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Neuroscience Graduate Program at UCSF

Faculty - Stephen Hauser, M.D.

Neurogenetics and Neuroimmunology of Demyelinating Diseases


Research Description

The Genomics of Multiple Sclerosis (MS)

My laboratory has a longstanding interest in the genetic basis of MS.  This work involves collaborations with colleagues at UCSF (Jorge Oksenberg and Sergio Baranzini), and more recently with a large global consortium that I helped create. I am the Principal Investigator of NIH grants that support all of these efforts.  Accomplishments include mapping of causative genes within the HLA region in MS and other autoimmune diseases; identification of non-HLA risk genes for MS - currently numbering 60 – and elucidation of functional consequences of causative variants; application of admixture analyses to identify MS risk genes in non-Caucasian populations; and recently use of whole genome sequencing and epigenetic studies to understand missing heritability.  We are also developing novel informatics tools that integrate clinical, imaging, and genomic data at the bedside, setting the stage for personalized medicine approaches to MS and other neurodegenerative diseases. 

Humoral Immune Mechanisms in MS

A second area is the role of humoral immunity in MS. My laboratory developed an animal model that faithfully recapitulates the core pathologic features of MS, and demonstrated that auto-antibodies directed against myelin oligodendrocyte glycoprotein (MOG), a quantitatively minor myelin protein, is a major factor in producing MS-like lesions. These data challenged previous assumptions on the pathogenesis of MS, and indicated clearly that autoimmune T cells, previously thought to be the trigger of MS, synergize with pathogenic autoantibodies. We then identified myelin reactive autoantibodies in direct contact with disintegrating myelin membranes within demyelinating lesions, both in the animal model and also in humans with MS.  Current studies are focused on defining the repertoire of pathogenic B cell and antibody specificities in the nervous system and peripheral blood.

These findings also led to the development of randomized placebo-controlled multicenter clinical trials of the B-cell (anti-CD20) targeted monoclonal antibodies rituximab and ocrelizumab in MS. The first phase 2 trial, reported in 2007, found that chimeric rituximab reduced disease activity, measured by MRI scanning, by 91% in relapsing-remitting MS; a second phase 3 trial, reported in 2008, found that rituximab may similarly be effective in some patients with primary progressive MS. A phase 2 clinical trial with humanized ocrelizumab, published in November 2011, reported a very positive efficacy signal compared with placebo and beta-interferon (current standard of care) arms. If these findings, including the favorable safety profile, are sustained in phase 3 trials currently in progress, B-cell based therapies will represent a major therapeutic advance.

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Current Projects

See current experimental work listed above.

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Selected Publications

Selected publications

Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, de Bakker PIW, Gabriel SB, Mirel DB, Ivinson AJ, Pericak-Vance MA, Gregory SG, Rioux JD, McCauley JL, Haines JL, Barcellos LF, Oksenberg JR, Hauser SL.  Risk alleles for multiple sclerosis identified by a genomewide study.  New Eng J Med.  357:851-62, 2007.

Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzaro M, Sarkar N, Agarwal S, Langer-Gould A, Smith CH; HERMES Trial Group.  B-cell depletion with rituximab in relapsing-remitting multiple sclerosis.  N Eng J Med.  358:676-88, 2008.

The International Multiple Sclerosis Genetics Consortium (IMSGC) and the Wellcome Trust Case Control Consortium 2 (WTCCC2).  Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature, 476:214-9, 2011.

Baranzini SE, Mudge J, van Velkinburgh JC, Khankhanian P, Khrebtukova I, Miller NA, Zhang L, Farmer AD, Bell CJ, Kim RW, May GD, Woodward JE, Caillier SJ, McElroy JP, Gomez R, Pando MJ, Clendenen LE, Ganusova EE, Schilkey FD, Ramaraj T, Khan OA, Huntley JJ, Luo S, Kwok P-Y, Wu TD, Schroth GP, Oksenberg JR, Hauser SL, Kingsmore SF.  Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature.  464:1351-6, 2010.

Kappos L, Li D, Calabresi PA, O’Connor P, Bar-or A, Barkhof F, Yin M, Leppert D, Glanzman R, Tinbergen J, Hauser SL.  Ocrelizumab in relapsing-remitting multiple sclerosis: results of a Phase II randomized placebo-controlled multicentre trial.  Lancet, 378:1779-87, 2011.

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Stephen Hauser, M.D.



Email

hausers@neurology.ucsf.edu

Phone

415-476-9211

Office Address

UCSF MC 3208
675 Nelson Rising Lane, Room 218
San Francisco, CA 94158

Other Websites

Multiple Sclerosis Center

Neurology Website

Clinical Profile