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Principal Investigator: John B Barnett
Organization: EXESALIBERO, INC.
Fiscal Year: 2020
Award: $1,103,697
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
We are working on a new approach to treating acute arthritis based on a common pathway in the cellular
infiltrates that damage bones and joints. Inflammatory arthritis disables thousands of people each year. It occurs
in children and adults, after trauma and infections but most cases are idiopathic. Millions of adults live with
chronic RA, which has similar features. Inflammatory arthritis often requires treatments with serious side effects.
Later in arthritis, bone erosion is a major problem that causes severe pain and debilitation. There is no small
molecule drug available to specifically treat arthritic bone erosion. We show that osteoclast maturation is
suppressed by blocking a calcium-release activated calcium channel, called Orai. A Orai antagonist, N-methyl-
3,4-dichloropropionaniline (N-MeDCPA), suppressed osteoclast maturation and strongly suppressed collagen-
induced arthritis (CIA) in mice, even after symptoms of arthritis were measureable. We propose that
pharmacologically suppressing CRAC channels with N-MeDCPA will prevent bone erosion due to arthritic stimuli
without major adverse effects.
We hypothesize that Ca2+ signals mediated by Orai channels modulate final differentiation of osteoclasts,
and that related effects on T cells might reinforce bone and joint sparing in acute arthritis. We expect toxicity of
N-MeDCPA to be low when treatment is for several weeks in animals with mature immune systems. We propose
comprehensive pharmacokinetic and toxicokinetic testing in addition to mechanistic experiments with Ca2+
signaling, immunology, and bone biology expertise.
Phase I - AIM 1: - Drug formulation, route of administration optimization and Orai specificity. N-
MeDCPA is lipid soluble. This aim will define a suitable nanoparticle (NP) or liposome formulation of N-
MeDCPA for parenteral or oral administration. Drug blood levels versus ease/convenience and effectiveness will
be assessed.
Phase I – AIM 2: - Complete the dose-response studies of N-MeDCPA using the CIA model. Having
demonstrated that N-MeDCPA can prevent bone erosion and arrest inflammation in symptomatic mice, the
emphasis of this aim will be to define its effect against the standard CIA measures, arthritic index, bone erosion,
volume by µCT and inflammation (swelling) using the optimized dosing regimen.
Phase II - AIM 1: Pharmacology and toxicology assessment of N-MeDCPA under non-GLP and GLP
conditions in vitro and in vivo. An extensive suite of tests will be performed by a contract research organization
(CRO) under contract with ExesaLibero (see letter of support from Covance).
Phase II - AIM 2: Determine the therapeutic-potential of N-MeDCPA. Critical to demonstrating that N-
MeDCPA will improve the standard of care/quality of life, is confirmation of equal effectiveness in both sexes
using SKG mice, determining its cellular specificity, checking for potential immunotoxicity of N-MeDCPA in tests
not covered by the CRO and exploring possible additive/synergistic effects of N-MeDCPA in combination with
other current non-biological treatments, e.g., methotrexate. We will also study the in vitro effects on human cells
to avoid the pitfall of rodent-human physiological differences.
Phase II - AIM 3: Assess the specificity and mechanism of action of N-MeDCPA. We will assess the action
of the N-MeDCPA on monocyte differentiation to osteoclasts, and investigate the possible side effects on
osteoblasts and its specificity for ion channels.
The development of N-MeDCPA as a drug for treatment of bone erosion promises to prevent the life-
changing debilitation associated with RA, effectively with low toxicity.
Terms: <(TNF)-α><0-11 years old><21+ years old><Acute><Adult><Adult Human><Adverse effects><Animals><Arthritis><Atrophic Arthritis><Autoimmune Status><Autoimmunity><Biological><Biology><Blood drug level result><Blood monocyte><Bone Inflammation><Bone Resorption><Cachectin><Calcium><Calcium Channel><Calcium Channel Antagonist Receptor><Calcium Channel Blocker Receptors><Calcium Ion Channels><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell membrane><Cells><Cellular Infiltrate><Child><Child Youth><Children (0-21)><Chronic><Climacteric><Collaborations><Collagen Arthritis><Collagen-Induced Arthritis><Contracting Opportunities><Contracts><Cytoplasmic Membrane><D2E7 antibody><Data><Development><Dose><Drug Formulations><Drug Kinetics><Drug Therapy><Drugs><Effectiveness><Enbrel><Etanercept><Evolution><Excretory function><Formulation><Gene Transcription><Genetic Transcription><Goals><Home><Home environment><Human><Humira><Immune system><Immunology><Immunotoxicology><In Vitro><Infection><Inflammation><Inflammation Mediators><Inflammatory Arthritis><Institution><Intermediary Metabolism><Intracellular Communication and Signaling><Ion Channel><Ionic Channels><Joints><Lead><Letters><Leucocytic infiltrate><Lipids><Liposomal><Liposomes><Liver><Macrophage-Derived TNF><Marrow monocyte><Measures><Mediating><Medication><Membrane Channels><Metabolic><Metabolic Processes><Metabolism><Methotrexate><Methotrexate Methylaminopterin><Methotrexatum><Metotrexato><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Monocyte-Derived TNF><Murine><Mus><NSAIDs><Non Steroidal Antiinflammatory Agents><Non-Steroidal Anti-Inflammatory Agents><Nonsteroidal Anti-Inflammatory Agents><Nonsteroidal Antiinflammatory Agents><Nonsteroidal Antiinflammatory Drug><Oral Administration><Oral Drug Administration><Osteitis><Osteoblasts><Osteoclastic Bone Loss><Osteoclasts><Pain><Painful><Pathway interactions><Pb element><Pharmaceutic Preparations><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Pharmacology><Pharmacology and Toxicology><Pharmacotherapy><Phase><Physiologic><Physiological><Plasma Membrane><Prevention><Production><Proteins><QOL><Quality of life><RNA Expression><Regimen><Request for Proposals><Research Contracts><Rheumatoid Arthritis><Risk><Rodent><Rodentia><Rodents Mammals><Route><STTR><Short interfering RNA><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Small Business Technology Transfer Research><Small Interfering RNA><Specificity><Steroid Compound><Steroids><Stimulus><Swelling><Symptoms><T-Cell Activation><T-Cells><T-Lymphocyte><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic><Toxic effect><Toxicities><Toxicokinetics><Transcription><Trauma><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><VDCC><Voltage-Dependent Calcium Channels><Work><absorption><adalimumab><adult animal><adulthood><allergic/immunologic body system><allergic/immunologic organ system><arthritic><base><biological signal transduction><bone><bone erosion><children><childrens'><combat><cost><developmental><drug blood level><drug candidate><drug development><drug treatment><drug/agent><excretion><experiment><experimental research><experimental study><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><immunotoxicity><improved><in vivo><indexing><inflamed bone><inflammatory mediator><inhibitor><inhibitor/antagonist><intraoral drug delivery><joint damage><joint injury><joint trauma><life change><mature animal><monocyte><nano particle><nano-sized particle><nanoparticle><nanosized particle><new approaches><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><non-steroidal anti-inflammatory drugs><non-steroidal antiinflammatory drugs><nonsteroidal anti-inflammatory drugs><novel><novel approaches><novel drug treatments><novel drugs><novel strategies><novel strategy><novel therapeutics><novel therapy><parenteral administration><parenteral delivery><parenteral infusion><pathway><plasmalemma><pre-clinical development><pre-clinical study><preclinical development><preclinical study><prevent><preventing><response><rheumatic arthritis><sex><siRNA><side effect><small molecule><small molecule inhibitor><standard of care><thymus derived lymphocyte><toxic reaction in immunology><youngster>