Development of CaSR nutrient therapy for childhood diarrhea

Project Abstract
Acute infectious diarrhea is a worldwide problem especially among infants young children and
immune compromised patients Sadly million children die each year not because of the infections causing
diarrhea but due to the associated dehydration The pro absorptive Oral Rehydration Solution ORS is the
only recommended oral therapy for children with acute diarrhea yet it neither reduces diarrhea secretion nor
alters the overly active enteric nerve ENS activity gut inflammation and dysbiosis key contributors to
diarrhea The overarching question of this application is the following can we develop a novel anti
diarrheal therapy that is as simple and has both pro absorptive and anti secretory properties while
reducing ENS activity inflammation and microbial imbalance Based upon preliminary data Medosome
Biotec LLC and its research partners at University of Florida hypothesize that the intestinal Calcium Sensing
Receptor CaSR is a likely candidate target for developing such a therapeutic The preliminary data show that
CaSR is expressed in the gut epithelium both in the absorbing surface epithelium and the secreting crypts
Also CaSR is densely present in the ENS both in the fluid modulating submucosal plexus and the motility
modulating myenteric plexus Using in vitro or ex vivo models it was observed that activating the CaSRs either
by nutritional agonists e g calcium spermine or by chemical agonists e g R reversed cholera toxin
induced fluid movement from secretion to absorption and reduced gut motility inflammation and dysbiosis
Furthermore mice lacking the CaSR displayed increased intestinal permeability imbalanced microbiota and
skewed immune responses from regulatory towards pro inflammatory This Phase I STTR project will use two
mouse models of diarrhea i e cholera toxin model of secretory diarrhea and citrobacter model of infectious
diarrhea to further examine diarrhea therapeutic potentials of CaSR activating nutrients agonists calcium
orthosteric agonist spermine and tryptophan both allosteric and biased agonists Aim will examine
efficacy and safety of increasing doses of calcium to define an optimal dose that produces maximal
therapeutic and minimal adverse effects Aim will determine if adding spermine and or tryptophan to
calcium adds additional efficacy and safety in treating diarrhea and dysbiosis The results from these
studies will determine which strategy provides the best therapy for diarrhea single nutrient therapy vs
combination therapy Once an optimal recipe composition and doses of the CaSR antidiarrheal therapy is
defined it will be further tested in humans Phase II III studies The overall goal of the STTR project is to
develop a novel widely available child friendly anti diarrheal therapy to complement current ORS for acute
diarrhea If these studies are promising CaSR based therapies will have clinical utility in hundreds of millions
of infants and children worldwide Project Relevance
Despite vaccinations millions of infants and children die each year from acute infectious diarrhea not because
of the infection but due to the associated diarrhea and or dysbiosis Medosome Biotec LLC and its research
partners at University of Florida have newly discovered that the ancient Calcium Sensing Receptor in the gut is
a potent anti diarrheal symbiosis preserving mechanism In this STTR the team proposes to use animal
models of diarrhea and determine whether activating this mechanism with simple nutrient calcium spermine
and tryptophan alone or in combinations reduces diarrhea and preserves microbial balance