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Principal Investigator: Robert J DeVita
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $383,980
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
SUMMARY
Therapies to treat Crohn's disease (CD) and ulcerative colitis (UC), the types of inflammatory bowel disease
(IBD) characterized by severe chronic inflammation of the gastrointestinal tract, have greatly improved over the
past three decades; yet, a large proportion of IBD patients fail to achieve sustained remission. Genetic
biomarkers may offer an avenue toward the dissecting heterogeneity of disease etiology, and improving
personalized therapeutic approaches. Our group has recently identified a coding gain-of-function mutation in the
LRRK2 (leucine-rich repeat kinase 2) gene that conferred a ~70% increased CD risk and affected CD age of
onset, disease location, LRRK2 kinase activity, and autophagy flux. Importantly, LRRK2 has also attracted
considerable attention for its causal link to Parkinson's disease (PD). Further analyses identified dozens of
additional variants within LRRK2 that were associated with the risk of both CD and PD, suggesting shared
pathogenesis between these diseases. Given extensive efforts to target LRRK2 kinase activity as a means to
treat PD, we explored known LRRK2 inhibitors developed for PD as potential therapies for IBD. We showed that
selective LRRK2 inhibitors have ameliorated experimental colitis and reduced inflammatory cytokine TNF-α
levels, a hallmark of IBD-associated inflammation, in dendritic cells of IBD patients. However, studies of LRRK2
kinase inhibition in preclinical models suggest that brain penetration and toxicity in peripheral tissues may be a
critical safety liability for these inhibitors in IBD patients. To advance this therapeutic hypothesis, we have
developed structure-based approach to design novel gut-restricted LRRK2 inhibitors, synthesized prototype
inhibitors, crystallized analogs in complex with kinases mutants that mimic LRRK2 binding site and tested their
LRRK2 potency and efficacy, which are maintained. Thus, we are proposing, starting from known LRRK2
inhibitor structures to 1) Develop proof-of-concept gut-restricted LRRK2 inhibitors as potential IBD therapeutics
using structure-based drug design and medicinal chemistry; 2) Evaluate novel compounds for LRRK2 inhibition,
in vitro absorption, distribution, metabolism, excretion and pharmacokinetics, off-target selectivity, and effects on
cellular substrate phosphorylation and cytokine activity using biochemical and cell-based assays, and 3) Pre-
clinically validate new inhibitors for in vivo absorption, distribution, metabolism, excretion and pharmacokinetics,
plasma exposures, and effects on inflammatory biomarkers and severity of experimental colitis. Our hypothesis
is that gut-restricted LRRK2 inhibitors could be a safe and effective therapeutic target of IBD therapy in the
presence or absence of IBD-associated LRRK2 mutations. These studies will provide a basis for future clinical
trials aimed at testing LRRK2 as an effective drug target for IBD. We believe our strong preliminary data and
relevant therapeutic hypothesis align well with the research goals and objectives of PAR-19-294 and will help
improve the current standard of clinical care for patients with this disease of interest to the National Institute of
Diabetes and Digestive and Kidney Diseases.
Terms: <(TNF)-α><Affect><Age of Onset><Alimentary Canal><Alleles><Allelomorphs><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Assay><Attention><Autophagocytosis><Binding><Binding Sites><Bioassay><Biochemical><Biological Assay><Biological Markers><Blocking Antibodies><Blood Plasma><Body Tissues><Brain><Brain Nervous System><Cachectin><Causality><Cell Body><Cells><Chemicals><Chronic><Circulation><Clinical Treatment Moab><Clinical Trials><Code><Coding System><Colitis><Colonic inflammation><Combining Site><Complex><Crohn disease><Crohn's><Crohn's disease><Crohn's disorder><Crystallization><Data><Dendritic Cells><Development><Digestive Tract><Disease><Disease remission><Disorder><Dose><Drug Design><Drug Kinetics><Drug Targeting><Drugs><Encephalon><Enzyme Gene><Enzymes><Epithelium><Etiology><Excretory function><Future><GI Tract><GWA study><GWAS><Gastrointestinal Tract><Gastrointestinal tract structure><General Population><General Public><Genes><Genetic Alteration><Genetic Change><Genetic Markers><Genetic defect><Goals><Granulomatous Enteritis><IL-23><In Vitro><Incidence><Inflammation><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Intellectual Property><Intermediary Metabolism><Kinases><LRRK2><LRRK2 gene><LRRK2 leucine-rich repeat kinase 2 gene><LRRK2 protein><Lead><Link><Location><Lung><Lung Respiratory System><Macrophage-Derived TNF><Medical><Medication><Medicinal Chemistry><Metabolic Processes><Metabolism><Mice><Mice Mammals><Molecular Interaction><Monoclonal Antibodies><Monocyte-Derived TNF><Murine><Mus><Mutate><Mutation><NIDDK><National Institute of Diabetes and Digestive and Kidney Diseases><Nephrotoxic><Operative Procedures><Operative Surgical Procedures><Oral><PARK8 protein><Paralysis Agitans><Parkinson><Parkinson Disease><Parkinson disease 8 protein><Pathogenesis><Pathogenicity><Pathway interactions><Patient Care><Patient Care Delivery><Patients><Pb element><Penetration><Peripheral><Persons><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmacokinetics><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Plasma><Plasma Serum><Population><Pre-Clinical Model><Preclinical Models><Primary Parkinsonism><Production><Property><Protein Phosphorylation><Reactive Site><Remission><Research><Reticuloendothelial System, Serum, Plasma><Risk><Roentgen Rays><Safety><Severities><Single Crystal Diffraction><Structure><Surgical><Surgical Interventions><Surgical Procedure><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic><Therapeutic Uses><Time><Tissues><Toxic effect><Toxicities><Transphosphorylases><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Ulcerated Colitis><Ulcerative Colitis><Validation><Variant><Variation><Veiled Cells><X Ray Crystallographies><X-Radiation><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray Radiation><X-Ray/Neutron Crystallography><X-ray><Xray><Xray Crystallography><absorption><alimentary tract><analog><autophagy><bio-markers><biologic marker><biomarker><care for patients><care of patients><caring for patients><causation><chemical group><clinical care><cytokine><dardarin><dardarin gene><dardarin protein><design><designing><developmental><digestive canal><disease causation><disease heterogeneity><disease risk><disorder risk><drug development><drug discovery><drug/agent><effective therapy><effective treatment><eleocolitis><excretion><gain of function mutation><gene biomarker><gene expression biomarker><gene marker><gene signature biomarker><genetic biomarker><genome mutation><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><heavy metal Pb><heavy metal lead><improved><in vivo><individualized therapeutic><inflamed colon><inflammatory disease of the intestine><inflammatory disorder of the intestine><inhibitor><interest><interleukin-23><intestinal autoinflammation><kidney toxicity><leucine-rich repeat kinase 2><loss of function><mAbs><monoclonal Abs><mutant><nephrotoxicity><novel><pathway><personalized therapeutic><pre-clinical><preclinical><prototype><pulmonary><regional enteritis><response><safety testing><scaffold><scaffolding><side effect><surgery><therapeutic target><therapeutically effective><validations><whole genome association analysis><whole genome association studies><whole genome association study>