New Therapeutic Approach for Ricin-Induced Lung Injury

New York University School Of Medicine, New York NY

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The increasing threat of bioterrorism worldwide has escalated the demand for the development of therapeutics for toxins that can be used as biological weapons. Ricin is a natural product of the castor bean (Ricinus communis) and a Category B toxin. It is a ribosome-inactivating protein that has the potential of being used as a biological weapon because of its heat stability, worldwide availability, ease in production and can be disseminated as an aerosol, a likely route that terrorists may use. When inhaled as a respirable aerosol, it causes irreversible pathological changes in the respiratory tract resulting in epithelial necrosis, pulmonary edema and alveolar flooding, and eventual death. The ricin toxin (RT) is a lectin consisting of two polypeptide chains linked by a disulfide bridge and cellular entry is required for toxicity. The B-chain (RTB) facilitates entry of the toxin into the cell and the A-chain (RTA) possesses RNA N-glycosidase activity that disables translation by depurinating a single adenine in the 28S eukaryotic ribosomal RNA (rRNA), thereby inducing ribotoxicity. In vitro selection has been used to generate RNA ligands (aptamers) specific for the catalytic RTA. These RNA aptamers inhibited RTA depurination and protects against ricin ribotoxicity. We hypothesize that post-exposure treatment can be developed against ricin ribotoxicity by delivering these novel anti-RTA aptamers intracellularly to inhibit RTA activity and toxicity. To test our hypothesis, the following aims are proposed: (1) To test the efficacy of the polycation polyethylenimine (PEI) in facilitating cellular uptake of aptamers and protective effects against ricin cytotoxicity in cell culture models; (2) To ascertain the efficacy of PEI-aptamers in the protection against ricin-induced lung injury and lethality and characterize the uptake of PEI-aptamers in the lungs; and (3) To validate the efficacy of PEI-aptamers in an aerosolized ricin mouse model. Relevance to Public Health: Since there is currently no treatment for ricin toxicity, there is an urgent need to develop effective antidotes for ricin. Because ricin is an important bioterrorist threat, our long-term goal is generate anti-toxin regimen for human use to protect the civilian and military populations against the use of ricin in acts of terrorism or war. [unreadable] [unreadable] [unreadable]