Developing the first TPI Df therapeutics

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Principal Investigator: Michael John Palladino
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $526,383
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development

Abstract/Project summary:
TPI Df is a devastating untreatable childhood metabolic disease resulting in anemia, paralysis, irreversible
brain damage and premature death. Numerous single amino acid substitutions in Triosephosphate
Isomerase (TPI) are pathogenic and result in rapidly progressing multisystem disease. Importantly, all
known pathogenic TPI Df mutations result in a protein that retains function and pathogenesis is known to
result from increased turnover of the functioning protein by Protein Quality Control pathways (PQC). We
have developed a human cellular TPI Df assay based on a cellular model of the “common” E104D mutation
and implemented it for high-content, high-throughput imaging. We have used this model in a pilot screen
and validated its utility to identify novel compounds that modulate mutant TPI protein levels in human cells.
We propose to develop the assay to full HTS standards, conduct a screen of several relevant compound
libraries, and identify first-in-class TPI Df small molecule therapies. We will validate hits in secondary
assays for TPI stability and activity in TPI Df patient cells, prioritize them in a panel of in vitro toxicology
and metabolic stability assays, examine structure activity relationships (SARs) of the lead compounds and
substantially validate them in vivo using a recently developed mouse TPI Df model. Overall this project will
discover and validate the first ever treatments for TPI Df that will provide the basis for clinical trials.

Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><APF-1><ATP-Dependent Proteolysis Factor 1><Acquired brain injury><Acute><Amino Acid Substitution><Anemia><Animal Model><Animal Models and Related Studies><Animals><Assay><Behavioral><Bioassay><Biological Assay><Blood><Blood Reticuloendothelial System><Brain><Brain Injuries><Brain Nervous System><CRISPR><CRISPR/Cas system><Catalogs><Cell Body><Cell Culture Techniques><Cell Line><Cell model><CellLine><Cells><Cellular model><Cessation of life><Chemicals><Childhood><Chronic><Clinical><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats><Collection><Data><Data Bases><Databases><Death><Defect><Development><Diagnosis><Disease><Disorder><Dose><Drosophila><Drosophila genus><Drug Therapy><Drug usage><Drugs><Dysfunction><Encephalon><Enzyme Gene><Enzymes><Exhibits><FDA approved><Fibroblasts><Flies><Foundations><Functional disorder><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Germ Lines><Goals><HMG-20><Heterozygote><High Mobility Protein 20><High Throughput Assay><Human><Image><Impairment><In Vitro><Inpatients><Intervention><Intervention Strategies><Isomerase><Isomerase Gene><KO mice><Knock-out Mice><Knockout Mice><Lead><Length of Life><Libraries><Library Collection Development><Liver><Longevity><Macropain><Macroxyproteinase><Mammalia><Mammals><Mediating><Medication><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Protein Degradation><Methodology><Mice><Mice Mammals><Missense Mutation><Modeling><Modern Man><Motor><Multicatalytic Proteinase><Murine><Mus><Muscle><Muscle Tissue><Mutation><NIH><National Institutes of Health><Neurologic><Neurological><Neuromuscular Diseases><Null Mouse><Optics><Palsy><Paralysed><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Pb element><Pharmaceutical Preparations><Pharmacotherapy><Phosphotriose Isomerase><Physiopathology><Pilot Projects><Plegia><Prosome><Proteasome><Proteasome Endopeptidase Complex><Proteasome Inhibitor><Protein Turnover><Proteins><Proteosome><Quality Control><Regulatory Protein Degradation><Research><Severity of illness><Solid><Strains Cell Lines><Structure-Activity Relationship><Symptoms><System><Testing><Therapeutic><Therapeutic Agents><Thesaurismosis><Toxic effect><Toxicities><Toxicology><Transmission><Triose-Phosphate Isomerase><Triosephosphate Isomerase><Triosephosphate Mutase><Ubiquitin><United States National Institutes of Health><Universities><Validation><analog><brain damage><brain-injured><catalog><cell culture><cell cultures><chemical library><chemical structure function><combinatorial chemistry><cultured cell line><data base><design><designing><developmental><disease severity><drug treatment><drug use><drug/agent><early childhood><efficacy testing><efficacy validation><fly><fruit fly><genome mutation><heavy metal Pb><heavy metal lead><hepatic body system><hepatic metabolism><hepatic organ system><heterozygosity><high throughput screening><human disease><imaging><immunocytochemistry><in vivo><indel><insertion-deletion><insertion-deletion mutation><insertion/deletion><insertion/deletion mutation><interventional strategy><lead series><life span><lifespan><liver metabolism><member><metabolism disorder><model of animal><mouse model><multicatalytic endopeptidase complex><murine model><muscular><mutant><myoneural disorder><neuromuscular><neuromuscular degenerative disorder><neuromuscular disorder><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><optical><paralysis><paralytic><pathophysiology><pathway><pediatric><pharmacologic><pilot study><premature><prematurity><protein degradation><protein function><response><small molecule><small molecule libraries><structure function relationship><transmission process><validate efficacy><validations>