Recent evidence implicates the formation of the toxic free radical nitric oxide (NO) derived from the inducible NO synthase (iNOS) in the pathogenesis of psoriasis. Inotek Corporation is developing a unique anti- inflammatory D Recent evidence implicates the formation of the toxic free radical nitric oxide (NO) derived from the inducible NO compound, mercaptoethylguanidine (MEG), which interrupts multiple pathogenic mechanisms identified in psoriatic lesions: MEG a) selectively inhibits iNOS activity, decreases iNOS mRNA translation, and accelerates iNOS degradation, b) potently scavenges peroxynitrite, a potent oxidant formed from the reaction of NO and superoxide anion, c) inhibits pro- inflammatory cytokine expression (TNF-alpha and IL-I beta), and d) inhibits chemokine expression (MIP-1 alpha, MIP-2) and thereby inhibits leukocytic infiltration.
In Specific Aim #1, we will establish a suitable topical formulation of MEG for the treatment of psoriasis. Formulations will be examined for stability under accelerated conditions of temperature and relative humidity in order to optimize shelf life. Permeation of 5-10 formulations will be established in a murine model, in which dermal concentrations of absorbed MEG are established by mass spectroscopy. The optimal formulation will be selected for in vivo efficacy studies.
In Specific Aim #2, we will determine the pharmacodynamic profile of MEG in a clinically relevant well-established model of psoriasis produced by xenotransplantation of human psoriatic skin onto SCID mice. The xenograft in this model shows virtual identity with clinical psoriatic pathology. After 4 weeks of engraftment, MEG will be administered topically at 2 dose levels TID in a randomized, blinded, post-insult paradigm for an additional 4 weeks. Tissue samples will be obtained for evaluation of histology, myeloperoxidase activity (a marker of neutrophil infiltration), cytokine mRNA expression for TNF-alpha, IL-Ibeta, IL-6, iNOS, and IL-8 (by RT-PCR), malondialdehyde (marker of lipoperoxidation), and immunohistochemistry (to identify iNOS expression and nitrotyrosine formation). Demonstration that MEG is effective in reducing dermatopathology in this SCID mouse and human psoriatic chimera will provide a rational foundation for a Phase I clinical trial for treatment of psoriasis, to be proposed in the second phase of the SBIR process.
The domestic market for a novel, effective therapy for psoriasis is estimated at> 2 billion per annum. Global markets are estimated at $10 billion.
