个人简介
Dr. Jean-Simon Diallo obtained his bachelor’s degree in biochemistry with honours in bioinformatics from the University of Ottawa in 2000. He went on to Montreal to pursue a masters’ degree in biochemistry at McGill University where he studied the epigenetic regulation of globin genes with the late Dr. Lee Wall. In 2003, he began his Ph.D in molecular biology at the Université de Montréal, in the laboratory of Drs. Anne-Marie Mes-Masson and Fred Saad. There he studied prognostic markers/models for prostate cancer as well as the use of naturally occurring phytochemicals for prostate cancer therapy. Funded by the Fonds de Recherche en Santé du Quebec (FRSQ) fellowship, he joined Dr. John Bell’s lab as a postdoctoral fellow in 2007, applying his broad expertise and collaborative approach to the field of oncolytic viruses. In Dr. Bell’s group, Dr. Diallo pioneered high-throughput methods to identify compounds that enhance viral replication. Now an Associate Scientist at the OHRI working with a multidisciplinary network of collaborators, he and his team are using medicinal chemistry, mass spectrometry and high-throughput molecular biology approaches to study how “viral sensitizer” drugs work. He is also expanding the scope of application of viral sensitizer drugs, which in addition to oncolytic virotherapy, show tremendous promise in virus/vaccine manufacturing and gene therapy applications.
研究领域
1. Understanding how viral sensitizers work
The innate cellular antiviral response is the first line of defense that all normal cells use to protect themselves against viral infections. While this is generally a good thing in the context of a pathogenic infection, for many therapeutics that are made using viruses, antiviral defenses can be a significant hurdle. For example, antiviral defenses in tumors lead to therapeutic failure when using oncolytic viruses. Similarly, antiviral defenses can lead to low productivity in cell-based viral vaccine manufacturing processes and lead to low transduction efficiency and transgene expression in gene therapy applications.
By boldly screening tens of thousands of small molecules using high-throughput robotics, we have uncovered several novel compounds we call “viral sensitizers” or VSes (Diallo et al. Mol Ther, 2010). In some contexts, these molecules can increase the output of virus from cells by over 1000-fold. While the specific targets of many of these VSe drugs are unknown, evidence suggests that they effectively disable cellular antiviral defenses in different and unique ways. An important focus of our laboratory is to elucidate how each VSe drug elicits its effects at the molecular level in order to improve our knowledge of how they work and to better understand how cells defend against viral infections. To this end, we are using a variety of chemical, molecular biology, and high-throughput biology / computational approaches. We ultimately aim to use this knowledge to develop even better VSe compounds and engineer more effective oncolytic viruses.
2. Viral sensitizers for oncolytic virotherapy
Many VSe compounds we have discovered as well as some viral sensitizing drugs that were discovered by other groups have the ability to enhance oncolytic virus activity in tumors but not in normal cells (Nguyen et al, PNAS, 2008; Diallo et al. Mol Ther, 2010; Alain et al. PNAS, 2010). This property makes it possible to use viral sensitizers to improve the activity of oncolytic viruses in animals and humans. As such, one pursuit of our laboratory is to delineate which viral sensitizers are most suitable for this application and whether some can be combined together for even greater activity. In addition, we also aim to better understand why these viral sensitizers improve oncolytic virus activity in a tumor selective fashion. To this end, we are using a variety of molecular biology techniques, mathematical modeling, and employing several animal tumor models.
3. Viral sensitizers for improving vaccine manufacturing and global health
With the exception of clean water, vaccines have arguably had the most significant impact on human global health. While global vaccine demands continue to rise with the ever-increasing world population, there is tremendous pressure on vaccine manufacturers and governments to provide sufficient quantities of vaccines for the population, particularly during pandemics such as experienced in 2009 for Influenza A H1N1. To cater more reliably to this demand, manufacturers around the world are turning away from egg-based manufacturing systems towards continuously growing cells. Because regulators have limited to only a few cell lines the substrates that can be used to produce viral vaccines, this can cause problems because some viruses are poorly adapted to the cell lines in question. Among others, viral vaccine strains are often ill equipped to fight against the “foreign” antiviral defenses of these approved manufacturing cell lines. Because viral sensitizer compounds have been shown to increase viral production by > 1000-fold in some contexts, their application to vaccine manufacturing is therefore a primary focus of our research team. With the help of academic and industrial partners, we are refining viral sensitizer formulations for use with vaccines, aiming to to robustly and safely increase the production of commercial vaccine strains using viral sensitizer technology. We thereby hope to improve global heath outcomes by increasing the efficiency of vaccine manufacturing and providing access to cheaper vaccines, particularly for developing nations.
4. Viral sensitizers for Gene Therapy applications
Gene therapy often uses non-replicating viral vectors encoding a therapeutic gene product that are transduced in order to correct genetic defects within diseased cells or tissues. While gene therapies have recently been approved for use in man, insufficient gene transduction efficiency or generation of immune responses against the vector and transgene continue to plague certain applications. As a potential solution to this, we are exploring the possibility that viral sensitizers may be used to improve gene therapy.
近期论文
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R Arulanandam, C Batenchuk, O Varette, C Zakaria, NE Forbes, C Davis, R Krishnan, V Garcia, R Karmacharya, J Cox, A Sinha, Andrew Babawy, K Waite, E Weinstein, T Falls, A Chen, J Hamill, N Da Silva, DP Conrad1, H Atkins, K Garson, C Ilkow, M Kaern, B Vanderhyden, N Sonenberg, T Alain, F Le Boeuf, JC Bell, JS Diallo, Microtubule Disruption Synergizes with Oncolytic Virotherapy by Inhibiting Interferon Translation and Potentiating Bystander Killing, Nat Commun. 2015 Mar 30;6:6410.
C Ilkow, M Marguerie , C Batenchuk , D Ben Neriah , S Cousineau , T Falls , C Tanese de Souza , F Le Boeuf , R Arulanandam , L Stubbert , S Thorne , P Paramananthan, A Chatterjee , C Addison , D Stojdl , Diallo J-S , B Lichty, JC Bell, Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity, Nat Med. 2015 Apr 20
R Arulanandam, C Batenchuk, FA Angarita Celis, K Ottolino-Perry, S Cousineau, C Ilkow, A Mottashed, E Burgess, T Falls, N De Silva, J Tsang, G Howe, D Conrad, CJ Brietbach, DH Kirn, JS Diallo, B Lichty, C Addison, JA McCart, John C. Bell, VEGF-mediated innate immune suppression sensitizes tumour vasculature to oncolytic virus infection, Cancer Cell, Jul 22 2015
F Le Boeuf*, C Batenchuk*, M Vähä-Koskela, S Breton, D Roy, C Lemay, J Cox, H Abdelbary, T Falls, G Waghray, H Atkins, D Stojd, JS Diallo, M Kaern*, JC Bell*. Model-based Rational Design of an Oncolytic Virus with Improved Therapeutic Potential. Nat Commun. 2013 Jun 14;4:1974.
Diallo JS, Le Boeuf F, Lai F, Cox J, Vaha-Koskela M, Abdelbary H, MacTavish H, Waite K, Falls T, Wang J, Brown R, Blanchard JE, Brown ED, Kirn DH, Hiscott J, Atkins H, Lichty BD, Bell JC. A high-throughput pharmacoviral approach identifies novel oncolytic virus sensitizers. Mol Ther. 2010 Jun;18(6):1123-9.
Ilkow CS, Swift SL, Bell JC, Diallo JS, From Scourge to Cure: Tumour-Selective Viral Pathogenesis as a New Strategy against Cancer, PLoS Pathog. 2014 Jan;10(1):e1003836. doi: 10.1371/journal.ppat.1003836. Epub 2014 Jan 16
Bridle BW, Chen L, Lemay CG, Diallo JS, Pol J, Nguyen A, Capretta A, He R, Bramson JL, Bell JC, Lichty BD, Wan Y. HDAC Inhibition Suppresses Primary Immune Responses, Enhances Secondary Immune Responses, and Abrogates Autoimmunity During Tumor Immunotherapy. Mol Ther. 2013
Conrad DP, Tsang JJ, Maclean M, Diallo JS, Le Boeuf F, Lemay CG, Falls TJ, Parato K, Bell JC, Atkins H., Leukemia Cell-Rhabdovirus Vaccine: Personalized Immunotherapy for Acute Lymphocytic Leukemia. Clin Cancer Res. 2013 May 28.
CJ Breitbach , J Burke, D Jonker, J Stephenson, A Haas, L Chow, J Nieva , TH Hwang, A Moon, R Patt, A Pelusio, F Le Boeuf, J Burns, N De Silva, S Cvancic, JE Je, YS Lee, K Parato, JS Diallo, M Daneshmand, JC Bell, DH Kirn, Intravenous administration of the cancer-targeted poxvirus JX-594 results in tumor-specific replication, transgene expression and anti-tumoral efficacy in patients with metastatic solid tumors, Nature, 2011 Aug 31;477(7362):99-102
Nguyên TL, Abdelbary H, Arguello M, Breitbach C, Leveille S, Diallo JS, Yasmeen A, Bismar TA, Kirn D, Falls T, Snoulten VE, Vanderhyden BC, Werier J, Atkins H, Vähä-Koskela MJ, Stojdl DF, Bell JC, Hiscott J, Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis, Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14981-6.
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