Oral rice-derived lactoferrin reduced the severity of Crohn's disease through anti-inflammatory regulation of T cells

DESCRIPTION provided by applicant The scope of this proposed study is to demonstrate the efficacy of recombinant human lactoferrin rhLF to act as an immune modulator through T cell regulation in distinct murine models of inflammatory bowel disease IBD which best recapitulate Crohnandapos s like ileitis and colitis Crohnandapos s disease CD affects as many as people in the United States with current therapies relying on anti inflammatories and immune modulators which are palliative at best or expensive TNF antibody therapies each of which have associated toxicities Therefore we propose to investigate the use of Ventriaandapos s rice derived rhLF in preclinical models to demonstrate its efficacy as a cost effective therapeutic option in th treatment of CD Lactoferrin LF is an endogenous anti inflammatory molecule secreted at mucosal sites within the body While originally identified as a key component of innate immunity because of its antimicrobial properties increasing evidence points to the ability of lactoferrin to additionally modulate the adaptive immune system making it an ideal therapeutic target for chronic mucosal inflammatory conditions such CD Our preliminary studies have effectively demonstrated the therapeutic potential of subcutaneous rhLF in a murine model of CD thereby negating its direct interaction with the intestinal microbiota and toxins Specifically rhLF administration significanly decreased na ve T cell infiltration and proliferation in the intestinal lamina propria mesenteric lymph nodes and spleen of wk old TNF ARE mice which similar to CD patients develop a spontaneous chronic transmural intestinal inflammation rhLF treated mice also exhibited improved histological indices and had improved intestinal barrier function indicating efficacy for rhLF to decrease inflammation in a preclinical model of CD Given the broad spectrum of disease phenotypes that CD encompasses from mild to severe disease involving strict ileitis colitis or both it is prudent to validate these findings in multple preclinical models Ventria Bioscience currently uses a rice expression system to produce recombinant human LF at high levels of purity at a cost effective scale and has demonstrated the safety and efficacy of rhLF in clinical trials when administered to human subjects Based on the proven safety record of rhLF and the capacity within Ventria for large scale production of this recombinant protein success in these phase I trials will allow us to rapidly translate these findings into a phase II clinical trial in pediatric patients Nonetheless we must first demonstrat that rhLF remains effective when administered orally and more crucially validate the protective effect of rhLF in an additional preclinical model of CD Specifically we seek to investigate the following Investigate the efficacy of oral rhLF in a relevant pre clinical model of chronic CD and demonstrate the mechanism of action of rhLF through its ability to enhance a pro regulatory environment Previous studies have used harsh and very acute chemical models of ulcerative colitis UC to demonstrate a protective effect of purified bovine or human LF when orally administered These studies did not attempt to demonstrate a clear mechanism of action of LF nor do the models themselves recapitulate the human condition very well Therefore we will test the efficacy of oral rhLF to induce remission in a chronic model of TNF driven ileitis TNF ARE which best displays the hallmarks of human disease We will investigate the role of rhLF in the regulation of specific T cell phenotypes characterized by their ability to exacerbate or suppress the inflammatory response The activity of rhLF is not limited to a single pre clinical model of CD by further investigating its immunoregulatory role in a T cell mediated model of colitis In an effort both to demonstrate that the effect of rhLF is not model specific ad to evaluate rhLFandapos s efficacy a model of Crohnandapos s like colitis a common feature of CD we have chosen a T cell driven model of colitis CD CD RBhigh adoptive transfer model In this model we will test the ability for rhLF to regulate T cell populations from the earliest to pervasive staes of inflammation with particular regard to the role of regulatory T cells Tregs and their abilityto suppress the pathogenic immune response Together these models will define an immunomodulatory role of rhLF in two distinct chronic models of CD testing the hypothesis that rhLF exerts its protective effect in part by induction of a pro regulatory environment within the intestine PUBLIC HEALTH RELEVANCE Crohnandapos s disease is a chronic debilitating and incurable disease that is increasing annually in both incidence and prevalence Current therapies fail to provide lasting disease remission have significant ill side effects and in the case of many of the targeted biologics are extremely expensive to administer to patients In the present application we propose to investigate the use of Ventriaandapos s rice derived recombinant human lactoferrin rhLF in pre clinical models of Crohnandapos s disease as an efficacious and cost effective alternative to current therapies