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Principal Investigator: Wei Zheng
Organization: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
Fiscal Year: 2023
Award: $2,859,284
Funding agency: National Center for Advancing Translational Sciences
In collaboration with NIH and external academic and industry researchers, we have carried out assay development and performed drug repurposing screens for multiple projects across a range of therapeutic areas, including COVID-19, rare genetic disorders and rare drug resistant cancers.
DISEASE MODELING USING PATIENT IPSC-DERIVED CELLS: Disease modeling using patient cells is an effective approach to enable establishment of new alternative / non-animal disease models. Human induced pluripotent stem cells (iPSCs) are generated from patient samples that can be further differentiated to various cell types such as neuronal cells, cardiomyocytes, and hepatocytes for disease modeling. These cell-based models are particularly useful for drug discovery and development for rare genetic diseases, as animal models are not always available. The patient derived iPSCs share the same genetic background with patients and have the same cellular disease phenotypes that are suitable for assay development to screen compounds. We have generated over 100 patient-derived iPSC lines for rare genetic diseases. In this period, we generated several iPSC lines from samples of Alagille Syndrome and healthy donors (Owusu-Ansah K et al., 2023. Stem Cell Res 71, 103135. PMID: 37393720). The iPSCs have been characterized and stably passaged over 10 passages. These iPSCs were differentiated to support generation of hepatocytes and liver organoids for ALGS disease modeling and assay development for repurposing screens. We have also deposited 6 patient iPSC lines previously generated, including for Mucopolysarcharidosis type I (MPS I) and Hunters syndrome (MPS II), to the Coriell Cell Repository as public resources to other researchers.
DRUG-RESISTANT CANCER: Cancer drug resistance is a severe clinical problem that often results in patient death. We performed drug repurposing screens for drug-resistant cell lines of liver cancer, and ovarian cancer refractory to multiple standard care chemotherapies. Several approved drugs have been identified that either suppress the drug-resistant cancer cells directly or re-sensitize the cells to the anticancer activities of the standard drugs. We found that terfenadine re-sensitized doxorubicin activity in drug-resistant ovarian cancer cells via inhibition of CaMKII/CREB1-mediated ABCB1 expression (Huang W et al., 2022. Front Oncology 12, 1068443. PMID: 36439493). We also found that PD1938306, a MEK inhibitor, enhances the efficacy of sorafenib (a standard therapeutic for liver cancer) in hepatocellular carcinoma cells through a repurposing screen (Hong J eta al. 2023. Comb Chem High Throughput Screen. 26: 1364-74. PMID: 36043792). These results are useful for further studies of the mechanisms of drug resistance and cancer target identification for new drug development.
SARS-CoV-2 and COVID-19: We have developed a SARS-CoV-2 pseudotyped particle entry assay for use in BSL-2 laboratories to screen compound libraries and evaluate compound efficacy as SARS-CoV-2 entry inhibitors (Xu M et al. 2022. SLAS Discovery. 27:86-94. PMID: 35086793). We have also developed a homogenous compound screening assay that detects the nucleocapsid protein of SARS-CoV-2 in the viral replication process for high throughput screening in our collaborators BSL-3 lab (Gorshkov K et al. 2022. ACS Pharmacol Transl Sci 5, 8-19. PMID: 35036857). We performed repurposing screens using the pseudotyped particle assay and another assay to target the fusion process of SARS-CoV-2 infection (Park SB et al. 2022. mBio. e0323821. PMID: 35012356). Additionally, we collaborated with other NIH researchers on COVID-19 screens related to a nanobody against the SARS-CoV-2 spike protein, TMPRSS2 inhibitors, heparan-spike interaction, and estrogen receptor-spike interaction (Fu Y et al. 2022. PLoS One. 17: e0272364. PMID: 35947606; Shrimp JH. Et al. 2022. ACS Infect Dis. 8:1191-03. PMID: 35648838; Zhang Q. et al. 2022. Sci Rep. 12:6294. PMID: 35440680; Solis O et al. 2022. Sci Adv 8, eadd4150. PMID: 36449624).
FOXG1 SYNDROME: FOXG1 Syndrome is a rare and debilitating neurodevelopmental disorder causing severe cognitive impairment. The disease is caused by heterozygous mutations in the transcription factor Forkhead Box G1 (FOXG1). Currently, there is no approved therapy for FOXG1 Syndrome. BELIEVE IN A CURE is a non-profit organization focused on developing treatments for FOXG1 syndrome. NCATS collaborated with the foundation to perform a drug repurposing screen in a FOXG1 reporter assay to identify up-regulators of the FOXG1 gene. Hits from the primary screen were further tested in a Western blot assay in patient iPSC-derived neural stem cells.
NGLY1 DEFICIENCY: This is a low incidence genetic disease that primarily affects the neuronal system, resulting in neuromotor impairment, intellectual disability, and neuropathy. We have generated brain organoids using the NGLY1 patient iPSCs for disease modeling. We found that the patient midbrain organoids show altered neuronal development and reduced dopaminergic neurons compared to wild type organoids (Abbott J. et al. 2023. Front Cell Dev Biol. 11: 1039182. PMID: 36875753). We also worked on a neuromuscular junction platform using the patient iPSC-derived motor neurons to study the pathogenesis of disease. We observed reduced axon length, increased and shortened axon branches, motor neuron action potential bursting, and decreased action potential firing rate and amplitude in this system (Sasserath T. et al. 2022. Adv Ther 5:2200009, PMID: 36589922). The NGLY1 brain organoids and motor neurons are useful models for the study of disease mechanisms and evaluation of therapeutic candidates.
LEBER CONGENITAL AMAUROSIS (LCA): LCA is an inherited disease of the eye that causes loss of sight in early childhood and lacks effective treatment. We performed a drug repurposing screen using retinal organoids differentiated from the iPSCs from a model of Leber congenital amaurosis. Reserpine, a drug used for the treatment of hypertension, was identified among a few other compounds that maintains photoreceptor survival in retinal ciliopathy (Chen HY. Et al. 2023. Elife, 12:e83205. PMID: 36975211). Currently, further study of the mechanism of action and potential preclinical development are in process.
AI-BASED MODELING AND VIRTUAL SCREENING: Recent advancements in artificial intelligence (AI)- based modeling have enabled virtual compound screening for lead compound identification. The advantages of this approach for drug discovery are (1) a reduction in physical compound screening experiments that significantly decreases project costs; and (2) a significantly increased screening capacity, as virtual screens can cover in-house compound collections as well as large commercial collections (i.e., millions of compounds), both of which save time during the lead identification process. We have developed and optimized several AI-based compound screening tools that have been applied to several projects. The experimental screening data from a small compound collection (such as the collection of 2800 approved drugs available at NCATS) is typically used to establish, train, and optimize a computer model for a given project that is then employed in a virtual compound screen of larger compound collections (up to millions of compounds) to identify hits. After computerized hit selection and confirmation, the top list compounds (typically 50 to 200) are selected and ordered for a laboratory experiment to evaluate their activities. We have published the method of AI-based modeling and virtual screening using the SARS-CoV-2 entry inhibitor project as an example (Gao P et al., 2023. J Chem Inf Model. 62: 1988-97. PMID: 35404596) with several other manuscripts under preparation.
Terms: <14-Hydroxydaunomycin><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ABC20><ABCB1><ABCB1 gene><AI based method><AI system><Acceleration><Action Potentials><Adriamycine><Affect><Alagille Syndrome><Alagille-Watson Syndrome><Animal Model><Animal Models and Related Studies><Area><Artificial Intelligence><Assay><Axon><BAY 54-9085><BF1><Bioassay><Biologic Assays><Biological Assay><Biotech><Biotechnology><Brain><Brain Factor 1><Brain Nervous System><COVID-19><COVID-19 S protein><COVID-19 infection><COVID-19 screening><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID-19 virus infection><COVID19><COVID19 S protein><COVID19 infection><COVID19 screening><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><CREB><CREB1><CREB1 gene><CV-19><CV19><CaM KII><CaM PK II><CaM kinase II><CaMKII><Cancers><Carcinoma Cell><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cell Body><Cell Differentiation><Cell Differentiation process><Cell Line><CellLine><Cells><Cessation of life><Cholestasis with Peripheral Pulmonary Stenosis><Clinical><Clinical Data><Clinical Treatment><Clinical Trials><CoV-2><CoV2><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Collaborations><Collection><Computer Models><Computer Reasoning><Computerized Models><DA Neuron><Data><Death><Deposit><Deposition><Development><Disease><Disease model><Disorder><Disturbance in cognition><Dopamine neuron><Doxorubicin><Doxorubicina><Drug Costs><Drug Industry><Drug Screening><Drug Targeting><Drug resistance><Drug usage><Drugs><Encephalon><Epitheliasin Gene><Estrogen Receptors><Eye diseases><FKHL1><FOXG1><FOXG1B gene><Forkhead Box G1><Forkhead Box G1B><Forkhead Protein G1B><Forkhead-Like 1><Foundations><GP170><Generations><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic defect><Goals><Heart Muscle Cells><Heart myocyte><Hepatic Cancer><Hepatic Cells><Hepatic Parenchymal Cell><Hepatic ductular hypoplasia><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatocyte><Hepatoma><Hereditary Disease><Heterozygote><High Throughput Assay><Human><Hunter Syndrome Gargoylism><Hunter syndrome><Hunter-Fraser syndrome><Hydroxyl Daunorubicin><Hydroxyldaunorubicin><Immunoblotting><Impaired cognition><Impairment><In Vitro><Inborn Genetic Diseases><Incidence><Industry><Inherited disorder><Intellectual disability><Intellectual functioning disability><Intellectual limitation><Investigators><Laboratories><Lead><Leber congenital amaurosis><Leber's amaurosis><Leber's congenital amaurosis><Length><Libraries><Liver><Liver Cells><Liver Cells Carcinoma><MDR-1><MDR1><MDR1 Protein><MEKs><MPS II><Machine Intelligence><Malignant Cell><Malignant Epithelial Cell><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Ovary><Malignant neoplasm of liver><Malignant neoplasm of ovary><Manuscripts><Mediating><Medication><Mesencephalon><Mid-brain><Midbrain><Midbrain structure><Modeling><Modern Man><Motor Cell><Motor Neurons><Mucopolysaccharidosis 2><Mucopolysaccharidosis II><Multidrug Resistance 1><Multidrug Resistance Gene-1><Multidrug Resistance Gene-1s><Multidrug Resistance Proteins><Multidrug Resistant Proteins><Mutation><Myoneural Junction><NCATS><NIH><National Center for Advancing Translational Sciences><National Institutes of Health><Nerve Cells><Nerve Unit><Neural Cell><Neural Stem Cell><Neurocyte><Neurodevelopmental Disorder><Neurological Development Disorder><Neuromuscular Junction><Neurons><Neuropathy><Non-Profit Organizations><Nonprofit Organizations><Nucleocapsid Proteins><Oncogene QIN><Oncology><Oncology Cancer><Organoids><Ovary Cancer><P-GP><P-Glycoprotein><P-Glycoprotein 1 Gene><PGY-1 Protein><PGY1><PRSS10><Pathogenesis><Patients><Pb element><Pharmaceutic Industry><Pharmaceutic Preparations><Pharmaceutical Industry><Pharmaceutical Preparations><Phenotype><Photoreceptor Cell><Photoreceptors><Photosensitive Cell><Position><Positioning Attribute><Preparation><Primary carcinoma of the liver cells><Process><Progenitor Cells><Publishing><Replication Process><Replication-Associated Process><Reporter><Research Personnel><Research Resources><Researchers><Reserpine><Resources><Retina><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 entry inhibitor><SARS-CoV-2 infection><SARS-CoV-2 screening><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Screening procedure><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 entry inhibitor><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Shrimp><Sight><Sorafenib><Strains Cell Lines><Study models><Syndromatic Hepatic Ductular Hypoplasia><Syndrome><System><TMPRSS2><TMPRSS2 gene><TRND><Terfenadine><Terfenidine><Testing><Therapeutic><Therapeutics for Rare and Neglected Diseases><Time><Training><United States National Institutes of Health><Universities><Virus Replication><Vision><Visual Receptor><Watson-Miller syndrome><Western Blotting><Western Immunoblotting><Work><Wuhan coronavirus><X-linked Hurler syndrome><amaurosis congenita of Leber><anti-cancer activity><anticancer activity><arteriohepatic dysplasia><artificial intelligence method><assay development><block SARS-CoV-2 entry><block severe acute respiratory syndrome coronavirus 2 entry><cAMP Response Element-Binding Protein 1><calcium-dependent CaM kinase II><calmodulin-dependent protein kinase II><cancer cell><cancer drug resistance><cardiomyocyte><cardiovertebral syndrome><cell repository><cell type><cellular repository><chemotherapy><cholestasis-peripheral pulmonary stenosis><ciliopathy><cognitive dysfunction><cognitive loss><computational modeling><computational models><computer based models><computerized><computerized modeling><congenital amaurosis of retinal origin><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 infection><coronavirus disease 2019 screening><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><cost><cultured cell line><detection assay><developmental><disease mechanisms study><disease phenotype><disorder model><dopaminergic neuron><drug development><drug discovery><drug repurposing><drug resistant><drug standard><drug use><drug/agent><early childhood><effective therapy><effective treatment><experiment><experimental research><experimental study><experiments><eye disorder><fork head protein><forkhead protein><forkhead transcription factors><genetic condition><genetic disorder><genome mutation><hCoV19><heavy metal Pb><heavy metal lead><hepatic body system><hepatic ductular hypoplasia-multiple malformations syndrome><hepatic organ system><hepatofacioneurocardiovertebral syndrome><hereditary disorder><heritable disorder><heterozygosity><high throughput screening><hypertension treatment><iPS><iPSC><iPSC technology><iPSCs><iduronate sulfatase deficiency><iduronate-2-sulfatase deficiency><in vitro Assay><inborn error><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cell technology><inducible pluripotent stem cell><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inherited diseases><inherited genetic disease><inherited genetic disorder><inhibit SARS-CoV-2 entry><inhibit severe acute respiratory syndrome coronavirus 2 entry><inhibitor><intellectual and developmental disability><lab assignment><lab experiment><laboratory activity><laboratory assignment><laboratory exercise><laboratory experiment><limited intellectual functioning><liver cancer><liver carcinoma><liver malignancy><malignancy><malignant liver tumor><model of animal><motoneuron><mucopolysaccharide storage disease II><mucopolysaccharidosis type II><nCoV2><nanobodies><nanobody><neglect><neoplasm/cancer><nerve stem cell><neural precursor><neural precursor cell><neural progenitor><neural progenitor cells><neurodevelopmental disease><neuron development><neuron progenitors><neuronal><neuronal development><neuronal progenitor><neuronal progenitor cells><neuronal stem cells><neuropathic><neuroprogenitor><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new technology><new therapeutics><new therapy><next generation therapeutics><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel technologies><novel therapeutics><novel therapy><ocular disease><ocular disorder><ophthalmopathy><ovarian cancer><particle><paucity of interlobular bile ducts><pre-clinical><pre-clinical development><preclinical><preclinical development><preparations><protein blotting><rare genetic disease><rare genetic disorder><refractory cancer><repurposing agent><repurposing medication><resistance to Drug><resistance to cancer drugs><resistant cancer><resistant to Drug><resistant to cancer drugs><screening><screening tools><screenings><sdAb><severe acute respiratory syndrome coronavirus 2 screening><single domain antibodies><standard care><standard treatment><stem cells><sulfo-iduronate sulfatase deficiency><therapeutic candidate><therapeutic evaluation><therapeutic testing><trial regimen><trial treatment><viral multiplication><viral replication><virtual><virtual screening><virtual screenings><virus multiplication><visual function>