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EP-4735885-A1 - METHODS FOR IDENTIFYING COMPOUNDS AFFECTING HUMAN HEALTH

EP4735885A1EP 4735885 A1EP4735885 A1EP 4735885A1EP-4735885-A1

Abstract

This disclosure relates to the use of multi-omic data (transcriptomics, proteomics, metabolomics) in the preclinical setting of model organisms and/or cells treated with test sample exposure to identify which human health concerns are most impacted.

Inventors

  • HOPKINS, CHRIS
  • MCCORMICK, Kathryn
  • BROCK, Trisha

Assignees

  • Nemametrix Inc.

Dates

Publication Date
20260506
Application Date
20240701

Claims (20)

  1. CLAIMS What is claimed is: 1. A method for identifying a test composition that affects a human health concern using a non- human model organism, comprising: a. providing one or more look up tables comprising a list of genes associated with the human health concern; b. contacting the non-human model organism with one or more test compositions during an incubation period; c. generating one or more profiles of gene expression from the model organism after the incubation period; d. recording a change in the one or more profiles as compared to a control set of gene expression profiles generated from an untreated cohort of the non-human model organisms providing a subset of differentially expressed genes; and, e. mapping the subset to the look up table and identifying one or more differentially expressed genes in the subset that are common to those in the look up table, thereby identifying a test compound that affects the human health concern.
  2. 2. A method for identifying a test composition that affects a human health concern using variant non-human model organism, comprising: a. providing the variant non-human model organism comprising a knock-out (KO) or knock- in (KI) of a gene associated with the human health concern; b. providing one or more look up tables comprising a list of genes associated with the human health concern, wherein the list of genes comprises a profile of genes differentially expressed in the knock-out (KO) or knock-in (KI) non-human model organism compared to a corresponding model organism without the variant; c. contacting the variant non-human model organism with one or more test compositions during an incubation period; d. generating one or more profiles of differentially expressed genes from the variant model organism after the incubation period compared to a control variant model organism; and, e. mapping the profile of expressed genes to the look up table and identifying one or more expressed genes in the profile that are common to those in the look up table, thereby identifying a test compound that affects the human health concern.
  3. 3. A method for identifying a test composition that affects a human health concern using a non- human model organism, comprising: a. providing one or more look up tables comprising a list of genes associated with the human health concern, wherein the list of genes comprises a profile of genes differentially expressed in a knock-out (KO) or knock-in (KI) non-human model organism compared to a corresponding model organism without the variant; b. contacting the corresponding model organism without the variant or a cell line with one or more test compositions during an incubation period; c. generating one or more profiles of differentially expressed genes from the model organism or cell line of step b. after the incubation period compared to a control model organism that was not treated with the test composition; and, d. mapping the profile of expressed genes to the look up table and identifying one or more expressed genes in the profile that are common to those in the look up table, thereby identifying a test compound that affects the human health concern.
  4. 4. A method for identifying a test composition that affects a human health concern using an induced non-human model organism, comprising: a. providing the induced non-human model organism, wherein the non-human model organism is contacted with a health concern compound to induce a condition associated with the human health concern; b. providing one or more look up tables comprising a list of genes associated with the human health concern, wherein the list of genes comprises a profile of genes differentially expressed in the induced non-human model organism compared to a corresponding model organism without the induced condition; c. contacting the induced non-human model organism with one or more test compositions during an incubation period; d. generating one or more profiles of differentially expressed genes from the induced model organism after the incubation period compared to a control model organism not treated with the test compositions; and, e. mapping the profile of expressed genes to the look up table and identifying one or more expressed genes in the profile that are common to those in the look up table, thereby identifying a test compound that affects the human health concern.
  5. 5. A method for identifying a test composition that affects a human health concern using an induced non-human model organism, comprising: a. providing the induced non-human model organism, wherein the non-human model organism is contacted with a health concern compound to induce a condition associated with the human health concern; b. providing one or more look up tables comprising a list of genes associated with the human health concern, wherein the list of genes comprises a profile of genes differentially expressed in the induced non-human model organism compared to a corresponding model organism without the induced condition; c. contacting a non-human model organism or a cell line with one or more test compositions during an incubation period; d. generating one or more profiles of differentially expressed genes from the model organism or cell line after the incubation period compared to a control model organism or cell line not treated with the test compositions; and, e. mapping the profile of expressed genes to the look up table and identifying one or more expressed genes in the profile that are common to those in the look up table, thereby identifying a test compound that affects the human health concern.
  6. 6. A method for identifying a human health concern to be treated with a test composition, comprising: a. contacting a non-human model organism with one or more test compositions during an incubation period; b. generating one or more profiles of gene expression, protein and/or metabolite from the model organism after the incubation period; c. recording a change in the one or more profiles as compared to a control set of gene expression, protein and/or metabolite profiles generated from an untreated cohort of the non-human model organisms; and, d. mapping the change in one or more profiles, or a subset thereof, to a lookup table comprising one or more non-human model organism genotypic expression profiles correlated to the human health concern with a known genotypic expression profile; thereby identifying the human health concern to be treated with the test composition.
  7. 7. A method for identifying a test composition that affects a human health concern using variant non-human model organism, comprising: a. providing one or more look up tables comprising a list of genes associated with the human health concern b. mapping the profile of expressed genes after test compound treatment to the look up table and identifying the compound treatments with one or more expressed genes in the profile that are common to those in the look up table, thereby identifying a test compound that affects the human health concern; and, c. contacting the variant non-human model organism with one or more test compositions during an incubation period and measuring a phenotypic rescue effect - where the phenotype can be behavioral, physiological, or molecular.
  8. 8. The method of any preceding claim, wherein the human health concern is selected from longevity, energy metabolism, cardiovascular health, metabolic syndrome, neurodegenerative disorders, muscle function.
  9. 9. The method of any preceding claim, wherein the human health concern is longevity and the look up tables are selected from the group consisting of insulin signaling, autophagy, mTor signaling and energy metabolism, mitochondrial health and oxidative stress, stress response, and growth and development.
  10. 10. The method of any preceding claim, wherein the look up table is generated based on gene expression pathway analysis and expression profiles from the literature.
  11. 11. The method of any preceding claim, wherein the mapping comprises identifying one or more expressed genes in common between the profile and look up table.
  12. 12. The method of any preceding claim, wherein the differentially expressed gene is upregulated compared to a corresponding gene on the look up table.
  13. 13. The method of any one of claims 1-11, wherein the differentially expressed gene is downregulated compared to a corresponding gene on the look up table.
  14. 14. The method of any preceding claim, wherein the differentially expressed gene is identified based on a predetermined threshold value.
  15. 15. The method of any preceding claim, wherein the human health concern is a rare genetic disease.
  16. 16. The method of any preceding claim, wherein the differentially expressed gene is a gene having an expression level of equal to or greater than 1.5-fold with a false discovery rate (FDR)-adjusted P-value of < 0.05.
  17. 17. The method of any preceding claim, wherein the non-human model organism is selected from a nematode or zebrafish.
  18. 18. The method of any preceding claim, wherein the generating one or more profiles of differentially expressed genes comprises performing a transcriptional analysis, wherein the gene expression activity is characterized using at least one assay selected from the group consisting of RNA seq, microarray, quantitative polymerase chain reaction (QPCR), or transcriptional reporter construct.
  19. 19. The method of any preceding claim, wherein the test composition is selected from pre-clinical therapeutic agents, clinical development therapeutic agents, FDA approved therapeutic agents, dietary supplements, nutraceuticals or vitamins.
  20. 20. The method of any preceding claim, wherein the test composition comprises a mixture of active ingredients.

Description

METHODS FOR IDENTIFYING COMPOUNDS AFFECTING HUMAN HEALTH Related Applications [001] This application claims priority to U.S. Ser. No. 63/524,569 filed on June 30, 2023, which is hereby incorporated into this application in its entirety. Field of the Disclosure [002] This disclosure relates to the use of multi-omic data (transcriptomics, proteomics, metabolomics) in the preclinical setting of model organisms and/or cells treated with test sample exposure to identify which human health concerns are most impacted and to identify compounds with therapeutic potential. Background of the Disclosure [003] Recognition of the role that aging plays in disease has shifted some of the focus from treating individual age-related diseases to developing therapeutics that target the aging process itself. With that has come a demand for expanded testing of anti-aging therapeutics and nutraceuticals in a variety of model systems. The nematode worm C. elegans as one type of model system is an efficient and proven model for studying aging mechanisms and testing aging interventions. C. elegans are easily grown in a controlled environment using in vitro culture techniques and have a short, three-week lifespan that enables high throughput and multigenerational longevity studies. C. elegans is the most common model for testing age-related drugs owing to its relatively strong predictivity of the likelihood a drug might increase the lifespan in higher organisms. C. elegans lifespan assays can be used to meet growing demand for early qualification and safety testing of potential longevity drugs. As with other fields of drug discovery and development, those of skill in the art working on longevity drug development are increasingly emphasizing understanding the mode of action of such drugs. Understanding the mode of action of drugs enables the rational design of improved derivatives or combination therapies as well as identifying potential side effects early. Cross-species analysis of aging transcriptomes has revealed that there are evolutionarily conserved pathways influencing aging [Komljenovic A, Li H, Sorrentino V, Kutalik Z, Auwerx J, Robinson-Rechavi M. Cross-species functional modules link proteostasis to human normal aging. PLoS Comput Biol.2019;15: e1007162.; Möller S, Saul N, Cohen AA, Köhling R, Sender S, Murua Escobar H, et al. Healthspan pathway maps in and humans highlight transcription, proliferation/biosynthesis and lipids. Aging .2020;12: 12534–12581.; Fang EF, Waltz TB, Kassahun H, Lu Q, Kerr JS, Morevati M, et al. Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway. Sci Rep. 2017;7: 46208.; Chen J, Ou Y, Li Y, Hu S, Shao L-W, Liu Y. Metformin extends lifespan through lysosomal pathway. Elife. 2017;6. doi:10.7554/eLife.31268; Ewald CY, Castillo-Quan JI, Blackwell TK. Untangling Longevity, Dauer, and Healthspan in Caenorhabditis elegans Insulin/IGF-1-Signalling. Gerontology. 2018;64: 96–104.; Iwasa H, Yu S, Xue J, Driscoll M. Novel EGF pathway regulators modulate C. elegans healthspan and lifespan via EGF receptor, PLC-gamma, and IP3R activation. Aging Cell. 2010;9: 490–505.; Bansal A, Zhu LJ, Yen K, Tissenbaum HA. Uncoupling lifespan and healthspan in Caenorhabditis elegans longevity mutants. Proc Natl Acad Sci U S A. 2015;112: E277–86.; Newell Stamper BL, Cypser JR, Kechris K, Kitzenberg DA, Tedesco PM, Johnson TE. Movement decline across lifespan of Caenorhabditis elegans mutants in the insulin/insulin-like signaling pathway. Aging Cell. 2018;17. doi:10.1111/acel.12704 and a set of conserved signaling pathways can be derived. As a result, various model systems (e.g., mouse, rat, fly, worm, fish, and human, as well as cells derived from the same) can be used to find molecular mechanisms of action via transcriptomics mapped to pathways and cross correlated to health concerns. [004] This disclosure provides solutions to these problems. For instance, in some embodiments, this disclosure provides methods for identifying: 1) optimal structure-function claims for a test sample at molecular mechanism of action detail; 2) the molecular biomarkers for use in clinical trials; and, 3) the optimal sets of phenotyping assays for behavioral and morphological validation of the molecular health concern findings. This disclosure thereby provides solutions to these and other art-recognized, and unrecognized, problems. Summary of the Disclosure [005] This disclosure, in some embodiments, provides methods for identifying: 1) optimal structure-function claims for a test sample at molecular mechanism of action detail; 2) the molecular biomarkers for use in clinical trials; and, 3) the optimal sets of phenotyping assays for behavioral and morphological validation of the molecular health concern findings. [006] In embodiments provided herein are methods for identifying a test composition that affects a human health concern using a non-human model organism, comprising: providing