Michael Gantier

Areas of interest

COVID-19 Inflammation and cancer Influenza Lupus

Research group

Biography

A/Prof Michael Gantier is a molecular and cell biologist with expertise in the field of innate immunity – the system our bodies use to detect and fight infections.

An expert in nucleic acids biology, with a strong focus on their therapeutic implications in the modulation of immunity, A/Prof Gantier’s research focus is on the definition of how pathogenic nucleic acids (such as DNA or RNA) are recognised by a series of selective sensors of the immune system.

While these sensors are normally protective, they can also misfire and initiate a vicious circle of inflammation leading to autoimmunity.

By characterising how these sensors are kept in check at the molecular level, A/Prof Gantier’s research opens novel therapeutic avenues to dampen the inflammation causing autoimmunity.

A/Prof Gantier has published and patented works (see Publications below) that represent the largest characterisation of how synthetic nucleic acids can be used to modulate the activity of immune nucleic acids sensors.

His studies of how nucleic sensing operates at a cellular level has also led his team to discover the first clinic-ready TBK1 inhibitor, idronoxil (Nature Communications 2023).

A/Prof Gantier’s focus is twofold

Understanding how innate immune sensors misfire, with the goal of preventing autoimmunity.
Developing a new class of anti-inflammatory molecules, known as RNA therapeutics, to blunt aberrant inflammation at its source in a wide range of diseases.

A/Prof Michael Gantier’s research has led to the discovery of a new therapeutic approach to target skin lupus and psoriasis, currently clinically developed by ASX-listed Noxopharm Ltd and its subsidiary, Pharmorage Pty Ltd. These findings also have the capacity to improve emerging technologies such as mRNA vaccines.

RNA – changing the face of modern medicine

Student opportunities

Education

Awards and fellowships

Affiliations

Publication highlights

Ullah, T. R., Johansen, M. D., Balka, K. R., Ambrose, R. L., Gearing, L. J., Roest, J., Vivian, J. P., Sapkota, S., Jayasekara, W. S. N., Wenholz, D. S., Aldilla, V. R., Zeng, J., Miemczyk, S., Nguyen, D. H., Hansbro, N. G., Venkatraman, R., Kang, J. H., Pang, E. S., Thomas, B. J., … & Gantier, M. P. (2023). Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection. Nature Communications, 14(1), 5666. https://doi.org/10.1038/s41467-023-41381-9
Ullah, T. R., Balka, K. R., Ambrose, R. L., Pépin, G., Wilce, M. C. J., Wilce, J. A., Thomas, B. J., De Nardo, D., Williams, B. R. G., & Gantier, M. P. (2022). Genistein Targets STING-Driven Antiviral Responses. MBio, 13(4), e0206422. https://doi.org/10.1128/mbio.02064-22
Al-Asmari, S. S., Rajapakse, A., Ullah, T. R., Pépin, G., Croft, L. V., & Gantier, M. P. (2022). Pharmacological Targeting of STING-Dependent IL-6 Production in Cancer Cells. Frontiers in Cell and Developmental Biology, 9(January), 709618. https://doi.org/10.3389/fcell.2021.709618
Prompsy, P. B., Toubia, J., Gearing, L. J., Knight, R. L., Forster, S. C., Bracken, C. P., & Gantier, M. P. (2021). Making use of transcription factor enrichment to identify functional microRNA-regulons. Computational and Structural Biotechnology Journal, 19, 4896–4903. https://doi.org/10.1016/j.csbj.2021.08.032
Brown, G. J., Cañete, P. F., Wang, H., Medhavy, A., Bones, J., Roco, J. A., He, Y., Qin, Y., Cappello, J., Ellyard, J. I., Bassett, K., Shen, Q., Burgio, G., Zhang, Y., Turnbull, C., Meng, X., Wu, P., Cho, E., Miosge, L. A., …Gantier, M.P, Athanasopoulos,V. & Vinuesa, C. G. (2022). TLR7 gain-of-function genetic variation causes human lupus. Nature, 605(7909), 349–356. https://doi.org/10.1038/s41586-022-04642-z
Valentin R, Wong C, Alharbi AS, Pradeloux S, Morros MP, Lennox KA, Ellyard JI, Garcin AJ, Ullah TR, Kusuma GD, Pépin G, Li HM, Pearson JS, Ferrand J, Lim R, Veedu RN, Morand EF, Vinuesa CG, Behlke MA, Gantier MP. Sequence-dependent inhibition of cGAS and TLR9 DNA sensing by 2′-O-methyl gapmer oligonucleotides. Nucleic Acids Res. 2021 Jun 21;49(11):6082-6099. doi: 10.1093/nar/gkab451. PMID: 34057477
Alharbi AS, Garcin AJ, Lennox KA, Pradeloux S, Wong C, Straub S, Valentin R, Pépin G, Li HM, Nold MF, Nold-Petry CA, Behlke MA, Gantier MP. Rational design of antisense oligonucleotides modulating the activity of TLR7/8 agonists. Nucleic Acids Res. 2020 Jul 27;48(13):7052-7065. doi: 10.1093/nar/gkaa523. PMID: 32544249
Pépin G, De Nardo D, Rootes CL, Ullah TR, Al-Asmari SS, Balka KR, Li HM, Quinn KM, Moghaddas F, Chappaz S, Kile BT, Morand EF, Masters SL, Stewart CR, Williams BRG, Gantier MP (2020) Connexin-Dependent Transfer of cGAMP to Phagocytes Modulates Antiviral Responses. mBio. 2020 Jan 28;11(1):e03187-19. doi: 10.1128/mBio.03187-19. PMID: 31992625; PMCID: PMC6989113.
Pillman KA, Goodall GJ, Bracken CP, Gantier MP (2019) miRNA length variation during macrophage stimulation confounds the interpretation of results: implications for miRNA quantification by RT-qPCR. RNA. 2019 Feb;25(2):232-238. doi: 10.1261/rna.069047.118. Epub 2018 Nov 28. PMID: 30487268; PMCID: PMC6348984.
Ferrand J, Croft NP, Pépin G, Diener KR, Wu D, Mangan NE, Pedersen J, Behlke MA, Hayball JD, Purcell AW, Ferrero RL, Gantier MP (2018) The Use of CRISPR/Cas9 Gene Editing to Confirm Congenic Contaminations in Host-Pathogen Interaction Studies. Front Cell Infect Microbiol. 2018 Mar 19;8:87. doi: 10.3389/fcimb.2018.00087. PMID: 29616197; PMCID: PMC5867302.
Pépin G, Nejad C, Thomas BJ, Ferrand J, McArthur K, Bardin PG, Williams BR, Gantier MP (2016) Activation of cGAS-dependent antiviral responses by DNA intercalating agents. Nucleic Acids Res pii: gkw878. [Epub ahead of print] PubMed PMID: 27694309.
Pépin G, Ferrand J, Höning K, Jayasekara WS, Cain JE, Behlke MA, Gough DJ, G Williams BR, Hornung V, Gantier MP (2016) Cre-dependent DNA recombination activates a STING-dependent innate immune response. Nucleic Acids Res 44(11):5356-64. doi: 10.1093/nar/gkw405. PubMed PMID: 27166376; PubMed Central PMCID: PMC4914124.
Sarvestani ST, Stunden HJ, Behlke MA, Forster SC, McCoy CE, Tate MD, Ferrand J, Lennox KA, Latz E, Williams BR, Gantier MP (2015) Sequence-dependent off-target inhibition of TLR7/8 sensing by synthetic microRNA inhibitors. Nucleic Acids Res 43:1177-1188.
This work represents the first demonstration that microRNA inhibitors to be used in the clinic can have detrimental effects on the innate immune system.
Sarvestani ST, Tate MD, Moffat JM, Jacobi AM, Behlke MA, Miller AR, Beckham SA, McCoy CE, Chen W, Mintern JD, O’Keeffe M, John M, Williams BR, Gantier MP (2014) Inosine-mediated modulation of RNA sensing by Toll-like receptor 7 (TLR7) and TLR8. J Virol 88:799-810.
This work represents the first demonstration that inosine incorporation into viral RNA can potentiate the innate immune sensing of infected cells by phagocytes’ TLR7/8.
Wu D, Hu Y, Tong S, Williams BR, Smyth GK, Gantier MP (2013) The use of miRNA microarrays for the analysis of cancer samples with global miRNA decrease. RNA 19:876-888.
This work identified a novel normalization procedure for the use of miRNA microarrays of cancer samples.
Gantier MP, Stunden HJ, McCoy CE, Behlke MA, Wang D, Kaparakis-Liaskos M, Sarvestani ST, Yang YH, Xu D, Corr SC, Morand EF, Williams BR (2012) A miR-19 regulon that controls NF-kappaB signaling. Nucleic Acids Res 40:8048-8058.
This work identified a network of miR-19 targets controlling NF-kappaB-driven inflammation.
Gantier MP, McCoy CE, Rusinova I, Saulep D, Wang D, Xu D, Irving AT, Behlke MA, Hertzog PJ, Mackay F, Williams BR (2011) Analysis of microRNA turnover in mammalian cells following Dicer1 ablation. Nucleic Acids Res 39:5692-5703.
This work represents the first global analysis of miRNA turnover in mammalian cells. It is in the top 1% of its field based on citations and publication year.
Gantier MP, Irving AT, Kaparakis-Liaskos M, Xu D, Evans VA, Cameron PU, Bourne JA, Ferrero RL, John M, Behlke MA, Williams BR (2010) Genetic modulation of TLR8 response following bacterial phagocytosis. Hum Mutat 31:1069-1079.
This is the first demonstration of a direct role for TLR8 in bacterial sensing and establishes an important genetic modulation of TLR8 function.
Gantier MP, Tong S, Behlke MA, Irving AT, Lappas M, Nilsson UW, Latz E, McMillan NA, Williams BR (2010) Rational design of immunostimulatory siRNAs. Mol Ther 18:785-795.
This work characterises a microRNA modification amenable to any siRNA, allowing for increased activation of TLR7/8 and antiviral effects.
Gantier MP, Williams BR (2009) siRNA delivery not Toll-free. Nat Biotechnol 27:911-912.
Scientific commentary on a novel strategy to deliver siRNAs.
Gantier MP, Tong S, Behlke MA, Xu D, Phipps S, Foster PS, Williams BR (2008) TLR7 is involved in sequence-specific sensing of single-stranded RNAs in human macrophages. J Immunol 180:2117-2124.
This work was first to demonstrate that TLR7 and TLR8 sense distinct RNA motifs, and that TLR7 plays a role in RNA recognition in macrophages.
Gantier MP, Williams BR (2007) The response of mammalian cells to double-stranded RNA. Cytokine Growth Factor Rev 18:363-371.
This review links the fields of RNA interference and innate immunity around their common substrate: double-stranded RNA.
Pépin G, Nejad C, Ferrand J, Thomas BJ, Stunden HJ, Sanij E, Foo CH, Stewart CR, Cain JE, Bardin PG, Williams BRG, Gantier MP (2017) Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses. MBio 8(5):e01611-17
Nejad C, Pillman KA, Siddle KJ, Pepin G, Änkö ML, McCoy CE, Beilharz T, Quintana-Murci L, Goodall GJ, Bracken CP, Gantier MP (2017) miR-222 isoforms are differentially regulated by type-I interferon. RNA pii: rna.064550.117. doi: 10.1261/rna.064550.117.
PATENT | Oligonucleotides
MPM Gantier
Patent App. WO/2021/232099PATENT |Methods for the treatment of inflammation associated with infection
G Kelly, O Laczka, M Gantier
Patent WO2021195698PATENT |Oligonucleotides
MPM
Patent App. WO/2022/213153

Associate Professor Michael Gantier