New pharmaceuticals 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 a new study by a research team led by UC San Francisco and Harvard researchers, in collaboration with Tempero and GlaxoSmithKlein.
In a study reported online April 17, 2014 in the journal Immunity, 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 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.
“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,” saidAlexander Marson, MD, PhD, a leading T cell expert and 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.”
The research team, led by Marson and Vijay K. Kuchroo, PhD, an immunologist at Brigham and Women’s Hospital in Boston and Harvard Medical School, combined powerful techniques to shed light on a class of protein molecules within cells known as transcription factors.
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.
Different transcription factors shape the development of different types of T cells within the immune system, Marson and others are discovering. In their new study, Marson found that the transcription factor called ROR gamma t has a unique role in guiding development of Th17 cells, while inhibiting the development of other immune cells.
Preventing Th17 cells from developing by inhibiting the function of ROR gamma t appears to be an effective strategy for fighting autoimmune diseases, Marson said.
“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,” Marson said, 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,” he said.
“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,” Marson said. “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, Marson said. 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.
Analyzing the large data sets generated through such experiments could help pharmaceutical companies wading into development of drugs that target transcription factors to test the waters, Marson said, enabling drug developers to better understand mechanisms of drug action and to more easily see gene activity that could trigger side effects.
According to Marson, “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.
I’m very happy to learn about this new study, as someone whose sister was diagnosed with rheumatoid arthritis (an autoimmune disease) at the age of 15, this is great news.
Rheumatoid arthritis is fairly uncommon for younger people, especially teenagers. It is an inflammatory disease which specifically causes pain in the joints and causes the carrier to have a sensitive immune system. Pills prescribed for this disease so far like Cortisone and Imuran have very harmful side effects like extreme nausea, fatigue, weight gain and, cortisone especially, makes the skin pale and more sensitive.
Knowing that there are currently studies going on to better the treatment for this terrible disease brings hope for carriers like my sister, and would be a great advanced in the field of medicine
I’m very happy to learn about this new study, as someone whose sister was diagnosed with rheumatoid arthritis (an autoimmune disease) at the age of 15, this is great news.
Rheumatoid arthritis is fairly uncommon for younger people, especially teenagers. It is an inflammatory disease which specifically causes pain in the joints and causes the carrier to have a sensitive immune system. Pills prescribed for this disease so far like Cortisone and Imuran have very harmful side effects like extreme nausea, fatigue, weight gain and, cortisone especially, makes the skin pale and more sensitive.
Knowing that there are currently studies going on to better the treatment for this terrible disease brings hope for carriers like my sister, and would be a great advanced in the field of medicine.
I’m very happy to learn about this new study, as someone whose sister was diagnosed with rheumatoid arthritis (an autoimmune disease) at the age of 15, this is great news.
Rheumatoid arthritis is fairly uncommon for younger people, especially teenagers. It is an inflammatory disease which specifically causes pain in the joints and causes the carrier to have a sensitive immune system. Pills prescribed for this disease so far like Cortisone and Imuran have very harmful side effects like extreme nausea, fatigue, weight gain and, cortisone especially, makes the skin pale and more sensitive.
Knowing that there are currently studies going on to better the treatment for this terrible disease brings hope for carriers like my sister, and it would definitely be a great advancement in the field of medicine.
Autoimmune diseases are crippling to most sufferers and unless you know someone who has it or have it yourself you do not know how desperate they are for a cure. Like the previous comments on the article my concern is also that it has only been tested on mice, would it not be more significant to test on sufferers who are willing to be treated with the drug who are desperate for a cure ? It is great news that funding is put towards finding a cure for this disease. It seems that there is a lot of speculation in the research when referring to the “ROR gamma and the pocket that looks like it should bind a hormone” not stating that it definitely binds the hormone, and not knowing which hormone it might be, as well as the effects that it might have. Although a lot of research still needs to be done we hope that a cure is found in the near future.
I feel the fact that new treatment strategies regarding autoimmune diseases are being researched is ground breaking news to all those affected by these diseases. The option of an alternative treatment rather than some of the treatments currently available is especially good news due to the fact that the side effects of some of these treatments can be just as devastating as the diseases themselves (as I have discovered from personal experiences). My only concern is that the treatment has only been tested on mice thus far, and many treatments which have been successful in animals first end up failing in humans. Ultimately, although the research and testing regarding this treatment strategy still has a long way to go before being finalized and hopefully declared successful in humans, I feel that this is a huge first step in the right direction concerning autoimmune diseases.
This new development in autoimmune treatment is extremely fascinating. I do wonder however just how effective this new development will be on humans considering it has only been affective on mice thus far? Does this suggest that mice have similar or the same genomes as us humans? I also wonder how they plan to make this treatment available to autoimmune suffers and if it matters how severe a person’s symptoms are and how long they have suffered for if it affects them receiving the treatment? I also wonder how this treatment plans to work in humans. In the mice it only lessened the symptoms, will it do the same for humans or will it completely rid sufferers of the disease?
This research would help many autoimmune disease sufferers, however I wonder how affective the medicine would be for humans considering it has only been tested on mice, does this mean that mice have the same or similar genomes as we do? I also wonder how long this will take before its available? This new discovery is ground breaking but I wonder how they plan to make it available to autoimmune suffers and if it would make a difference on how long a person has suffered or how severe their disease is? The idea of using genomes to help autoimmune suffers is extremely fascinating.
This research is definitely significant to any individual suffering from autoimmune diseases. Presently accessible treatment procedures can either cause powerful side effects or are generally remarkably costly. According to research a third of patients treated do not respond to the treatment received. The increased perception of the molecular basis of the autoimmune diseases is the driving force to allow researchers to focus on distinct areas. Research has shown that animals are being used broadly to detect and verify antigens elaborated in autoimmune diseases.
With every experiment there are challenges that come with it. The challenge with establishing therapies for autoimmune diseases is the cross awareness between the natural body proteins and those of a diversity of pathogenic agents.
In the future the researchers understanding about the autoimmmune diseases molecular and cellular aspects will increase, and more attention will be directed at understanding the correlation between autoimmune diseases.
The research in this article is ground breaking work for the autoimmune affected community. This might be the first long term cure that could go a long way to provide a bright future for these people. Besides the already stated fact about how costly the procedures could be, there are other factors that could have an influence .The only aspect I would criticise is the problems that might arise from the ROR gamma t cells. As it was stated in the article there is a pocket that looks like it should bind to a hormone, but its effects are unknown. This unknown factor might have an adverse effect in the long term. Because it is so closely related to the transcription of DNA, it might change more than the purpose it was intended for. This might lead to worse changes in the genome and have a greater negative impact on the patient. My feeling toward this discovery is that it is a great step closer to a cure for these diseases, but there is still much research to be done before it can be threat free.
This is amazing news for autoimmune disease sufferers such as those within my own family. Hopefully medicine like this will be available sooner rather than later to prevent further suffering.I wonder how expensive this medication will be as it includes mapping genomes? It is not stated very clearly in the article, but will each patient`s specific genome be mapped? Or was the mapping only to study the Th17 cells? Lastly will this be beneficial for all sufferers or, like penicillin, will some be allergic/immune?