therapeutic strategy for ocular inflammatory diseases.