Abbreviated Journal Title
Proc. Natl. Acad. Sci. U. S. A.
Keywords
allergy; chloroplast; genetic disorders; oral tolerance; plant-made; therapeutics; HEAT-LABILE ENTEROTOXIN; CHOLERA-TOXIN; TRANSGENIC CHLOROPLASTS; FUNCTIONAL-EVALUATION; TOBACCO CHLOROPLASTS; ESCHERICHIA-COLI; VACCINE; ANTIGENS; IMMUNE-RESPONSES; GENE-THERAPY; MOUSE MODEL; Multidisciplinary Sciences
Abstract
To address complications of pathogenic antibody or life-threatening anaphylactic reactions in protein replacement therapy for patients with hemophilia or other inherited protein deficiencies, we have developed a prophylactic protocol using a murine hemophilia B model. Oral delivery of coagulation factor IX fused with cholera toxin beta-subunit (with or without a furin cleavage site; CTB-FFIX or CTB-FIX), expressed in chloroplasts (up to 3.8% soluble protein or 0.4 mg/g leaf tissue), bioencapsulated in plant cells, effectively blocked formation of inhibitory antibodies (undetectable or up to 100-fold less than controls). Moreover, this treatment eliminated fatal anaphylactic reactions that occurred after four to six exposures to intravenous F. IX. Whereas only 20-25% of control animals survived after six to eight F. IX doses, 90-93% of F.IX-fed mice survived 12 injections without signs of allergy or anaphylaxis. Immunostaining confirmed delivery of F. IX to Peyer's patches in the ileum. Within 2-5 h, feeding of CTB-FFIX additionally resulted in systemic delivery of F. IX antigen. This high-responder strain of hemophilia B mice represents a new animal model to study anaphylactic reactions. The protocol was effective over a range of oral antigen doses (equivalent to 5-80 mu g recombinant F.IX/kg), and controlled inhibitor formation and anaphylaxis long-term, up to 7 months (similar to 40% life span of this mouse strain). Oral antigen administration caused a deviant immune response that suppressed formation of IgE and inhibitory antibodies. This cost-effective and efficient approach of antigen delivery to the gut should be applicable to several genetic diseases that are prone to pathogenic antibody responses during treatment.
Journal Title
Proceedings of the National Academy of Sciences of the United States of America
Volume
107
Issue/Number
15
Publication Date
1-1-2010
Document Type
Article
Language
English
First Page
7101
Last Page
7106
WOS Identifier
ISSN
0027-8424
Recommended Citation
Verma, Dheeraj; Moghimi, Babak; LoDuca, Paul A,; Singh, Harminder D.; Hoffman, Brad E.; Herzog, Roland W.; and Daniell, Henry, "Oral delivery of bioencapsulated coagulation factor IX prevents inhibitor formation and fatal anaphylaxis in hemophilia B mice" (2010). Faculty Bibliography 2010s. 903.
https://stars.library.ucf.edu/facultybib2010/903
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