Human Health Therapeutics: development of support technology

Funding period: 2014-2023
Lead: Susan Twine
Total GRDI funding: $6,216,000

The GRDI supports genomics and proteomics research at NRC's Human Health Therapeutic Research Centre. Activities include the development of a CRISPR/Cas whole-genome functional screening target discovery and validation platform to identify genes and biological pathways important for cellular phenotypes relevant to traits or pathologies of interest; the development of Next-generation sequencing and Single-cell analytics platforms; the development and application of bioinformatics algorithms to identify germline genetic biomarkers predictive of cancer relapse; the development of novel therapeutic strategies for neurological diseases using molecular map of genes and proteins expressed in brain cells; and the identification and validation of ferroptosis, a novel controlled cell death pathway, as a potential therapeutic avenue for B-cell acute lymphoblastic leukemia.

Publications
  • Akache B, Renner TM, Stuible M, Deschatelets L, Dudani R, Harrison BA, Gervais C, Hill JJ, Hemraz UD, Lam E, Regnier S, Durocher Y, McCluskie MJ. 2022. Proteomic workflows have been developed and applied to identify new targets for biotherapeutic development for cancer and for blood-brain barrier, and to characterize SARS-CoV-2 spike protein antigens for vaccine development. Immunogenicity of SARS-CoV-2 Spike Antigens Derived from Beta & Delta Variants of Concern. NPJ Vaccines. 2022 Oct 12;7(1):118. https://doi.org/10.1038/s41541-022-00540-7
  • Alata W, Yogi A, Brunette E, Delaney CE, van Faassen H, Hussack G, Iqbal U, Kemmerich K, Haqqani AS, Moreno MJ, Stanimirovic DB. 2022. Targeting insulin-like growth factor-1 receptor (IGF1R) for brain delivery of biologics. FASEB J. 2022 Mar;36(3):e22208. https://doi.org/10.1096/fj.202101644R. PMID: 35192204
  • Alpuche-Lazcano SP, Stuible M, Akache B, Tran A, Kelly J, Hrapovic S, Robotham A, Haqqani A, Star A, Renner TM, Blouin J, Maltais JS, Cass B, Cui K, Cho JY, Wang X, Zoubchenok D, Dudani R, Duque D, McCluskie MJ, Durocher Y. 2023. Preclinical evaluation of manufacturable SARS-CoV-2 spike virus-like particles produced in Chinese Hamster Ovary cells. Commun Med (Lond). Aug23;3(1):116. https://doi.org/10.1038/s43856-023-00340-7
  • Badhwar AP, Haqqani AS. 2020. Biomarker potential of brain-secreted extracellular vesicles in blood in Alzheimer's disease. Alzheimer's Dement Diagnosis, Assess Dis Monit 12:e12001. https://doi.org/10.1002/dad2.12001
  • Caron NS, Haqqani AS, Sandhu A, Aly AE, Findlay Black H, Bone JN, McBride JL, Abulrob A, Stanimirovic D, Leavitt BR, Hayden MR. 2022. Cerebrospinal fluid biomarkers for assessing Huntington disease onset and severity. Brain Commun. Nov25;4(6):fcac309. https://doi.org/10.1093/braincomms/fcac309. PMID: 36523269; PMCID:PMC9746690
  • Chen R et al. 2023. Integrated Immunopeptidomics and Proteomics Study of SARS-CoV-2-Infected Calu-3 Cells Reveals Dynamic Changes in Allele-specific HLA Abundance and Antigen Presentation. Mol Cell Proteomics. 22(10): 100645. https://doi.org/10.1016/j.mcpro.2023.100645
  • Fauteux F, Surendra A, McComb S, Pan Y, Hill JJ. 2021. Identification of transcriptional subtypes in lung adenocarcinoma and squamous cell carcinoma through integrative analysis of microarray and RNA sequencing data. Sci Rep. 2021 Apr 22;11(1):8709. https://doi.org/10.1038/s41598-021-88209-4. PMID: 33888829 Free PMC article.
  • Haqqani AS, Mianoor Z, Star AT, Detcheverry FE, Delaney CE, Stanimirovic DB, Hamel E, Badhwar A. 2023. Proteome Profiling of Brain Vessels in a Mouse Model of Cerebrovascular Pathology. Biology. Dec 7;12(12):1500. https://doi.org/10.3390/biology12121500
  • Haqqani AS, Stanimirovic DB. 2019. Prioritization of Therapeutic Targets of Inflammation Using Proteomics, Bioinformatics, and In Silico Cell-Cell Interactomics. Methods Mol Biol 2024:309–325 . https://doi.org/10.1007/978-1-4939-9597-4_20
  • Jezierski A, Huang J, Haqqani AS, Haukenfrers J, Liu Z, Baumann E, Sodja C, Charlebois C, Delaney CE, Star AT, Liu Q, Stanimirovic DB. 2023. Mouse embryonic stem cell-derived blood-brain barrier model: applicability to studying antibody triggered receptor mediated transcytosis. Fluids and Barriers of the CNS 19:2023. Fluids Barriers CNS 20, 36. https://doi.org/10.1186/s12987-023-00437-0
  • Lalonde M-E, Sasseville M, Gélinas A-M, Milanese J-S, Béland K, Drouin S, Haddad E, Marcotte R. 2022. Genome-wide CRISPR screens identify ferroptosis as a novel therapeutic vulnerability in acute lymphoblastic leukemia. Haematologica 108:382-393. https://doi.org/10.3324/haematol.2022.280786
  • Lei EK et al. 2023. Isolation and characterization of a VHH targeting the Acinetobacter baumannii cell surface protein CsuA/B. Appl Micriobiol Biotechnol. 107(14):4567. https://doi.org/10.1007/s00253-023-12594-1
  • Liu DY et al. 2023. Collateral sensitivity profiling in drug-resistant Escherichia coli identifies natural products suppressing cephalosporin resistance. Nat Commun. 14: 1976. https://doi.org/10.1038/s41467-023-37624-4
  • Milanese JS, Marcotte R, Costain WJ, Kablar B, Drouin S. Roles of Skeletal Muscle in Development: A Bioinformatics and Systems Biology Overview. Adv Anat Embryol Cell Biol. 2023;236:21-55. https://doi.org/10.1007/978-3-031-38215-4_2
  • Milanese JS, Tibiche C, Zou J, Meng Z, Nantel A, Drouin S, Marcotte R, Wang E. 2019. Germline variants associated with leukocyte genes predict tumor recurrence in breast cancer patients. NPJ Precision Oncol. 3:28. https://doi.org/10.1038/s41698-019-0100-7
  • Ouellette J, Toussay X, Comin CH, Costa LdF, Ho M, Lacalle-Aurioles M, Freitas-Andrade M, Liu QY, Leclerc S, Pan Y, Liu Z, Thibodeau JF, Yin M, Carrier M, Morse CJ, Van Dyken P, Bergin CJ, Baillet S, Kennedy CR, Tremblay ME, Benoit YD, Stanford WL, Burger D, Stewart DJ, Lacoste B. 2020. Vascular contributions to 16p11.2 deletion autism syndrome modeled in mice. Nature Neuroscience. 23:1090–1101. https://doi.org/10.1038/s41593-020-0663-1
  • Rossotti MA, van Faassen H, Tran AT, Sheff J, Sandhu JK, Duque D, Hewitt M, Wen X, Bavananthasivam J, Beitari S, Matte K, Laroche G, Giguère PM, Gervais C, Stuible M, Guimond J, Perret S, Hussack G, Langlois MA, Durocher Y, Tanha J. 2022. Arsenal of nanobodies shows broad-spectrum neutralization against SARS-CoV-2 variants of concern in vitro and in vivo in hamster models. Commun Biol. 2022 Sep 9;5(1):933. https://doi.org/10.1038/s42003-022-03866-z. PMID: 36085335 Free PMC article.
  • Sasseville M, Nguyen HDT, Drouin S, Bahadoor A. 2024. Production of Ochratoxin A and Citrinin and the Expression of Their Biosynthetic Genes from Penicillium verrucosum in Liquid Culture. ACS Omega. 2024 Apr 23;9(18):20368-20377. https://doi.org/10.1021/acsomega.4c00874
  • Sauvageau J, Koyuturk I, St Michael F, Brochu D, Goneau MF, Schoenhofen I, Perret S, Star A, Robotham A, Haqqani A, Kelly J, Gilbert M, Durocher Y. 2023. Simplifying glycan monitoring of complex antigens such as the SARS-CoV-2 spike to accelerate vaccine development. Commun Chem. Sep 8;6(1):189. https://doi.org/10.1038/s42004-023-00988-1
  • Semmler S, Gagné M, Garg P, Pickles SR, Baudouin C, Hamon-Keromen E, Destroismaisons L, Khalfallah Y, Chaineau M, Caron E, Bayne AN, Trempe JF, Cashman NR, Star AT, Haqqani AS, Durcan TM, Meiering EM, Robertson J, Grandvaux N, Plotkin SS, McBride HM, Velde C Vande, DeMartino GN. 2020. TNF receptor-associated factor 6 interacts with ALS-linked misfolded superoxide dismutase 1 and promotes aggregation. J Biol Chem 295:3808–3825. https://doi.org/10.1074/jbc.RA119.011215
  • Sheff J, Kelly J, Foss M, Brunette E, Kemmerich K, van Faassen H, Raphael S, Hussack G, Comamala G, Rand K, Stanimirovic DB. 2023. Epitope mapping of a blood-brain barrier crossing antibody targeting the cysteine-rich region of IGF1R using hydrogen-exchange mass spectrometry enabled by electrochemical reduction. J Biochem. 2023 Feb 3;173(2):95-105. https://doi.org/10.1093/jb/mvac088. PMID: 36346120
  • Sheff JG, Kelly JF, Robotham A, Sulea T, Malenfant F, L'Abbé D, Duchesne M, Pelletier A, Lefebvre J, Acel A, Parat M, Gosselin M, Wu C, Fortin Y, Baardsnes J, Van Faassen H, Awrey S, Chafe SC, McDonald PC, Dedhar S, Lenferink AEG. 2021. Hydrogen-deuterium exchange mass spectrometry reveals three unique binding responses of mAbs directed to the catalytic domain of hCAIX. MAbs. 2021 Jan-Dec;13(1):1997072. https://doi.org/10.1080/19420862.2021.1997072
  • Sheff J, Wang P, Xu P, Arbour M, Masson L, van Faassen H, Hussack G, Kemmerich K, Brunette E, Stanimirovic D, Hill JJ, Kelly J, Ni F. 2021. Defining the epitope of a blood-brain barrier crossing single domain antibody specific for the type 1 insulin-like growth factor receptor. Sci Rep. 2021 Feb 19;11(1):4284. https://doi.org/10.1038/s41598-021-83198-w. PMID: 33608571 Free PMC article.
  • Shin JW, An S, Kim D, Kim H, Ahn J, Eom J, You WK, Yun H, Lee B, Sung B, Jung J, Kim S, Son Y, Sung E, Lee H, Lee S, Song D, Pak Y, Sandhu JK, Haqqani AS, Stanimirovic DB, Yoo J, Kim D, Maeng S, Lee J, Lee SH. 2022. Grabody B, an IGF1 receptor-based shuttle, mediates efficient delivery of biologics across the blood-brain barrier. Cell Rep Methods. 2022 Nov 21;2(11):100338. https://doi.org/10.1016/j.crmeth.2022.100338. eCollection 2022 Nov 21. PMID: 36452865 Free PMC article
  • Sodja C, Callaghan D, Haqqani AS, Stanimirovic DB, Costain WJ, Jezierski A. Immunoassay for Quantitative Detection of Antibody Transcytosis Across the Blood-Brain Barrier In Vitro. 2021. Methods Mol Biol. 2022;2549:345-357. https://doi.org/10.1007/7651_2021_456. PMID: 35218529
  • Tremblay TL, Alata W, Slinn J, Baumann E, Delaney CE, Moreno M, Haqqani AS, Stanimirovic DB, Hill JJ. 2024. The proteome of the blood-brain barrier in rat and mouse: highly specific identification of proteins on the luminal surface of brain microvessels by in vivo glycocapture. Fluids Barriers CNS. Mar4;21(1):23. https://doi.org/10.1186/s12987-024-00523-x
  • Tremblay TL, Hill JJ. 2021. Adding polyvinylpyrrolidone to low level protein samples significantly improves peptide recovery in FASP digests: An inexpensive and simple modification to the FASP protocol. Journal of Proteomics. 2021 Jan 6;230:104000. https://doi.org/10.1016/j.jprot.2020.104000
  • Yogi A, Hussack G, van Faassen H, Haqqani AS, Delaney CE, Brunette E, Sandhu JK, Hewitt M, Sulea T, Kemmerich K, Stanimirovic DB. 2022. Brain Delivery of IGF1R5, a Single-Domain Antibody Targeting Insulin-like Growth Factor-1 Receptor. Pharmaceutics. 2022 Jul 12;14(7):1452. https://doi.org/10.3390/pharmaceutics14071452
  • Zhang W, Liu QY, Haqqani AS, Liu Z, Sodja C, Leclerc S, Baumann E, Delaney CE, Brunette E, Stanimirovic DB. 2023. Differential expression of ABC transporter genes in brain vessels vs. peripheral tissues and vessels from human, mouse and rat. Pharmaceutics 15:1563. https://doi.org/10.3390/pharmaceutics15051563
  • Zhang W, Liu QY, Haqqani AS, Leclerc S, Liu Z, Fauteux F, Baumann E, Delaney CE, Ly D, Star AT, Brunette E, Sodja C, Hewitt M, Sandhu JK, Stanimirovic DB. 2020. Differential expression of receptors mediating receptor-mediated transcytosis (RMT) in brain microvessels, brain parenchyma and peripheral tissues of the mouse and the human. Fluids Barriers of the CNS 17:47. https://doi.org/10.1186/s12987-020-00209-0

Contact us

For additional information, please contact:
Genomics R&D Initiative
Email: info@grdi-irdg.collaboration.gc.ca

From: Genomics R&D Initiative

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