Departmental Papers (Dental)
Document Type
Journal Article
Date of this Version
4-13-2010
Publication Source
Proc Natl Acad Sci U S A
Volume
107
Issue
15
Start Page
7101
Last Page
7106
DOI
10.1073/pnas.0912181107
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 β-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 μg recombinant F.IX/kg), and controlled inhibitor formation and anaphylaxis long-term, up to 7 months (∼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.
Copyright/Permission Statement
© [2010] National Academy of Sciences
Keywords
allergy, chloroplast, genetic disorders, oral tolerance, plant-made therapeutics
Recommended Citation
Verma, D., Moghimi, B., LoDuca, P., Singh, H. D., Hoffman, B. E., Herzog, R. W., & Daniell, H. (2010). Oral delivery of bioencapsulated coagulation factor IX prevents inhibitor formation and fatal anaphylaxis in hemophilia B mice. Proc Natl Acad Sci U S A, 107 (15), 7101-7106. http://dx.doi.org/10.1073/pnas.0912181107
Date Posted: 01 March 2022
This document has been peer reviewed.