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Tohemeh Mahmoudi
Researcher

Dr. T. (Tokameh) Mahmoudi

Principal Investigator

Group leader

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About

Introduction

Tokameh Mahmoudi studied Molecular Biology at UC Berkeley where she completed her Balechor's degree followed by her Masters studies in Biochemistry at the Hospital for Sick Children, University of Toronto. She performed her PhD research at Leiden University Medical Centre (LUMC) in Leiden, The Netherlands where she studied the role of trithorax and polycomb group proteins in chromatin mediated gene regulation. As a trained biochemist she applied her expertise into mechanistic dissection of the molecular events that drive viral pathogenesis and latency during her post-doctoral studies at UCSF at the Gladstone Institute of Immunology and Virology in the lab of Eric Verdin and later in stem cell based technologies in the lab of Hans Clevers at the Hubrecht Institute in The Netherlands. Research in Tokameh's lab focuses on delineation of the molecular events that control HIV transcriptional latency and HBV-mediated onset of hepatocellular carcinoma (HCC). Her lab uses a multidisciplinary approach combining current knowledge of HIV transcription and HBV infection together with state of the art high through-put approaches, virology, genetics, immunology and conventional biochemistry to identify novel druggable molecular targets and candidate therapeutics. Tokameh is a member of NL-4Cure and co-founder of EHEG, an Erasmus MC multidisciplinary consortium focused on translating basic advances in HIV Cure research into development of novel therapeutics and their testing and implementation in the clinic.

Publications

2019 Current Opinion in Virology A broad drug arsenal to attack a strenuous latent HIV reservoir.(accepted) M. Stoszko*, E. Ne*, E. Abner, T. Mahmoudi

2019 BioArxiv Human liver organoids; Modelling HBV Infection, Replication and Related Tumorigenesis. doi: https://doi.org/10.1101/568147 Crignis E, Carofiglio F, Moulos P, Verstegen MMA, Romal S, Khalid MM, Pourfarzad F, Koutsothanassis C, Gehart H, Kan TW, Palstra R-J, Boucher C, IJzermans JMN, Huch M, Boj SF, Vries R, Clevers H, van der Laan L, Hatzis P, Mahmoudi T.

2019 Pharmacological Research  T cell cytotoxicity of HIV latency reversing agents. Jan;139:524-534.

Zhao M, De Crignis E, Rokx C, Verbon A, van Gelder T, Mahmoudi T, Katsikis PD, Mueller YM.

2018 Cell Chemical Biology Identification of a novel macrolactam scaffold A novel class of BAF inhibitors that act as potent, nontoxic, HIV Latency reversal agents. pii: S2451-9456(18)30270-8.  Marian C, Stoszko M, Wang L, Leighty M, Chowdhury B, de Crignis E, Colling M, Hargreaves D, Duvall J, Dandapani S, Crabtree G*, Mahmoudi T* Dykhuizen EC*.

2018 Science Advances Allele-specific long distance regulation of IL-32 dictates isoform switching and confers susceptibility to HIV-14: e1701729  Palstra RJ,  De Crignis E, Röling MD, Kan TW , van Staveren T , van Ijcken W , Mueller YM, Katsikis PD, Mahmoudi T.

2016 EBioMedicine Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal. 3:108-21. doi: 1016/j.ebiom.2015.11.047.  Stoszko M, De Crignis E, Rokx C, Khalid MM, Lungu C, Palstra RJ, Kan TW, Boucher C, Verbon A, Dykhuizen EC, Mahmoudi T.

2012 Transcription The BAF complex and HIV Latency. Jul 1;3(4).     Mahmoudi T*

2012 Cell Wnt pathway activation through inhibition of proteosomal b-catenin degradation within the intact endogenous Axin1 complex.  149(6):1245-56. *corresponding author  Li VS, Ng SS, Boursma P, Karthaus RW, Gerlach JP, Mohammed S, Heck AJ, Maurice MM, Mahmoudi T*, and Clevers H*.

2011 PLoS Biology Repressive LTR Nucleosome Positioning by the BAF Complex is Required for HIV Latency. 9(11):e1001206.

Rafati H, Parra M, Hakre S, Moshkin Y, Verdin E and Mahmoudi T.

2007 Proc Natl Acad Sci USA. Conserved P-TEFb-interacting domain of BRD4 inhibits HIV transcription. 104(34):13690-13695.     Bisgrove DA, Mahmoudi T, Henklein P, Verdin E.

2006 Journal of Biological Chemistry The SWI/SNF chromatin-remodeling complex is a cofactor for Tat transactivation of the HIV promoter. . 281(29):19960-19968

Mahmoudi T, Parra M, Vries RG, Kauder SE, Verrijzer CP, Ott M, Verdin E.

Research

Research in the Mahmoudi lab aims to delineate the molecular events that lead to pathogenesis resulting from infection with two viruses: HBV, which causes onset of liver cirrhosis and is the leading cause of hepatocellular carcinoma (HCC) world-wide and HIV, which causes AIDS. Current antiviral drugs prevent HBV or HIV infection from becoming lethal. These viral infections instead lead to chronic infections. It is therefore necessary to eradicate the infections to prevent relapse, long term organ damage or cancer and to relieve patients from side effects of life-long medication. Our approach is to understand the molecular mechanisms that drive chronic HIV and HBV infections and the consequential pathology. Therefore, we combine our current expertise on HIV transcription and HBV infection-induced transformation to our novel cellular HBV/HCC modeling platforms. Using a multidisciplinary approach including virology, immunology, conventional biochemistry, genetics and high throughput omics we search for “drug-able” molecular targets, and candidate compounds active in HIV or HBV gene regulation. Using this approach, our lab, embedded within the Erasmus MC clinical infrastructure together with our national and international collaborators, works to identify and translate basic fundamental molecular advances in the HIV and HBV-liver cancer field into development and testing of novel therapeutics in the clinic.

 

HIV Cure: mechanisms, drug discovery, clinical study and valorization

Fundamental research in our group identified the BAF complex as a central player in repressing HIV transcription (Rafati et al., PLos Biology 2011), highlighting BAF as a potential target to reverse HIV latency. We then collaborated with Purdue and Stanford University and the Broad Institute to perform drug screens and found that small molecule inhibition of BAF re-activates latent HIV- in a spectrum of CD4+ T cell HIV latency models as well as in cells obtained from HIV infected patient volunteers (Stoszko et al., EBioMedicine 2016). Subsequently we successfully performed screens for next generation BAF inhibitors and other new potential latency reversal agents (LRAs). From a screen of more than 350,000 compounds, performed in collaboration with Stanford, Purdue, and Broad, we identified a novel class of ARID1A targeting macrolactam scaffold molecules that display potent latency reversal with significantly less associated cytotoxicity (U.S. Application Serial No. 62/697,002 July 12, 2018 ; Marian et al., Cell Chem Biol, 2018) and these compounds are under further development.

One of our most promising compounds, pyrimethamine, is an FDA/EMA approved drug used in treatment of toxoplasmosis. We are currently investigating the effect of pyrimethamine in latent reservoir reduction in Erasmus MC patients under suppressive therapy in a randomized clinical trial (clinicaltrials.gov: NCT03525730).

 

HBV infected patient-derived liver organoids; modelling HBV-induced hepatocellular carcinoma

We have recently developed a primary HBV infected and patient-derived human liver organoid model system. HBV research has been limited by lack of models systems to study HBV infection in vitro. This new model for the first time allows long term culturing and analysis of HBV infected patient livers and provides a cell system to culture virus. Furthermore, it is a platform suitable for antiviral drug screening (de Crignis et al, Bioarxive 2019) and allows us to examine the HBV-induced mechanisms of liver pathogenesis, allowing  identification of early aberrant gene regulatory networks and biomarkers that drive HBV-mediated HCC. We recently showed GWAS and genome-wide functional data can be leveraged to unravel the underlying biological basis of HIV non-coding disease associated genomic variants (Palstra et al., Science Advances  2018). We will apply this approach to liver organoids and decipher the functional significance of HBV/HCC/cirrhosis associated GWAS genomic variants whose functions currently remains elusive.

This translational project has resulted in a human liver organoid technology for HBV (ex vivo infected) healthy donor and patient livers. We will use this novel platform to study HBV replication and related tumorigenesis taking a similar approach of fundamental molecular research and unbiased drug screens that was previously very successful in our research into the molecular determinants of HIV.

From fundamental research to the clinic

Our bench to bedside research approach is dependent on close collaborations with clinical partners to obtain primary patient material for experiments as well as for enrolment of consenting patients for clinical trials. Therefore in 2012, we founded EHEG (Erasmus HIV Eradication Group), a multidisciplinary research environment and infrastructure within Erasmus MC (Biochemistry, Virology, Immunology, and Internal Medicine) that allowed us to translate new findings in HIV fundamental research into development and proof-of-concept testing of novel therapies in the clinic (part of Erasmus MC ACE VICER).

For our HBV/HCC studies we have established a collaborative network similar to the highly successful EHEG consisting of the Erasmus MC Biochemistry, Transplantation Surgery, Hepatology and Virology departments (part of Erasmus MC ACE SCORE). This in combination with our close collaborations with the foundation Hubrecht Organoid Technology and the Hubrecht Institute will allow us to quickly translate our results into clinical applications.