ABSTRACT
The promise of drug repurposing is to accelerate the translation of knowledge to treatment of human disease, bypassing common challenges associated with drug development to be more time- and cost-efficient. Repurposing has an increased chance of success due to the previous validation of drug safety and allows for the incorporation of omics. Hypothesis-generating omics processes inform drug repurposing decision-making methods on drug efficacy and toxicity. This review summarizes drug repurposing strategies and methodologies in the context of the following omics fields: genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiomics, phenomics, pregomics, and personomics. While each omics field has specific strengths and limitations, incorporating omics into the drug repurposing landscape is integral to its success.
Subject(s)
Drug Repositioning/methods , Pharmaceutical Preparations/administration & dosage , Animals , Decision Making , Drug Development/economics , Drug Development/methods , Drug-Related Side Effects and Adverse Reactions/prevention & control , HumansABSTRACT
Despite the potency of most first-line anti-cancer drugs, nonadherence to these drug regimens remains high and is attributable to the prevalence of "off-target" drug effects that result in serious adverse events (SAEs) like hair loss, nausea, vomiting, and diarrhea. Some anti-cancer drugs are converted by liver uridine 5'-diphospho-glucuronosyltransferases through homeostatic host metabolism to form drug-glucuronide conjugates. These sugar-conjugated metabolites are generally inactive and can be safely excreted via the biliary system into the gastrointestinal tract. However, ß-glucuronidase (ßGUS) enzymes expressed by commensal gut bacteria can remove the glucuronic acid moiety, producing the reactivated drug and triggering dose-limiting side effects. Small-molecule ßGUS inhibitors may reduce this drug-induced gut toxicity, allowing patients to complete their full course of treatment. Herein, we report the discovery of novel chemical series of ßGUS inhibitors by structure-based virtual high-throughput screening (vHTS). We developed homology models for ßGUS and applied them to large-scale vHTS against nearly 400,000 compounds within the chemical libraries of the National Center for Advancing Translational Sciences at the National Institutes of Health. From the vHTS results, we cherry-picked 291 compounds via a multifactor prioritization procedure, providing 69 diverse compounds that exhibited positive inhibitory activity in a follow-up ßGUS biochemical assay in vitro. Our findings correspond to a hit rate of 24% and could inform the successful downstream development of a therapeutic adjunct that targets the human microbiome to prevent SAEs associated with first-line, standard-of-care anti-cancer drugs.
Subject(s)
Antineoplastic Agents , Drug-Related Side Effects and Adverse Reactions , Microbiota , Neoplasms , Antineoplastic Agents/adverse effects , Early Detection of Cancer , Enzyme Inhibitors/pharmacology , Glycoproteins , HumansABSTRACT
Long COVID, a spectrum of symptoms and syndromes that can develop after SARS-COV-2 infection, can significantly affect patients' health, quality of life and impact their ability to productively function in society. There is currently no approved therapy for Long COVID and there is an urgent need for rigorous clinical trials to find such treatments. Although research into the pathophysiology of Long COVID is advancing, investigations into treatment for patients remain underfunded and, as a result, understudied. Owing to the urgency of the Long COVID pandemic and as a research collaborative across a diversity of biomedical innovation value propositions, we are calling for a new approach that parallelizes pathophysiologic and therapeutic research into this condition, leveraging patient-centered research and real-world data to generate hypotheses to assess the effectiveness of existing FDA approved drugs. Accelerated discovery of therapeutics for Long COVID can then be confirmed through efficient and cost-effective adaptive platform clinical trials.
Subject(s)
COVID-19 , Post-Acute COVID-19 Syndrome , SARS-CoV-2 , Humans , COVID-19/therapy , COVID-19 Drug Treatment , Antiviral Agents/therapeutic use , Clinical Trials as Topic , Quality of LifeABSTRACT
Objectives: To define pregnancy episodes and estimate gestational age within electronic health record (EHR) data from the National COVID Cohort Collaborative (N3C). Materials and Methods: We developed a comprehensive approach, named Hierarchy and rule-based pregnancy episode Inference integrated with Pregnancy Progression Signatures (HIPPS), and applied it to EHR data in the N3C (January 1, 2018-April 7, 2022). HIPPS combines: (1) an extension of a previously published pregnancy episode algorithm, (2) a novel algorithm to detect gestational age-specific signatures of a progressing pregnancy for further episode support, and (3) pregnancy start date inference. Clinicians performed validation of HIPPS on a subset of episodes. We then generated pregnancy cohorts based on gestational age precision and pregnancy outcomes for assessment of accuracy and comparison of COVID-19 and other characteristics. Results: We identified 628â165 pregnant persons with 816â471 pregnancy episodes, of which 52.3% were live births, 24.4% were other outcomes (stillbirth, ectopic pregnancy, abortions), and 23.3% had unknown outcomes. Clinician validation agreed 98.8% with HIPPS-identified episodes. We were able to estimate start dates within 1 week of precision for 475â433 (58.2%) episodes. 62â540 (7.7%) episodes had incident COVID-19 during pregnancy. Discussion: HIPPS provides measures of support for pregnancy-related variables such as gestational age and pregnancy outcomes based on N3C data. Gestational age precision allows researchers to find time to events with reasonable confidence. Conclusion: We have developed a novel and robust approach for inferring pregnancy episodes and gestational age that addresses data inconsistency and missingness in EHR data.
ABSTRACT
Background: Systematic exclusion of pregnant people from interventional clinical trials has created a public health emergency for millions of patients through a dearth of robust safety data for common drugs. Methods: We harnessed an enterprise collection of 2.8 M electronic health records (EHRs) from routine care, leveraging data linkages between mothers and their babies to detect drug safety signals in this population at full scale. Our mixed-methods signal detection approach stimulates new hypotheses for post-marketing surveillance agnostically of both drugs and diseases-by identifying 1,054 drugs historically prescribed to pregnant patients; developing a quantitative, medication history-wide association study; and integrating a qualitative evidence synthesis platform using expert clinician review for integration of biomedical specificity-to test the effects of maternal exposure to diverse drugs on the incidence of neurodevelopmental defects in their children. Results: We replicated known teratogenic risks and existing knowledge on drug structure-related teratogenicity; we also highlight 5 common drug classes for which we believe this work warrants updated assessment of their safety. Conclusion: Here, we present roots of an agile framework to guide enhanced medication regulations, as well as the ontological and analytical limitations that currently restrict the integration of real-world data into drug safety management during pregnancy. This research is not a replacement for inclusion of pregnant people in prospective clinical studies, but it presents a tractable team science approach to evaluating the utility of EHRs for new regulatory review programs-towards improving the delicate equipoise of accuracy and ethics in assessing drug safety in pregnancy.
ABSTRACT
Repurposing is an increasingly attractive method within the field of drug development for its efficiency at identifying new therapeutic opportunities among approved drugs at greatly reduced cost and time of more traditional methods. Repurposing has generated significant interest in the realm of rare disease treatment as an innovative strategy for finding ways to manage these complex conditions. The selection of which agents should be tested in which conditions is currently informed by both human and machine discovery, yet the appropriate balance between these approaches, including the role of artificial intelligence (AI), remains a significant topic of discussion in drug discovery for rare diseases and other conditions. Our drug repurposing team at Vanderbilt University Medical Center synergizes machine learning techniques like phenome-wide association study-a powerful regression method for generating hypotheses about new indications for an approved drug-with the knowledge and creativity of scientific, legal, and clinical domain experts. While our computational approaches generate drug repurposing hits with a high probability of success in a clinical trial, human knowledge remains essential for the hypothesis creation, interpretation, "go-no go" decisions with which machines continue to struggle. Here, we reflect on our experience synergizing AI and human knowledge toward realizable patient outcomes, providing case studies from our portfolio that inform how we balance human knowledge and machine intelligence for drug repurposing in rare disease.
ABSTRACT
Pregnant women are an especially vulnerable population, given the sensitivity of a developing fetus to chemical exposures. However, prescribing behavior for the gravid patient is guided on limited human data and conflicting cases of adverse outcomes due to the exclusion of pregnant populations from randomized, controlled trials. These factors increase risk for adverse drug outcomes and reduce quality of care for pregnant populations. Herein, we propose the application of artificial intelligence to systematically predict the teratogenicity of a prescriptible small molecule from information inherent to the drug. Using unsupervised and supervised machine learning, our model probes all small molecules with known structure and teratogenicity data published in research-amenable formats to identify patterns among structural, meta-structural, and in vitro bioactivity data for each drug and its teratogenicity score. With this workflow, we discovered three chemical functionalities that predispose a drug towards increased teratogenicity and two moieties with potentially protective effects. Our models predict three clinically-relevant classes of teratogenicity with AUCâ¯=â¯0.8 and nearly double the predictive accuracy of a blind control for the same task, suggesting successful modeling. We also present extensive barriers to translational research that restrict data-driven studies in pregnancy and therapeutically "orphan" pregnant populations. Collectively, this work represents a first-in-kind platform for the application of computing to study and predict teratogenicity.
Subject(s)
Abnormalities, Drug-Induced , Machine Learning , Teratogenesis , Teratogens/toxicity , Female , Humans , Pregnancy , Quantitative Structure-Activity RelationshipABSTRACT
Drug repurposing is the application of approved drugs to treat diseases separate and distinct from their original indications. Herein, we define the scope of all practical precision drug repurposing using DrugBank, a publicly available database of pharmacological agents, and BioVU, a large, de-identified DNA repository linked to longitudinal electronic health records at Vanderbilt University Medical Center. We present a method of repurposing candidate prioritization through integration of pharmacodynamic and marketing variables from DrugBank with quality control thresholds for genomic data derived from the DNA samples within BioVU. Through the synergy of delineated "target-action pairs," along with target genomics, we identify â¼230 "pairs" that represent all practical opportunities for genomic drug repurposing. From this analysis, we present a pipeline of 14 repurposing candidates across 7 disease areas that link to our repurposability platform and present high potential for randomized controlled trial startup in upcoming months.