New classes of pharmaceutical agents tailored to fight autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and psoriasis, may be identified more effectively by adding genome analysis to standard drug screening, according to results of a new study by a collaborative research team led by UC San Francisco and Harvard researchers, in collaboration with pharmaceutical industry partners Tempero and GlaxoSmithKline.
A UCSF release says that in 2009, GlaxoSmithKline’s Immuno-Inflammation Center of Excellence in Drug Discovery (iiCEDD) initiated a program in the field of Th17 and Treg biology. The iiCEDD externalized this program into an independent company in order to benefit from the unique entrepreneurial spirit of an early stage biotech while leveraging the breadth of knowledge and resources of a well established pharmaceutical company. The Immuno-Inflammation Centre of Excellence for Drug Discovery is dedicated to discovering therapies for inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease and psoriasis, and designed to integrate and better coordinate the progression of inflammatory disease medicines from therapeutic hypothesis to clinical proof of concept. Its focus is on building an innovative pipeline through both internal efforts and external alliances with other companies and research institutions and will focus on ‘virtualizing’ a portion of the inflammatory diseases pipeline by forming multiple risk-sharing/reward-sharing alliances.
Tempero was established in March of 2009 and chose to base its operations in the Boston area where it can establish relationships with key opinion leaders and have access to a deep talent pool. Tempero’s expertise in this emerging area of biology has been strengthened by its collaborations with key academic thought leaders in the field. Harvard Medical School Professor of Neurology and Associate Immunologist at Boston’s Brigham and Women’s Hospital Dr. Vijay Kuchroo’s seminal contributions to the characterization of Th17 cells, Harvard Medical School professor Dr. Christophe Benoist’s detailed understanding of the diversity of Tregs and former Professor of Medicine at Brigham and Women’s Hospital and Harvard Medical School Dr. Diane Mathis’ emerging research in tissular Tregs were instrumental in the formation of Tempero.
With its facilities in Kendall Square, Cambridge, Tempero has built a series of chemistry, biology, tissue culture labs and offices in order to develop next-generation therapies that selectively prevent Th17-driven diseases, or enhance the development of specialized Treg subsets, while generating significant intellectual property in target biology and chemical matter. Some of the diseases Tempero’s research may benefit include multiple sclerosis, inflammatory bowel disease, psoriasis, lupus, and rheumatoid arthritis
In a study reported online April 17, 2014 in the journal Immunity entitled “Small-Molecule ROR t Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms” (http://dx.doi.org/10.1016/j.immuni.2014.04.004 Immunity, Volume 40, Issue 4, 17 April 2014, Pages 451-452), co-authored by UCSF School of Medicine Clinical Fellow Alexander Marson MD PhD, and Vijay K. Kuchroo, et al, the scientists combined drug screening with state-of-the-art techniques for analyzing the genome, leading to three small molecules that improved symptoms in a mouse form of multiple sclerosis.
The research team, led by Dr. Marson and Dr. Kuchroo, combined powerful techniques to shed light on a class of protein molecules within cells known as transcription factors. Different transcription factors shape the development of different types of T cells within the immune system, Drs. Marson, Kucheroo, and their research colleagues discovered.
The UCSF release notes that drug designers have rarely targeted transcription factors. Each transcription factor binds to DNA at a unique set of locations along the 23 pairs of chromosomes, and thereby influences which genes are turned on and off to trigger the protein production that drives cell development and function.
The study identified three ROR t inhibitors, which are effective in animal models of autoimmunity, including an orally bioavailable one, have been identified, and notes that Th17 cell genomics is integrated into drug discovery, and chemical inhibitors have distinct effects on ROR t binding
The three retinoid-related orphan receptor gamma t (ROR t)-specific inhibitors were found to suppress T helper 17 (Th17) cell responses, including Th17-cell-mediated autoimmune disease, and ROR t found to act as a direct activator of Th17 cell signature genes and a direct repressor of signature genes from other T cell lineages; its strongest transcriptional effects are on cis-regulatory sites containing the ROR binding motif.
The three potential drug candidates, selected from a large library of screened chemicals, each knocked down the response of Th17 cells, a type of immune cell that drives many autoimmune diseases by attacking normal cells in the body. More specifically, the drugs homed in on an essential molecule within the Th17 cells.
The researchers summarize that their work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity.
“We examined what makes Th17 cells — which play a crucial role in multiple autoimmune diseases — distinct from other closely related T cells within the immune system,” says study co-author Dr. Marson who is also a leading T cell expert and a member of the UCSF Diabetes Center. “Then we investigated several small molecules that inhibit the development and function of these cells. When the Th17 cells were hit by these molecules we saw less severe multiple-sclerosis-like symptoms in the mice.”
Preventing Th17 cells from developing by inhibiting the function of ROR gamma t appears to be an effective strategy for fighting autoimmune diseases, Dr. Marson notes in the UCSF release.
“There already are drugs in clinical trials for autoimmune diseases – including psoriasis and rheumatoid arthritis – that are antibodies for IL-17 or IL-17 receptors,” Dr. Marson continues, referring to signaling molecules secreted by Th17 cells that can help trigger an attack our own healthy tissue, and the receptors that receive those signals. “This is an entirely different and promising approach to fight autoimmune disease. Our studies map a path to targeting transcription factors and provide both insight into how transcriptional regulators shape the identity and affect the development of Th17 cells, and also into how different drug molecules might affect these regulatory circuits in the cells,” he said.
To reveal the distinct and sometimes subtle effects of the drug candidates, the researchers studied the entire genome to see where ROR gamma t attached to DNA, which genes were activated or turned off as a result, and how these effects were altered by the drug candidates.
“Not only did we look at which genes are turned on and off, but we also systematically looked at DNA-binding sites across this genome,” Dr. Marson explains. “This pushes the boundary of what’s typically done.”
In addition to attaching to DNA, ROR gamma t has a pocket that looks like it should bind a hormone, he says. But what this hormone might be, and its effects, are unknown. The different drug candidates that inhibited Th17 development had different effects on ROR gamma t and resultant DNA binding and gene activation, possibly because of distinct interactions with the hormone-binding pocket, Marson said.
However, Dr. Marson maintains that analyzing large data sets generated through such experiments could help pharmaceutical companies wading into development of drugs that target transcription factors to test the waters, enabling drug developers to better understand mechanisms of drug action and to more easily see gene activity that could trigger side effects, observing that: “This is a new, broadly applicable approach for systematically evaluating leading drug candidates for autoimmune diseases.”
The National Multiple Sclerosis Society and the National Institutes of Health provided major funding for the research.
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