Pharmacogenomic studies in Multiple Sclerosis

Project Details

Synopsis

Multiple sclerosis, an autoimmune, neurodegenerative condition, is the most common cause of non-traumatic neurological disability in young adults.  At present twelve immunomodulatory or immunosuppressive therapies with varying levels of treatment efficacy are approved for the treatment of MS in Australia (13 globally).  All drugs have been shown to reduce relapse rates in clinical trials, and some have also been shown to have disability progression and MRI benefits.  However, individuals are known to have variable responses to these therapies, and can be classed as treatment responders, intermediate responders and non-responders.  This project aims to identify genetic markers of treatment response to three of the newer, and more commonly prescribed MS drugs; the monoclonal antibody against ³a4-integrin, natalizumab,  the sphingosine-1-phosphate receptor modulator, fingolimod, and the monoclonal antibody targeted against the B-Cell antigen CD20, rituximab.

This PhD project will utilise genetic data that is linked to a global observational cohort to identify genetic markers of treatment response and non-response.

Outcomes and impact

The identification of genetic predictors of MS treatment response will have a significant impact on MS clinical management, and treatment decision making.  It will allow the stratification of patients for therapeutic choice, reduce treatment trial-and-error and prolong patient quality of life.

Research Environment

The proposed project will be undertaken using the MSBase Registry, an international, prospective, observational MS cohort study.  It currently contains over 50,000 longitudinal patient records, with over 230,000-patient years of follow-up.  Within the MSBase observational cohort study, we have formed a special interest group to examine genetic factors associated with disease outcome and treatment response.  This group comprises 12 centres that have the capacity to undertake genetic studies. Here, our cohort comprises 8,574 patients, with 60,000 patient-years of follow-up with visits occurring on average every 6 months, thus allowing for accurate stratification of treatment responders and non-responders.

Researchers

Collaborators

  • Prof Dana Horakova, and Prof Eva Havrdova, Charles University Prague, Czech Republic
  • Prof Guillermo Izquierdo, Hospital Universitario Virgen Macarena, Seville, Spain
  • Dr Fuencisla Matesanz Instituto de Parasitolog√≠a y Biomedicina L√≥pez Neyra, CSIC, Granada, Spain
  • A. Prof Nikolaos Patsopoulos, Brigham and the Women's Hospital, Harvard Medical School, Boston, MA, USA
  • A. Prof Tomas Kalincik, Department of Medicine, CORe Unit, University of Melbourne, VIC, Australia
  • Prof. Trevor Kilpatrick, Melbourne Neuroscience Institute, University of Melbourne, VIC, Australia
  • Prof Jeannette Lechner-Scott, University of Newcastle, Newcastle, NSW, Australia
  • Prof Mark Slee, Flinders University and Medical Centre, Adelaide, SA, Australia
  • Prof. Michael Barnett, Brain and Mind Centre, University of Sydney, NSW, Australia
  • Dr Steve Vucic and Prof David Booth, Westmead Institute, University of Sydney, NSW, Australia
  • Prof. Bruce Taylor, Menzies Research Institute, Univesity of Tasmania, TAS, Australia

Funding

  • The Royal Melbourne Hospital [MH2013-055]
  • MSBase Foundation Project Grant
  • CharityWorks for MS/MS Research Australia [MSRA12-062]

Research Publications

  1. Mahukar S, Moldovan M, Suppiah V, et al., Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study. The Pharmacogenomics Journal. 2017;17(4):312-318.
  2. Jokubaitis, V.G. and Butzkueven, H., 2016. A genetic basis for multiple sclerosis severity: Red herring or real?. Molecular and cellular probes, 30(6), pp.357-365.
  3. Jokubaitis VG, Spelman T, Kalincik T, et al., Predictors of long-term disability accrual in relapse-onset multiple sclerosis. Annals of Neurology. 2016; 80(1): 89-100
  4. Jokubaitis VG, Spelman T, Kalincik T, et al., Predictors of disability worsening in clinically isolated syndrome. Ann Clin Transl Neurol. 2015; 2(5): 479-91
  5. Jokubaitis, V.G., Kalincik, T., Horakova, D., Havrdova, E., Kleinova, P., Izquierdo, G., Matesanz, F., Kilpatrick, T.J., Lechner-Scott, J., Slee, M. and Barnett, M., et al. Genotype-phenotype correlations in relapsing-remitting multiple sclerosis: making use of a robust severity phenotype. Multiple Sclerosis Journal 2017; 23, No. 1, pp. 59-59
  6. Jokubaitis, V.G., Kalincik, T., Horakova, D., Havrdova, E., Kleinova, P., Kucerova, K., Izquierdo, G., Matesanz, F., Lugaresi, A., Kilpatrick, T.J. and Lechner-Scott, J.,et al. Defining a robust disease severity phenotype for use in genetic association studies. Multiple Sclerosis Journal 2016; 22, pp. 168-169

Research Group

MS-BioGaPs



Faculty Research Themes

Neuroscience

School Research Themes

Neuroscience & Psychiatry



Key Contact

For further information about this research, please contact the research group leader.

Department / Centre

Medicine and Radiology

Node

Royal Melbourne Hospital

Unit / Centre

MS-BioGaPs