Open Targets Initiative Finds DNA Variations Underlying Immune Diseases

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The Open Targets Initiative has just released data from a major study investigating the causes of immune conditions such as asthma, multiple sclerosis, and arthritis. Under the initiative, researchers from the Wellcome Sanger Institute, GSK, Biogen, and others have uncovered thousands of individual DNA differences associated with immune diseases and linked with the switching-on of a specific subtype of immune cells.  Their work is published today (23rd September) in Nature Genetics. This study aims to help narrow the search for molecular pathways of immune diseases and could lead to finding drug targets for developing new treatments.

Immune diseases represent one of the largest unmet medical markets in the world. The medical spend on asthma alone is expected to exceed $20 billion by 2024.

The new study has revealed some important new leads for researchers. “Our study is the first in depth analysis of immune cells and cytokine signals in the context of genetic differences linked to immune diseases. We found links between the disease variants and early activation of memory T cells, suggesting that problems with regulating this early T cell activation could lead to immune diseases,” said Blagoje Soskic, Ph.D. a lead author on the paper.

Previous research has revealed thousands of variants that are more common in patients with immune diseases than in healthy people. Many of these genetic variants are in poorly understood areas of the genome and are thought to be involved in regulating functions of immune cells. The Open Targets Initiative aims to understand which immune cell states are most important for these diseases, in an effort to hone in on potential new drug targets for conditions like asthma and IBD.

In this new study, the team looked at which parts of the genome were active in three types of immune cells from healthy volunteers, and cross-checked these positions against all the genetic variants implicated in different immune diseases. Researchers also examined different cytokines, creating a total of 55 different cell states, to mimic immune disease inflammation and understand the effects of the signaling chemicals in these cells.

The study revealed that one particular cell type and cell state—early activation of memory T cells—had the most active DNA across the same regions as the genetic variants implicated in immune diseases. This pointed towards the initial activation of these T cells being important in disease development. Surprisingly, the research showed that the cytokines generally only had subtle effects on the DNA activity, and played a lesser role in most of the diseases studied.

“At GSK, we deploy both genetics and genomics to identify which parts of the immune system are central to a range of human diseases and to yield better validated targets that could become transformational medicines. To investigate the science of the immune system, functional genomics helps us better understand the role that individual genes may or may not play in triggering pathogenic immune mechanisms,” said Rab Prinjha, Chair of the Open Targets Governance Board and Head of Adaptive Immunity and Immuno-Epigenetics Research Unit, GSK.

Open Targets is a pioneering public-private collaboration aiming to transform drug discovery through the systematic identification and prioritization of drug targets to improve the success rate for developing new medicines. The consortium is a unique, pre-competitive partnership between pharmaceutical companies and not-for-profit research institutes. The partners are GSK, Biogen, Takeda, Celgene, Sanofi, the Wellcome Sanger Institute and the EMBL’s European Bioinformatics Institute (EMBL-EBI).

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