Archive for May, 2010
Using Nitroglycerin To Treat Prostate Cancer Shows Potential
Last Updated on Wednesday, 12 May 2010 01:41 Written by Editor Wednesday, 12 May 2010 01:41
Treatment of prostate cancer using a very low dose of nitroglycerin may slow and even halt the progression of the disease without the severe side effects of current treatments, Queen’s University researchers have discovered
The findings are the result of the first-ever clinical trial using nitroglycerin to treat prostate cancer.
The 24-month, Phase II study targeted 29 men with increasing levels of prostate-specific antigen (PSA) following prostate surgery or radiation. PSA levels are a key predictor of cancer progression.
“We were very excited to see a significant slowing in the progression of the disease as evidenced by the men’s PSA levels, and to see this result in many of the men who completed the study,” says Robert Siemens, the leader of the study and a Professor of Urology at Queen’s University and urologist at Kingston General Hospital.
The researchers are encouraged by the results, particularly because safe and effective treatments for men with rising PSA levels following surgery or radiation are limited. They note that further testing needs to be done to confirm the results of this very small study.
The men were treated with a low-dose, slow-release nitroglycerin skin patch and their PSA levels monitored. Of the 17 patients who completed the study, all but one showed a stabilization or decrease in the rate of cancer progression, as measured by their PSA Doubling Time.
Nitroglycerin has been used at significantly higher doses for more than a century to treat angina. This trial was based on a key finding from pre-clinical research carried out at Queen's, which showed that decreases in nitric oxide play an important role in tumor progression and that this progression can be stopped by low-dose nitroglycerin.
Prostate cancer is diagnosed in approximately 235,000 men per year in the United States and 20,700 in Canada. Of patients who have undergone radical prostatectomy and/or radiation treatment, it is estimated that 30 to 50 percent will experience a recurrence of cancer.
Results of the study, conducted by Queen's University researchers Robert Siemens, Jeremy Heaton, Michael Adams, Jun Kawakami and Charles Graham, appeared in a recent issue of the journal Urology.
Research into the use of nitroglycerin and similar compounds for the treatment of cancer by Drs. Adams, Graham and Heaton has resulted in the issue of 10 patents worldwide. PARTEQ Innovations, the technology transfer office of Queen's, has licensed some of this intellectual property to Nometics Inc., a Queen's spinoff company, which is developing products and therapies based on this and related research.
"This peer-reviewed research is our first clear clinical evidence that low-dose nitric oxide therapy offers prostate cancer patients a new non-invasive treatment option," says Robert Bender, CEO of Nometics. "It is our intention to start broader clinical trials in 2010 to confirm and expand these results."
source: redorbit.com
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Experimental drug shows some benefit for Huntington’s disease
Last Updated on Wednesday, 12 May 2010 01:32 Written by Editor Wednesday, 12 May 2010 01:32
An experimental drug call latrepirdine has produced a small improvement in the mental abilities of some patients with Huntington’s disease, a finding that sets the stage for a larger clinical trial. Although the improvement was modest, the study marks the first time that a drug has been shown to improve brain function in the disorder.
Huntington’s is one of the more common inherited brain disorders. About 25,000 Americans have it and an additional 60,000 carry the defective gene that causes it and will develop the disorder as they age. It strikes between age 30 and 50 and is characterized by jerky, involuntary movements called chorea; loss of control of bodily functions; and dementia, a progressive deterioration of memory and thought processes. The only drug formally approved for treatment of Huntington’s is tetrabenazine, which improves chorea but does nothing for mental faculties.
Latrepirdine was originally developed in Russia nearly three decades ago as a treatment for hay fever, but it is no longer sold anywhere. Russian researchers screening compounds for potential effects on the brain found that it appears to stabilize mitochondria, the power source of brain and other cells. Because of that activity, Medivation Inc. of San Francisco and Pfizer Inc, which purchased the rights to the drug, conducted a Phase 2 clinical trial of the drug in Alzheimer’s patients and found some benefit. A larger Phase 3 trial, required for Food and Drug Administration approval, is now under way and results are expected later this year.
They also began testing it against Huntington’s, which is marked by a deterioration of mitochondria in brain cells. In a Phase 2 trial, Dr. Kurt Kieburtz of the University of Rochester Medical Center and his colleagues studied the drug in 91 Huntington’s patients over a 90-day period. Half received the drug in three daily doses and half received a placebo. The study was primarily a safety trial and the researchers concluded that the drug posed no untoward risks: About 70% of patients receiving the drug reported adverse side effects, but so did 80% of those receiving a placebo.
The drug produced no benefits on motor function, but it did yield an improvement in a mental test called the Mini-Mental State Examination, in which patients answer questions about what year it is and where they are, count backward, and try to recall words they haver recently heard. Patients receiving the drug showed an average improvement of 0.86 point on the 30-point scale, while those on placebo showed an 0.12-point decline. Kieburtz said he was surprised to see the improvement because the exam is a relatively crude test of mental function.
The trial was sponsored by Medivation and Pfizer, which hope to market the drug under the brand name Dimebon. The company now has a larger trial of 350 Huntington’s patients in progress as a final step toward winning FDA approval.
source: latimesblogs.latimes.com
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Glaxo shows the way in making research pay
Last Updated on Wednesday, 12 May 2010 01:27 Written by Editor Wednesday, 12 May 2010 01:27
The world’s top 10 pharmaceutical companies spend around $50bn a year on research & development…but have very little to show for it.
The cost of bringing a new drug from the laboratory to market has risen to around $1bn and, in an influential study released last year, McKinsey estimated that the industry’s return on R&D over the past decade has averaged just 7 per cent, below its cost of capital. It is startling that companies boasting operating margins of 30 per cent or more are actually destroying value in their core activity. No wonder the sector has been de-rated so substantially over the past 10 years.
It was meant to be very different. The introduction of “industrial†technologies, including genomics and high-frequency screening of chemical compounds in the 1990s was supposed to lead to an explosion in productivity. Pharma companies built huge research compounds and started to think of their scientists as engineers, perhaps even factory workers that would reliably churn out new medicines. That turned out to be a blind alley: drug discovery remains an almost personal process, based on intuition and serendipity as much as technology.
Now the industry, led by GlaxoSmithKline, is reversing course. Over the past few years, GSK has progressively started to break up its research clusters again, from thousands of people, to 300-400 and most recently units as small as 60-80 people, with more responsibility. At the same time, it is saving money by trimming the gold-plated physical infrastructure with which its boffins like to surround themselves. And it is becoming better at killing off drugs early that have a poor chance of making it to market. Each research project now has to pass a “Dragons Denâ€-type committee before it gets substantial funding.
The early results look encouraging. GSK had no new products approved in the US between 1998 and 2007 but 15 since then with another six in its late-stage pipeline. And at yesterday’s results presentation, chief executive Andrew Witty said that the group’s return on investment in R&D had risen from the 7 per cent industry average to 11 per cent in 2009 and that he “aspired†to 14 per cent. The fact that GSK – first among its peers – has revealed a proper measure of research productivity is as encouraging as the numbers. It may even tempt investors back into the sector.
source: blogs.ft.com
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Roche Allies with MGH and Harvard to Develop Stem Cell-Derived Cell Lines for Drug Discovery
Last Updated on Wednesday, 12 May 2010 01:26 Written by Editor Wednesday, 12 May 2010 01:26
Roche is teaming up with the Massachusetts General Hospital and Harvard University to develop new stem cell-based cell lines as disease models for early drug candidate testing. The 3–5 year partnership will initially focus on metabolic disorders and cardiovascular disease and will expand to cover a range of other diseases.
The collaboration aims to develop cell lines that can be used to evaluate the potential efficacy, safety, and toxicology profiles of new drugs pulled from Roche’s compound library. The company says that the cell lines will be derived from the tissues of both healthy volunteers and patients with a range of diseases.
Roche will provide research funding over the term of the agreement and will have access to cell lines, protocols, data, and materials. The firm will also pay clinical development milestones for drug candidates discovered through stem cell disease models.
The ultimate goal is to use stem cells for discovering new treatment approaches and bridging the gap between the laboratory and the clinic. “This technology is like having a disease in a test tube and being able to test possible effects of drugs on virtual patients—translational medicine at its best,†states Jacques Garaud, global head of pharma research and early development at Roche.
Roche has forged a number of collaborations focused on evaluating stem cell-based approaches for drug discovery. In June 2009, the firm signed a €7.5 million (about $10.36 million), two-year collaboration with I-STEM (Institute for Stem Cell Therapy and Exploration of Monogenic Diseases) focused on the use of I-STEM’s neuronal stem cell proliferation technologies in the screening of Roche’s compounds for potential new candidates against neurodegenerative diseases.
In 2008, Roche partnered with U.K.-based stem cell consortium SC4SM (Stem Cells 4 Safer Medicines) to generate a repository of stem cells suitable for toxicology testing in high-throughput platforms. The initiative is being fund primarily by the U.K. Government, with Roche and two other pharmaceutical companies also contributing. During the same year the firm signed an agreement with Cellular Dynamics to test a number of its drug compounds for cardiotoxicity.
source: genengnews.com
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Eli Lilly and GlaxoSmithKline: A Tale of Two Different Pharmas
Last Updated on Saturday, 24 July 2010 04:09 Written by Editor Wednesday, 12 May 2010 01:10
New models for drug development, especially in big pharma, are being experimented by different companies. Eli Lilly (LLY) and GlaxoSmithKline (GSK) have two different models. These models do not throw out the old ones – but do offer additional routes going forward.
Lilly has a Phenotypic Drug Discover Initiative, (or PD2), launched in 2009. Lilly solicits compounds from other companies so long as they are in certain therapeutic areas (oncology, diabetes, osteoporosis, and Alzheimer’s Disease). Compound structures are sent to Lilly electronically where they are evaluated using modeling and simulation. If the compound passes the screen, the physical compound is sent to Lilly for further testing. If the compound passes the physical test, the fun begins.
All testing by Lilly is free and IP remains with the originating company or institution. What Lilly gets in return is the first right to exclusively negotiate an agreement. If talks break down, the originator keeps all the data generated by Lilly.
Having had some personal experience through my biotechnology company (IMC Biotechnology), I think this is a very interesting approach. We submitted 9 compounds to Lilly and one of them went through the screening process. The software had some minor glitches but the Lilly representatives were very helpful in addressing those glitches.
I think this is a great way for Lilly to expand its repertoire of compounds beyond those invented by its chemists. Certainly one way of going beyond the NIH (not invented here) syndrome.
GSK has come up with an opposite approach where it is offering its library of compounds to researchers in a certain therapeutic area (under-served tropical diseases). For example, it is offering 13,500 compounds that appear to work in malaria. GSK will let other scientists try to develop malaria drugs — free from royalties or other payments to GSK. They were narrowed down from more than 2 million compounds.
More unusual is its open lab project. GSK plans to give up to 60 outside scientists from around the globe access to what it called the “Open Lab,” at an existing company research lab in Spain. Researchers from universities, foundations, etc will be able to use the facilities to try to develop new medicines for diseases plaguing poor countries.
GSK is to start a foundation to fund research and idea sharing, kicking in $8 million initially. It also plans to work with the Emory Institute for Drug Discovery. I have worked a bit with the Emory Institute of Drug Discovery and know they have an excellent drug development team, but have not learnt anything from them about what their exact role in this project is going to be.
While a small fraction of overall R&D efforts, it nevertheless is a significant departure from business as usual. And while GSK does not expect to get royalties, the halo effect, especially with health care reform in the spotlight, cannot be neglected. One could criticize GSK in pointing out that the company does not have much to lose by sharing data in neglected diseases – and that it is not doing so in the more lucrative markets such as oncology. But I doubt that the millions of patients suffering from malaria and TB will support such criticism. New models for drug development, especially in big pharma, are being experimented by different companies. Eli Lilly and GlaxoSmithKline have two different models. These models do not throw out the old ones – but do offer additional routes going forward.
So the two companies have differing strategies that actually could be quite synergistic. Maybe it is time to pay the ultimate compliment and copy each other.
source: seekingalpha.com
Posted under Business and Investment, Collaborations, Compound Screening, Discoveries, Innovations and Patents, Press Releases, Research Projects | Comments Off
Scientists Create New Way to Screen Libraries of 10 Million or More Compounds
Last Updated on Wednesday, 12 May 2010 12:53 Written by Editor Wednesday, 12 May 2010 12:53
The search for new drug compounds is probably worse than looking for a needle in a haystack because scientists are limited in the size of the haystacks they can rummage through — time and money make it virtually impossible to screen or search through super-large libraries of potential compounds. This is a serious problem, because there is enormous interest in identifying synthetic molecules that bind to proteins for applications in drug discovery, biology, and proteomics, and larger libraries should mean higher odds of success.But large libraries come with large problems. Because even compounds with only modest affinity (binding to the target protein receptor with less force than those with high affinity) are usually marked as hits, researchers often end up with several hundred of them and, because of practical constraints involving time and money, no easy way to determine which might be the highest affinity or best compound to serve as a starting point to design a drug. These limitations and others have drastically blunted the use of very large libraries — monster libraries — in binding assays.
Now, in research published in the most recent issue of the journal Chemistry & Biology, Tom Kodadek, a professor at The Scripps Research Institute’s Florida campus, and his colleagues at Scripps Florida and the University of Texas Southwestern Medical Center have devised an innovative new way to solve this longstanding problem.
“Current methods severely limit the size of the libraries you can screen,” said Kodadek. “If you get 20 hits out of a 100,000 compound library, it’s feasible to re-synthesize each of those hits to test which are the most effective. But what if you want to screen 10 million compounds? It takes an impossible amount of time to re-synthesize promising compounds for further study. To find the most potent ligands, our new method stands head and shoulders over what is available to researchers today.”
Ligands are compounds that attach to proteins and alter their expression, potentially affecting a particular biomolecular activity, say, a protein pathway involved in a disease.
The new method displays millions of compounds on the surface of resin-based beads, each type of compound on a different bead. The hits are culled from the beads using a unique magnetic signature and then transferred to a microarray format — glass slides or silicon chips that can hold large numbers of compounds on their surface. The microarray format allows quantitative comparison of binding affinity that can be carried out without the need for tedious re-synthesis of many different compounds.
In the study, the team used mixed peptide/peptoid libraries — peptides make up proteins; peptoids are molecules closely related to, but more stable than peptides, making them more convenient for testing — but the method could be applied to any class of compound, according to Kodadek.
Changing the Paradigm
The Kodadek group’s method combines several different technical advances to enable this convenient and efficient screening.
These days, most active molecules are discovered through screening of two basic types. There are functional screens, in which small molecules are introduced into the wells of microtiter plates — flat plates with multiple wells that can reach as high as 9,600 — and tested individually for their ability to alter the activity of an enzyme. Alternatively, there are binding assays, an approach first developed for bead-displayed peptide libraries, where each bead displays many copies of a single molecule.
“Our new method for screening synthetic libraries and characterizing the resultant hits combines many of the features of bead library screening and microarray-based analysis in a seamless fashion,” Kodadek said. “The new technique uses several million beads, each of which displays a unique ligand — theoretically as many as 64 million compounds. The target protein has an antibody attached to it that is covered with iron oxide particles — magnetic dust. If the peptoid ligand is a legitimate ligand, and attaches to the protein, we can pull it from the mass by using a magnetized centrifuge.”
The selected compounds are then removed from the beads through a unique cleaving process and attached to glass microarray slides. These arrays are mixed with different concentrations of the target protein, allowing the affinity strength of each compound on the array to be determined quickly and efficiently.
“This technology is relevant to custom libraries that are produced on beads,” Kodadek said. “Right now, that probably constitutes five percent of screening going on. My guess, however, is that ratio will change once researchers begin to adopt this new method.”
Adoption of this new technique will take time and something of a paradigm shift, Kodadek notes. The new screening technology monitors binding of the bead-immobilized molecule to the target protein; currently, the most widely used high-throughput screens monitor function of the compound. In addition, not all laboratories currently have the equipment and expertise necessary to make microarrays of small molecules.
“I think our method can revolutionize medicinal chemistry,” said Kodadek, “but this is only the first step.”
source: sciencedaily.com
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New compounds may help develop drugs for degenerative nerve diseases
Last Updated on Wednesday, 12 May 2010 12:52 Written by Editor Wednesday, 12 May 2010 12:52
Scientists at Duke University Medical Centre have discovered certain compounds that could lead to promising new drugs for degenerative nerve diseases, such as Huntington’s disease, Alzheimer’s disease and Parkinson’s disease.
Misfolded proteins in nerve cells (neurons) are a common factor in all of these diseases.
These new compounds improve a cell’s ability to properly “fold†proteins.
It activates a master regulator to increase the supply of “protein chaperone†molecules that help fold proteins properly.
The scientists further explored one of the candidate molecules to activate the master regulator of chaperone gene expression, Heat Shock Factor 1 (HSF1), to learn whether it would work in model systems of Huntington’s disease, a devastating neurodegenerative disease of protein misfolding.
They were able to show that the molecule stimulated protein chaperones in cells and in an animal system.
The damage to early-state rat neurons was much lower in cells pre-treated with the HSF1 activator, and damage to the neurons of fruit flies that had a Huntington’s-like disorder was also greatly reduced.
The study provides a new approach to address the root cause of these diseases – protein misfolding.
“The advantage of our screen is that it identifies molecules that can elevate the levels of chaperones without inducing cellular stress and that don’t inhibit a key protein chaperone called Hsp90 that is needed for cells to function normally,†said senior author Dennis J. Thiele, Ph.D., Professor of Pharmacology and Cancer Biology.
“We found a creative way to identify new molecules that can activate the body’s natural protein folding machinery,†he added.
Lead author Daniel Neef, Ph.D., says they used genetically altered yeast to find compounds that might aid chaperone development.
The study appears online in PLoS Biology. (ANI)
Posted under Alzheimer's disease, Compound Screening, Press Releases | Comments Off
New class of brain-protecting drugs emerging
Last Updated on Wednesday, 12 May 2010 12:51 Written by Editor Wednesday, 12 May 2010 12:51
Researchers have identified a compound that mimics one of the brain’s own growth factors and can protect brain cells against damage in several animal models of neurological disease.
7,8-dihydroxyflavone is a member of the flavonoid family of chemicals, which are abundant in fruits and vegetables. The compound’s selective effects suggest that it could be the founder of a new class of brain-protecting drugs.
The results were published online this week in the Proceedings of the National Academy of Sciences.
Investigators at Emory University School of Medicine, led by Keqiang Ye, PhD, associate professor of pathology and laboratory medicine, were searching for a way to mimic a protein found in the brain called BDNF (brain-derived neurotrophic factor).
“BDNF has been studied extensively for its ability to protect neurons vulnerable to degeneration in several diseases, such as ALS, Parkinson’s and Alzheimer’s disease,” Ye says. “The trouble with BDNF is one of delivery. It’s a protein, so it can’t cross the blood-brain barrier and degrades quickly.”
Working with Ye, postdoctoral fellow Sung-Wuk Jang sifted through a library of chemicals to find those that could stimulate one of the proteins on the surfaces of neurons that BDNF binds to. They could show that 7,8-dihydroxyflavone sends survival signals to brain cells by pulling together two TrkB receiver-dish molecules, just like BDNF does.
Moreover, it is active in the brain when injected into the body cavity, meaning that it can cross the blood-brain barrier. Ye says many experimental “neuroprotectant” drugs have been unsuccessful in clinical trials for diseases such as stroke and Parkinson’s over the last decade.
“What’s different is this is a new pathway, offering us new opportunities,” he says. “This is the first molecule we’ve found that specifically triggers TrkB.”
7,8-dihydroxyflavone could partially prevent the death of neurons in experimental models of three neurological diseases:
- Seizure: Mice treated with the stimulant kainic acid
- Stroke: Loss of blood flow induced in mice by blocking a cerebral artery
- Parkinson’s disease: Mice treated with a toxin that kills the same neurons affected by Parkinson’s
To show that the effects of 7,8-dihydroxyflavone depended on TrkB, the authors used mice with a modified TrkB gene, which makes their neurons vulnerable to a chemical that is not otherwise toxic. That chemical could inhibit the effects of 7,8-dihydroxyflavone.
7,8-dihydroxyflavone is a member of a family of antioxidant compounds naturally found in foods ranging from cherries to soybeans. Tests in animals indicate that the compound has low chronic toxicity, Ye says. In clinical trials, BDNF itself can have side effects such as sensory alterations, weight loss or nausea.
“It is likely that many people take in small amounts of 7,8-dihydroxyflavone in their diets,” Ye says. “But drinking green tea or eating apples doesn’t give you enough for a sustained effect.”
In the initial screening process, several flavonoid compounds had similar properties to 7,8-dihydroxyflavone. Ye says his laboratory has already identified compounds that are several times more active. The next step is more animal studies to choose compounds likely to have the best drug profiles: stable and non-toxic.
Manuel Yepes, MD, assistant professor of neurology at Emory University School of Medicine, and his colleagues performed the stroke model experiments. Gary Miller, PhD, associate professor in Emory’s Rollins School of Public Health, and his colleagues performed the Parkinson’s-simulating toxin experiments.
Investigators from Georgia State University, UCLA, and the Centers for Disease Control and Prevention contributed to the research, which was supported by the National Institutes of Health.
Ye is an inventor of novel technology related to this research. Under Emory policies, he is eligible to receive a portion of any royalties or fees received by Emory from this technology. These relationships have been reviewed and approved by Emory University in compliance with its conflict of interest policies.
S.W. Jang, X. Liu, M. Yepes, K.R. Shepherd, G.W. Miller, Y. Liu, W.D. Wilson, G. Xiao, B. Blanchi, Y.E. Sun, and K. Ye.
A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. PNAS ##,## (2010)
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‘Open Labs, Open Minds’ – GSK’s top executive lays out new initiatives
Last Updated on Thursday, 6 May 2010 03:13 Written by Editor Thursday, 6 May 2010 03:13
NEW YORK – Thank you. It’s a great pleasure to be here today. A year ago at Harvard Medical School, I set out a new vision for GSK, building on the important work we were doing, but going further.
In that speech, I set out how we are changing GSK – making the company more responsive, more flexible and more open. A company actively searching for new ways of working, for new partners. A company willing to take risks, committed to doing all it can to address neglected tropical diseases. A company driven by the values of integrity, transparency and respect for people. A company constantly earning the trust of society, not just by meeting society’s expectations, but exceeding them.
Because, if you don’t have the trust of the societies you serve, you don’t have a long-term, sustainable business model.
To earn that trust, you have to be able to change. You have to be flexible, engaged, willing to learn.
It’s partly why we created a new volunteering program, Pulse, last year. Under this program, we will send up to 100 people – key talent – to work for NGOs [non-government organizations] in poorer communities and societies. These individuals will come back with new ideas, energized and motivated, which will help us be better and more effective in the future.
But let’s be clear. It’s only by delivering sustainable financial growth overall that allows us to be an open, generous company. One in which we can sustainably address the enormous challenges associated with neglected tropical diseases.
Reinvesting 20 percent of our profits from the Least Developed Countries back into those same countries, as I set out in my Harvard speech, is sustainable. It gives us the motive to grow our business and gives communities the assurance of a long-term funding commitment – not just funding for next year, but the year after that and the one after that.
It’s a win-win.
This profit is invested in projects to improve health care for people living with neglected diseases, such as malaria.
Just today, we announced four new projects under our Africa Malaria Partnership – working with NGOs in communities in Tanzania, Ghana, Nigeria and Kenya to reduce malaria at the community level.
It would be easy to say the challenges the Least Developed Countries face are too difficult to tackle.
But that is not the sort of company I want GSK to be, nor is it the sort of company our employees want to work for.
I have worked for this company for some 25 years. During that time, I have had long stints in Africa and Asia where I have seen what a difference our drugs can make, enabling many millions of people to live longer and healthier lives.
But I believe we can do more to help. However, given the scale of the problem, we can only do it in partnership.
So let me give you a flavor of how we are continuing to change and how, by adopting a more “Open Innovation†agenda, GSK is adapting its business model to find new solutions to neglected tropical diseases.
Open Labs, Open Minds – Three Interlinked Strategies
The most urgent need in the fight against neglected tropical diseases is the need for new and better medicines and vaccines. For that we need to think differently about how we do R&D.
And given the scale of the task we all face, that means finding new ways of industry, academia, NGOs and governments working together.
We are calling this the “Open Innovation†agenda. And it has three parts.
The first is greater flexibility around intellectual property.
The second is creating new broad-based partnerships, where researchers have access to our industrial scale expertise, processes, facilities and infrastructure, not just our “know how†or IP.
Third – and perhaps most interesting – is access to new compounds. Let me explain these three in more detail.
Being more flexible with our intellectual property.
Last year we announced that we would grant access to 800 patents and patent applications, commonly known as a “patent pool,” for researchers working in the field of neglected tropical diseases in the Least Developed Countries.
This was never meant to be a “GSK pool,†so I am delighted to say that BIO Ventures for Global Health has agreed to take over the administration of the pool.
When we announced our commitment, we should have called it a Proprietary Knowledge Pool because so much more than just patents are included, because we also said we would be give access to our general “know howâ€.
In fact, access to “know how†looks like being the most interesting aspect for other researchers.
Last July, we were excited to announce that Alnylam was the first company join us in adding IP to the pool. Just last week, we signed two memoranda of understanding – one with the Emory University Institute for Drug Discovery and another with iThemba Pharmaceuticals, a company based in South Africa, working on TB, with financial help from the South African government. Both agreements will give these organizations access to our “know howâ€.
Sometimes, though, there is a need for a deeper, more broad-based partnership, where access to our industrial scale expertise, processes, facilities and infrastructure, not just our “know how,†could make a difference to a project.
That is why the second element of our open innovation strategy is the creation of a new concept called the “Open Lab,†which will be part of our dedicated diseases of the developing world research center in Tres Cantos,Spain.
In the “Open Lab,†we will create capacity for up to 60 independent researchers to come and pursue their own projects as part of a drug discovery team, allowing them to tap into our expertise, facilities, knowledge and industrial-scale infrastructure.
In addition to the resources and benefits-in-kind we are putting into this project, we will also set up a not-for-profit foundation, with seed funding from GSK of $8 million initially, to help fund these research projects.
The important thing here is that we are not generating the ideas or the projects to work on. Rather, we are letting universities, not-for-profit partnerships, research institutes come to us with their projects and getting them to set out what they think we can do to help them. We will soon announce the first two organizations that will come to the “Open Lab.â€
The process of drug discovery is one that involves small scientific understandings to build up a story of how an enzyme might be critical to a disease developing or why one chemical might prevent that enzyme.
What anyone in the field of neglected tropical diseases will tell you is that we need more of these scientific discoveries – and we need new leads.
That is why the third element of our open innovation strategy is perhaps the most interesting.
This element involves opening up access to our compounds.
Malaria remains a huge challenge, and it’s a disease area we, GSK, have extensive expertise.
So we have spent the last 12 months screening 2 million molecules in our compound library for reactions to the malaria parasite P. falciparum, the deadliest form of malaria found primarily in sub-Saharan Africa. This exercise has yielded more than 13,500 “hits†that inhibited the parasite.
It took five people working in a special biohazard unit a year to screen the 2 million compounds in our library because it had to be done by hand, given the dangers of working with such a deadly parasite. Normally, a screening can be automated and takes eight to 10 weeks. This exercise was on a totally different scale.
Today, I am pleased to announce that we are committing to make these 13,500 compounds, their chemical structures and associated assay data, freely available to the public on leading scientific Web sites.
We hope this will encourage further research by the scientific community on the compounds and bring more brilliant minds to bear on this challenging problem. We believe that we are the first company to make such comprehensive data available.
Taken together – making the compounds available, granting access to our patents and know-how and creating the “Open Lab†– our aim is to encourage new discoveries and encourage others to work with us in the same spirit of open innovation.
The World’s First Malaria Vaccine
Let me conclude on a different but related issue and talk about the importance of vaccines in the developing countries. GSK is one of the world’s largest suppliers of vaccines. Eighty percent of all the vaccine we produce goes to developing countries.
Forty percent of all the vaccine we produce is supplied to GAVI. And over the past year, we became the first company to have WHO pre-qualified vaccines for pneumococcal disease, rotavirus and H1N1 pandemic flu.
Pneumococcal disease is a great example of partnership. GSK is likely to be the first company to supply the $1.5 billion Advanced Market Commitment (AMC). The AMC is the largest financing mechanism ever designed for a single vaccine and will dramatically increase sustainable access to pneumococcal vaccines with prices at a fraction of the cost paid by industrialized nations.
We are also, importantly, on the cusp of completing the world’s first malaria vaccine, which is now in pivotal Phase 3 trials in seven African countries. Of course, we don’t actually have a registered vaccine yet, and we are in no way taking anything for granted.
But that doesn’t mean we shouldn’t be thinking now about how we ensure this vaccine, should it make it, gets to all those that could benefit from it. Each time we have a new vaccine, we try to ensure the widest possible access by using tiered pricing, where the poorest countries pay the least. As a result, vaccines in the world’s poorest countries are typically a fifth or less of the price in industrialized countries.
So far, GSK has invested $300 million in R&D for this vaccine. Our partner, PATH Malaria Vaccine Initiative (MVI), has invested a further $200 million.
The dilemma we face is this: Unlike virtually every other vaccine, there is no rich market for our potential malaria vaccine. Tiered pricing simply doesn’t apply. So we cannot apply our normal model. It’s a unique problem and requires a unique solution, one that is sustainable and incorporates responsible pricing.
Let me describe the principles of how we will price this vaccine.
First, it must be sustainable to allow for continued investment in high-quality manufacture and follow-on R&D.
Second, we must also ensure that we do not do anything that would discourage other companies from entering into this field. If we set a precedent of not-for-profit, we could discourage others from doing research into malaria or other neglected tropical diseases.
We want to avoid that, but we want to be responsible, too. That’s why what we will do is set a price that covers our costs and generates a small return. A small return, all of which will be plowed back into R&D for next-generation malaria vaccines and vaccines against other neglected diseases. In addition to this price commitment, we are also committed to donating at least 12.5 million doses of vaccine to PATH.
Whatever the price, what we need is a partnership with donors and recipient countries to ensure access to all those that could benefit. We should be looking now to build on the fine example of the AMC for pneumococcal vaccination.
Conclusion
GSK is ready and willing to play its part in tackling global public health problems. Whether we’re sharing our compound library or making the world’s first malaria vaccine accessible, our goal is the same – to find tailor-made, targeted solutions to specific problems. One size really doesn’t fit all. We are evolving, becoming more open and finding new ways of working with others. This is our “open innovation†agenda.
Thank you for listening.
source: localtechwire.com
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An Emerald in the Rough
Last Updated on Thursday, 6 May 2010 03:10 Written by Editor Thursday, 6 May 2010 03:10
Late last year, scientists at Emerald BioStructures, located on Bainbridge Island just across the Puget Sound from downtown Seattle, experienced the bittersweet ride that so often characterizes the drug discovery business. In August 2009, a team led by CEO Lance Stewart published a major paper outlining the application of a Fragments of Life (FOL) drug discovery approach to help identify an exciting small-molecule drug candidate, DG051, in the Journal of Medicinal Chemistry. But publication came just a few months before Emerald severed ties with deCODE genetics after the Icelandic firm filed for bankruptcy in November (the company was formerly deCODE biostructures) and was acquired by Beryllium LLC.
Newly independent, Stewart has the goal of expanding its drug discovery services in the field of gene-to-structure research. Emerald bills itself as “the largest gene-to-structure CRO in the U.S.†One of its success stories was the development of DG051, one of two drug candidates it helped deCODE to identify. DG051 has completed Phase IIa studies, and the second drug candidate, DG071, is approved for entry into Phase I safety studies.
The DG051 story is remarkable for the speed with which deCODE’s biologists and chemists and Emerald’s structural biologists sped from target identification to IND in just 2.5 years, which might be a record. Yes, there were some fortuitous bounces along the way, but Stewart believes his high-throughput crystallography approach provides an attractive alternative to conventional high-throughput screening (HTS) techniques. It is, to his knowledge, “the first example of a human genomics target discovery that was followed up by a gene-to-clinic paradigm enabled by a fragment-based drug discovery effort.â€
deCODE’s strength was using genetic mapping studies to identify at-risk haplotypes for a host of common diseases. Several years ago, studies identified two genes in the leukotriene biosynthetic pathway that were incriminated in myocardial infarction. In January 2006, deCODE published a report that markers in the gene for LTA4H (leukotriene A4 hydrolase) were associated with increased risk of myocardial infarction, particularly in African Americans. After deCODE confirmed that those at-risk haplotypes were associated with higher levels of leukotriene B4, it targeted LTA4H as a viable drug target, bringing to bear the full capabilities of structure-based drug design (SBDD) and fragment lead identification, in a full-force effort to identify leads as quickly as possible.
By August 2006, DG051 was in Phase I clinical trials. “As far as we know, this molecule is the furthest along in a true genetic-underpinning, SBDD approach,†says Stewart. As of the end of 2009, DG051 had finished Phase 2A. Presently, the DG051 asset is tied up in deCODE’s bankruptcy proceedings.
Among the keys to identifying and developing DG051 so quickly was a fully integrated organization that saved a lot of time and money with integrated process chemistry, analytical chemistry and ADME-tox efforts. It wasn’t exactly under one roof—deCODE’s facilities were split between Seattle (now Emerald BioStructures) and Chicago (deCODE chemistry)—but that was a minor inconvenience. Stewart’s high-throughput crystallography operation dovetailed neatly with deCODE chemistry’s structure-based drug design, managed by president Alex Kiselyov.
When work began, there was little crystal structure data on LTA4H and only a few known inhibitors (from Searle). In all, Stewart’s group solved about 50 crystal structures, focusing on higher resolution, improved crystallization conditions, and structures with bound ligands. The goal, said Stewart, was “to make 100% sure we understood how fragments would interact with the target. We wanted to identify new chemotypes that could inspire chemistry on LTA4H.â€
An important in-house advantage for the crystallization work was software called Gene Composer, which is used to design and optimize the codon usage in the gene depending on the nucleotide bias of the expression system. “When you’re doing X-ray crystallography, you’re doing a lot of protein engineering, and so you’re better off synthesizing the gene,†says Stewart. “So you may as well tweak and engineer the overall molecule.â€
Synthesize This
While Stewart’s team was crystallizing the target, Kiselyov was leading the effort to identify the lead. “We were living the paradigm of moving therapeutic discoveries from gene to clinic,†says Kiselyov. Seeing DG051 finally reach the market would be “the key validation of this approach.†DG051 is actually 4-[(2S)-2-{[4-(4-Chlorophenoxy)phenoxy]methyl}-1-pyrrolidinyl]butanoic acid (See, Journal of Medicinal Chemistry. 2009 Dec 1).
Emerald used its FOL library of ~1,500 small molecules to initiate discovery of the DG051 drug candidate using high-throughput crystallography, rather than use the traditional funnel of HTS to screen large multi-million compound libraries. “It’s a bit like a Lego kit; every component makes sense and fits this selection.â€
Emerald gets “the biggest bang by doing structural biology and in parallel, doing the small-molecule chemistry. If they’re timed right, then like a Reese’s peanut butter cup, they come together.†The key to successful crystallography, he adds, is to feed the protein a well designed ligand, which aids the visualization of the enzyme-ligand complex.
Stewart’s iterative crystallization process produced a much more dynamic picture of the protein target in the presence of candidate small molecules. That enabled Kiselyov to do both docking and optimization studies. “Small molecule fragments bound to the target provided us with critical structural information for the design. Think of them as tiny pieces of clay, a molecular 3-D imprint of a specific protein sites. Previous art in the field, for example research done at Berlex and Searle, was also considered in a final assembly of these fragments into the ultimate clinical candidate, DG051.â€
“Instead of making thousands of compounds guiding us through the optimization process, synthesizing a matrix of about 500 molecules across four chemotypes was sufficient to identify a winner,†says Kiselyov. Notably, the deCODE team identified multiple chemotypes that occupied the buried active site of the target LTA4H enzyme. Fragments had to be lined up within three critical areas within the binding pocket—the catalytic zinc atom, a hydrophobic region, and a transitional kink or linker. “Since we identified the mode of binding and simultaneously optimized physiochemical and PKPD/tox parameters for our lead candidate, we didn’t even have to go to our backup. DG051 was good enough to push instantly from bench to a GMP production and clinic.†It took about 12 months from the initial structural biology efforts to finally settle on DG051.
One of the key observations was that the catalytic zinc atom liked to bind acetate, thus providing a hint regarding pharmacophore requirements for this portion of the enzyme. A rigid, prolinol derivative provided for a linker to combine a biaryl fragment with the acetate fragment culminating in DG051. Kiselyov’s team attempted various medicinal chemistry modifications, but most of them worsened the toxicology or metabolic properties of the molecule. “It’s almost like nature itself guided us and told us do not do silly things with this molecule,†he said. DG051 had outstanding specificity, with no HERG triggered toxicity. The molecule has very favorable drug-like properties including molecular weight, and production scaled nicely. Bioavailability was excellent in animal models and in human. The half-life was 9 hours, favoring a single daily clinical administration. There was also good evidence that DG051 affected levels of the key biomarker associated with the acute myocardial infarction and stroke.
From Genes 2 Drugs
DG051 is currently held up in Phase II trials. “We don’t know too many people who get molecules from scratch into the clinic in a safe way. Of course, efficacy is to be shown still, but we’d love to see them tried in phase 3,†said Stewart.
Another drug, DG071, did not progress as swiftly through development because it required some “heavy lifting†in structural biology, chemistry and enzymology. Additional crystallography information was required to picture the regulatory domains.
Stewart has seen upheavals in the market before. The predecessor to Emerald was a company called Medichem which acquired Emerald in 2000 and completed the last life science IPO as Medichem Life Sciences just before the 2001 market crash. In 2002, deCODE acquired Medichem and Emerald to run a hybrid business model, running contract research for multiple clients while executing a handful of drug discovery projects for itself.
So why was the development of DG051 so successful? Part of the answer was in the way the project was managed. Stewart says his group was driven by milestones and specified timelines. He says deCODE had a “gene to IND capability. We have goals and set timelines. We wanted an IND in two years… We wanted to meet those goals. When you put a number of shots on goal, in an integrated way, you don’t know when but you’ll catch a break somewhere.†Emerald did indeed catch a break—the acetate binding to catalytic zinc was deemed too good. “We still did more and more chemistry, thinking we could do better, but we didn’t need to do all that work.â€
Another critical factor at deCODE chemistry, says Kiselyov, was having the process chemists working closely with the medicinal chemists to jump into large-scale production. That helps rule out building blocks that are too expensive or commercially unavailable, and avoid the possibility of toxic impurities. In the event, deCODE chemistry was able to do just a 4-step synthesis from commercially available building blocks, and scale up production before the IND.
Stewart says the FOL collection creates new IP and the ability to identify new druggable sites, which in turn leads to selectivity. And with so many constructs, he could look at the same lead molecule in different protein environments as he considered the medicinal chemistry.
“I’m way too humble to say we’re the best in the field,†says Kiselyov. He quotes a phrase from Fiddler on the Roof: “We’re just trying to scratch a simple tune here.†It’s still the early stages of using fragment based crystallography for SBDD. “Whatever our fate, we’re somewhat monolithic,†says Kiselyov. “If we can take an IND, that would be ideal. deCODE has a drug candidate in DG051 that has completed Phase2A. That is what pharma is or will be looking for.â€
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Eiger BioPharmaceuticals Announces Identification of a Novel Class of HCV Inhibitors
Last Updated on Thursday, 6 May 2010 03:10 Written by Editor Thursday, 6 May 2010 03:10
PALO ALTO, Calif., Jan. 20, 2010 /PRNewswire/ — Eiger BioPharmaceuticals, Inc., a biotechnology company developing antiviral therapies, announced today the publication of research from the labs of Stanford scientist and Eiger Founder, Dr. Jeffrey Glenn, M.D., Ph.D. and colleagues entitled, “Identification of a Novel Class of HCV Inhibitors”. Â Published in the January 20th edition of Science and Translational Medicine, the research validates a domain, termed 4BAH2, within the non-structural protein (NS4B) of the HCV genome, as essential for HCV replication and describes the development of a high-throughput screen leading to the identification of small molecule inhibitors of 4BAH2.
“The 4BAH2 is the second new domain within NS4B now proven necessary and essential for HCV replication, and which has been shown to be susceptible to pharmacologic inhibition. Â Eiger is developing small molecule inhibitors of both NS4B-RNA binding and small molecule inhibitors of NS4B-AH2, each of which has significant activity alone and significant synergy when combined,” said David Cory, President and CEO of Eiger. “Inhibiting these NS4B functions represents an exciting new approach toward developing new classes of virus-specific agents to treat HCV.”
“The discovery of a new class of HCV inhibitors against a novel target that is described in this paper paves the way for the development of novel anti-HCV strategies. This is of particular benefit because, like AIDS and tuberculosis, future effective therapy for HCV is expected to require a cocktail of several independent classes of drugs, each designed against a different viral target. Â As such, the types of inhibitors described in this paper represent ideal components of future anti-HCV drug cocktails,” said Jeffrey Glenn, M.D., Ph.D., Founder of Eiger. Â ”I am particularly excited to be working with the Eiger team because they have proven their ability to rapidly develop potent derivatives of the initial compounds described in my lab, and to efficiently move leads to the clinic.”
About 4BAH2
Representing a second target of interest to Eiger within NS4B, 4BAH2 has been genetically-validated and consists of a conserved amphipathic helix (AH) essential for viral genome replication. 4BAH2 has a dramatic specific biochemical activity of promoting the aggregation of lipid vesicles, with likely relevance to the establishment of the membranous web, the site of HCV replication. Â This biochemical activity was leveraged into a new high throughput screening assay for pharmacologic inhibitors of 4BAH2 function. Â Analysis of these inhibitors reveals a mechanism of action involving inhibition of 4BAH2 induced vesicle aggregation. Â Eiger has developed a next generation series of potent 4BAH2 inhibitors that are highly active as single agents against HCV, and highly synergistic when combined with the NS4B-RNA inhibitor, clemizole.
About Eiger BioPharmaceuticals, Inc. www.eigerbio.com
Eiger is focused on the discovery and development of new antiviral agents against novel targets for the treatment of hepatitis virus infections. Eiger’s pipeline includes repurposed clinical stage therapeutic agents as well as preclinical NCEs from discovery that exhibit antiviral activity against Hepatitis C, Hepatitis D, and other viruses. Eiger investors include InterWest Partners www.interwest.com and Vivo Ventures www.vivoventures.com.
source: prnewswire.com
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A New Approach To Cancer Drug Development
Last Updated on Thursday, 6 May 2010 03:08 Written by Editor Thursday, 6 May 2010 03:08
Dr. Nick recently posted a blog entry describing the need for a change to the approach used to develop to new cancer therapeutics. Echoing a point made by Dr. Stephen Neidle (Dir. of Cancer Drug Development at the University of London), he says that most of the low-hanging fruit has been harvested. During the early part of the last decade drug discovery companies were able to use the knowledge gained from the Human Genome Project to understand drug targets better, and develop more targeted therapeutics. Companies doing Structure-Based Drug Discovery, crystalize the target protein, design a small molecule that best fits the binding pocket and after lots of screening and preclinical assays, release the results to a development partner to take it through clinical trials.
The problem with this approach is that most cancers are multigenic in nature. Hematopoeitic cancers like Chronic Myelogenous Leukemia are the exceptions and constitute the low-hanging fruit mentioned earlier because you can modulate a single target and get an effective outcome. Most solid tumor-forming cancers though are the result of mutations in a number of different key cellular processes: Cell-cycle disruption, apoptosis, proliferation, and metastasis
It’s like having a chorus of singers, where a few key choristers are singing off-key and leading neighboring choristers astray.  As Dr. Nick’s article (and other similar articles) have indicated, the pharmaceutical industry needs to focus on treating the disease, not simply identifying and addressing single targets. Ultimately, as a physician you want to modify the behaviour of those choristers and get the patient back on track. And thus single-target therapeutic approaches aren’t going to be very successful, especially in cancers that are asymptomatic until their latter stages. On average, 97% of pancreatic cancer patients diagnosed within a given year will die within a few months of diagnosis.
The current standard of care is Gemcitabine (which is as ineffective now, as it was 13 years ago when my mother and grandmother were both diagnosed). If we are to see some real changes in the way pancreatic cancer is treated, it will be because companies are willing to change the way in which new cancer drugs are developed. Imagine for a moment that you are a drug developer working on new cancer therapeutics. You’ve found a compound that could help address metastasis. Using deep sequencing, you know what variations of you target are addressed by the compound, and therefore what patients would benefit most from the compound. You also know what other mutations are common in DNA repair, proliferation and other cellular processes. And along with those mutations, you have the screening data for those compounds. So you know the best combination of drugs that will help the patient. You can then design smaller more focused trials around a particular set of common mutations. Mutations that you can easily test for with a SNP panel. This increases your chance of success, and also improves the chances of survival for the patient.
And this brings us to another problem with drug trials. The purpose of Phase II and Phase III trials are to establish the efficacy of the new compound. And the way this is currently measured is by analyzing the compound in case-control studies, or in comparative drug studies. But as we’ve seen, there are multiple processes at work in cancer, and these processes are not being addressed during the course of the trials. These trials help answer whether a compound is more or less effective than the current standard of care but they don’t help us establish is what combination of drugs is most effective. These types of combinatorial studies need to be standard operating procedure when creating new trials. Because at the end of the trial you don’t want to have to tell the patient’s family that “we fixed those off key sopranos, but the patient still died.”
source: jroller.com
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Fast Forward, Juvenile Diabetes Research Foundation and Axxam SpA Join Forces to Accelerate Development of Treatments for Multiple Sclerosis and Type 1 Diabetes
Last Updated on Thursday, 6 May 2010 02:46 Written by Editor Thursday, 6 May 2010 02:46
NEW YORK and MILAN, Italy, Jan. 19 /PRNewswire-USNewswire/ — Fast Forward, LLC, the commercial drug development arm of the National Multiple Sclerosis Society, and the Juvenile Diabetes Research Foundation (JDRF), the leader in research leading to a cure for type 1 diabetes in the world today announced a collaborative partnership with Axxam SpA — a leading company in conducting early-stage discovery research programs for the life science industry — to develop new treatments for two autoimmune diseases, multiple sclerosis (MS) and type 1 diabetes (T1D).
Under the terms of the agreement, Axxam will screen its extensive chemical library to identify compounds that can target specific ion channels in the immune system. Ion channels are tiny pores on the surface of immune cells that control the influx of charged particles and allow the cells to become activated to perform their natural surveillance and protection functions. Â Recent studies have found that immune cells in MS and T1D contain high levels of a specific ion channel, Kv1.3, and that the hyperactivity of this channel contributes to the dysfunction of the immune system in MS and T1D. Â If the initial research is successful, Axxam will have identified compounds that modulate Kv1.3 ion channel activities, and these will be further developed by the company as potential therapies for MS and T1D.
The agreement with Axxam is the first of its kind between cross-disciplinary patient advocacy organizations and represents a new frontier in which groups such as JDRF and Fast Forward ally to lessen the risk of drug discovery and accelerate the development of new therapies that can impact multi-disorders. Â ”We are pleased to partner with Axxam and JDRF to advance the development of new treatments for T1D and MS,” said Dr. Timothy Coetzee, President of Fast Forward. Â Adds Dr. Coetzee, “People with MS and T1D need more treatment options and the approach taken by Axxam holds great promise for both diseases.”
“Our partnership with Fast Forward and Axxam opens exciting new avenues for JDRF to speed the translation of basic research into drugs and treatments for type 1 diabetes,” said Alan J. Lewis, PhD, President and Chief Executive Officer of JDRF. “Research into the Kv1.3 ion channel has the potential to negate the autoimmune process causing type 1 diabetes and multiple sclerosis, which must be addressed to cure these diseases.”
“It’s rewarding for Axxam to be working with two world class non-profits dedicated to speeding new therapies to their constituencies,” said  Dr. Stefan Lohmer, Ph.D., Chairman and Chief Executive Officer of Axxam. “This collaboration recognizes the quality of our research in the challenging ion channels field and we hope to be on the cusp for developing potential new therapies for both type 1 diabetes and multiple sclerosis.”
About JDRF:
JDRF is the worldwide leader for research to cure type 1 diabetes. It sets the global agenda for diabetes research, and is the largest charitable funder and advocate of diabetes science worldwide.
The mission of JDRF is to find a cure for diabetes and its complications through the support of research. Type 1 diabetes is an autoimmune disease that strikes children and adults suddenly, and can be fatal. Until a cure is found, people with type 1 diabetes have to test their blood sugar and give themselves insulin injections multiple times or use a pump — each day, every day of their lives. And even with that intensive care, insulin is not a cure for diabetes, nor does it prevent its eventual and devastating complications, which may include kidney failure, blindness, heart disease, stroke, and amputation.
Since its founding in 1970 by parents of children with type 1 diabetes, JDRF has awarded more than $1.4 billion to diabetes research, including $101 million in FY2009. In FY2009, JDRF funded research projects in 22 countries throughout the world, including more than 40 human clinical trials.
About Fast Forward, LLC
Fast Forward, LLC is a nonprofit organization and critical initiative established by the National Multiple Sclerosis Society in order to accelerate the development of treatments for MS. Fast Forward will accomplish its mission by connecting university-based MS research with private-sector drug development and by funding small biotechnology/pharmaceutical companies to develop innovative new MS therapies and repurpose FDA-approved drugs as new treatments for MS. For more information visit: www.fastforward.org
About MS and the National Multiple Sclerosis Society
MS is a chronic, unpredictable neurological disease that affects the central nervous system. It is thought to be an autoimmune disorder, meaning the immune system incorrectly attacks healthy tissue. Symptoms may be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision. These problems may be permanent or may come and go. The National MS Society addresses the challenges of each person affected by MS by funding cutting-edge research, driving change through advocacy, facilitating professional education, collaborating with MS organizations around the world, and providing programs and services designed to help people with MS and their families move their lives forward. The Society is dedicated to achieving a world free of MS. Join the movement at  www.nationalMSsociety.org
About Axxam SpA
Axxam is a discovery company focused on research programs for different applications in the life science industry.  They are a privately owned biotech firm based at the San Raffaele Biomedical Science Park in Milan (Italy), with a team of about 60 highly skilled qualified people. Axxam began operations as an independent and privately owned company in November 2001, but its roots are built upon years of experience as part of the Bayer HealthCare, Research and Development organization.  The company performs a wide range of activities including assay development, high-throughput screening, compound profiling and hits to leads testing. In addition, Axxam conducts several discovery programs for selected targets which are carried out in partnership with other companies or non-profit organizations. For more information, please visit  www.axxam.com.
SOURCE Juvenile Diabetes Research Foundation
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Compounds that help protect nerve cells discovered by Duke team
Last Updated on Thursday, 6 May 2010 02:45 Written by Editor Thursday, 6 May 2010 02:45
DURHAM, N.C. – Scientists at Duke University Medical Center have found some compounds that improve a cell’s ability to properly “fold” proteins and could lead to promising drugs for degenerative nerve diseases, including Huntington’s disease, Alzheimer’s disease and Parkinson’s disease.
Misfolded proteins in nerve cells (neurons) are a common factor in all of these diseases. The Duke team has identified many new chemicals that activate a master regulator to increase the supply of “protein chaperone” molecules that help fold proteins properly.
The scientists further explored one of the candidate molecules to activate the master regulator of chaperone gene expression, Heat Shock Factor 1 (HSF1), to learn whether it would work in model systems of Huntington’s disease, a devastating neurodegenerative disease of protein misfolding.
They were able to show that the molecule stimulated protein chaperones in cells and in an animal system. The damage to early-state rat neurons was much lower in cells pre-treated with the HSF1 activator, and damage to the neurons of fruit flies that had a Huntington’s-like disorder was also greatly reduced.
Previous studies suggested that elevating the abundance of protein chaperones is effective in treating cell and animal models of Huntington’s and Parkinson’s diseases. This work provides a new approach to address the root cause of these diseases — protein misfolding. Earlier attempts had used heat shock and other approaches that stress a nerve cell in order to produce more chaperone molecules, but at a cost of damaging the cell to save it.
“The advantage of our screen is that it identifies molecules that can elevate the levels of chaperones without inducing cellular stress and that don’t inhibit a key protein chaperone called Hsp90 that is needed for cells to function normally,” said senior author Dennis J. Thiele, Ph.D., Professor of Pharmacology and Cancer Biology. “We found a creative way to identify new molecules that can activate the body’s natural protein folding machinery.”
The research was published in the Jan. 19 online issue of PLoS Biology.
Lead author Daniel Neef, Ph.D., says they used genetically altered yeast to find compounds that might aid chaperone development. The scientists took yeast with a deleted HSF1 (master regulator) gene and inserted the related human HSF1 gene. These yeast, however, still weren’t able to activate human HSF1 on their own, and in effect, died. They needed an additional molecule to make human HSF1 become active.
The team put these “humanized yeasts” into wells and started testing compounds that would provide the missing link. In several of the wells, if the compound worked, the yeast started multiplying. “Out of over 12,000 compounds tested from chemical libraries, about 50 compounds worked,” Neef said. The team decided to explore one of these compounds (HSF1A) in further experiments.
“The humanized yeast-based screening results in our study provide a way to identify new classes of small molecules, small enough to penetrate the blood-brain barrier to work in neurons, in flies as well as in humans,” Thiele said. “These small molecules may be effective therapies in neurodegenerative diseases caused by protein conformational disorders such as Huntington’s, Alzheimer’s and Parkinson’s disease.”
The scientists found that HSF1A could stimulate more protein chaperones and reduce the protein misfolding. They showed that adding a small amount of HSF1A to the developing rat neurons kept the proteins dissolved throughout the cell, rather than clumping visibly as speckled areas (as seen under microscopes).
“We enhanced the cells’ viability by four or five times by pre-treating them with this molecule,” Neef said. “Otherwise, the cells would have died.”
They used fruit flies with Huntington’s disease for experiments to prove that the principle would work in an animal. Adding HSF1A to the fly’s food produced more chaperone molecules in their neurons. This suggests that the molecule could travel from the fly’s stomach into its circulation and cross a barrier to the fly brain.
In the key experiment, the Huntington’s disease flies received either their usual food or food plus HSF1A. Those with untreated food developed eyes with dying photoreceptor neurons and lacking the normal red color. Those that ate HSF1A went on to have normal-colored eyes, indicating a repair had taken place, just by eating food laced with the promising compound.
source: eurekalert.org
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Open access drug discovery database launches with half a million compounds
Last Updated on Thursday, 6 May 2010 01:48 Written by Editor Thursday, 6 May 2010 01:48
ChEMBLdb, a vast online database of information on the properties and activities of drugs and drug-like small molecules and their targets, launches today with information on over half a million compounds. The data lie at the heart of translating information from the human genome into successful new drugs in the clinic.
The database is hosted by the European Molecular Biology Laboratory’s European Bioinformatics Institute (EMBL-EBI). It was transferred from biotech firm Galapagos NV in July 2008 through a £4.7 million Strategic Award from the Wellcome Trust.
ChEMBLdb is a unique resource because of its focus on drug discovery and its size: information on an additional 100 000 compounds has been added to the database for its launch, taking the number of small molecules to over 520 000, and it now contains over 2.4 million records of their effects on biological systems. The data include information about how small molecules bind to their targets, how these compounds affect cells and whole organisms, and information on the molecules’ absorption, distribution, metabolism, excretion and toxicity.
Dr John Overington, leader of the ChEMBL team at EMBL-EBI, said: “We hope ChEMBLdb will assist the translation of genomic-based insights into innovative drug therapies. We are pleased that there has already been big demand for ChEMBLdb data – not only from large pharmaceutical companies but also from academic institutions and small companies who will particularly benefit from free access to the data.”
The human genome sequence provided a molecular ‘parts list’ for a human being, comprising all the genes and proteins that are encoded by our genetic blueprint. In order to develop new medicines, it is important to catalogue how each of these ‘parts’ interacts with drugs and drug-like molecules. ChEMBLdb brings together information from the interface of the genome with chemistry into a set of ‘chemogenomic’ databases that can be used to help determine whether a particular molecule has the right properties to make an effective drug.
Professor Janet Thornton, Director of EMBL-EBI, said: “We are delighted to augment the biological data archived and served from EMBL-EBI with the ChEMBLdb resource. The database adds an important new capability to address the needs of the pharmaceutical and biotechnology industries, and provide the academic chemical biology communities with previously inaccessible data.”
Dr Alan Schafer, Director of Science Funding at the Wellcome Trust, said: “This unprecedented transfer of pharmaceutical data resources from the private sector to the public domain should have the greatest impact on researchers in academia and in small companies on limited budgets. ChEMBLdb will be a major resource of information for driving forward medicinal chemistry and drug development in the UK and internationally.”
The launch of ChEMBLdb is accompanied by the release of Kinase SARfari, an integrated resource of sequence, compound and screening data from a variety of sources for the protein kinases, a key family for drug discovery.
Image: Drug delivery capsules. Credit: Anna Tanczos, Wellcome Images
Contact
Craig Brierley
Senior Media Officer
Wellcome Trust
T +44 (0)20 7611 7329
E c.brierley@wellcome.ac.uk
Louisa Wright
Outreach Programme Project Leader
EMBL-EBI
T +44 (0)1223 494665
E louisa@ebi.ac.uk
Katrina Pavelin
Scientific Outreach Officer
EMBL-EBI
T +44 (0)1223 494452
E katrina@ebi.ac.uk
source; wellcome.ac.uk
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Kansas studies plants’ medicinal values
Last Updated on Thursday, 6 May 2010 11:55 Written by Editor Thursday, 6 May 2010 11:55
The snow on the ground keeps Lauren Ashman inside entering data about native plant species instead of out in the field. This is the dirty work of the $5 million Native Medicinal Plant Research Program.
Along with data entry, Ashman, junior from St. Louis, Mo., works on drying and putting the 10- to 20-pound bags of plant species in alphabetical order. Only then are they ready to go to the High Throughput Screening Lab at the Structural Biology Center on West Campus.
The project started Nov. 11, 2009, when two faculty members at the University received money from Heartland Plant Innovations, Inc., to study plants in the Kansas area. The Heartland Plant Innovations, Inc., branches from the Kansas Bioscience Authority, a center aimed at advancing Kansas’ leadership in bioscience.
Barbara Timmermann, a university distinguished professor in the Medicinal Chemistry Department, and Kelly Kindscher, associate scientist at the Kansas Biological Survey, will lead the research during the next five years.
In that time, the goal of the research is to gain credible findings and data on the local plants so various food and drug industries can understand the plants’ capabilities.
“There is a big interest in bringing business to Kansas,†Kindscher said. “The findings of this project could bring in herbal product to cosmetic or pet food companies.â€
Hayley Kilroy, graduate student from Cleveland, Ohio, said Native Americans and pioneers once used the native plants for medicinal purposes. Now that the University is looking at the plants for those uses again, it will help conserve the biodiversity of Kansas.
“Conservation is important,†Kilroy said, “but when you can make money through conserving, there is a lot more incentive for it.â€
The researchers face a long process of identifying, collecting and studying the plants for their medicinal uses and effectiveness. Kindscher and Timmermann said they were looking at hiring up to 12 new employees to handle maps, data and research.
Kindscher and students collected plants this summer from Douglas County and several areas of Western Kansas. The plants now sit in a lab waiting to be dried and cataloged.
“We go out in teams and gather all our plant material,†Kindscher said. “I love the field work.â€
In previous years, Kindscher and others collected plants for the main purpose of researching and replanting native prairie. But the grant has narrowed their focus to the medicinal uses of specific plants.
Quinn Long, doctoral student from Franklin County, Mo., said the team would collect multiple samples from different areas for each species. Then they can study how differences in location change what chemical compounds are present in a plant. Long said different stresses, such as drought, could increase medicinal compound.
Because the program started in late fall, Timmermann’s lab doesn’t have as many samples to study. However, that will change as spring arrives and more plants can be collected.
“It would be great if we found the next best cure,†Kindscher said. “But we are not directly focusing on that or the money.â€
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Proteins That Might Contribute to Memory Loss and Alzheimer’s Disease Identified
Last Updated on Thursday, 6 May 2010 11:53 Written by Editor Thursday, 6 May 2010 11:53
ScienceDaily (Jan. 17, 2010) — A scientific group led by the Translational Genomics Research Institute (TGen) have identified three kinases, or proteins, that dismantle connections within brain cells, which may lead to memory loss associated with Alzheimer’s disease.
These findings, the results of a multi-year TGen study, are published in this month’s edition of BMC Genomics in a paper titled: High-content siRNA screening of the kinome identifies kinases involved in Alzheimer’s disease-related tau hyperphosphorylation.The three kinases were found to cause a malfunction in tau, a protein critical to the formation of the microtubule bridges within brain cells, or neurons. These bridges support the synaptic connections that, like computer circuits, allow neurons to communicate with each other.
“The ultimate result of tau dysfunction is that neurons lose their connections to other neurons, and when neurons are no longer communicating, that has profound effects on cognition — the ability to think and reason,” said Dr. Travis Dunckley, an Associate Investigator in TGen’s Neurodegenerative Research Unit and the scientific paper’s senior author.
Tau performs a critical role in the brain by helping bind together microtubules, which are sub-cellular structures that create scaffolding in the neurons, allowing them to stretch out along bridges called axons. The axons support the synaptic, or chemical, connections with other neurons.
Under normal circumstances, kinases regulate tau by adding phosphates. This process, called tau phosphorylation, enables the microtubules to unbind and then bind again, allowing brain cells to connect and reconnect with other brain cells.
“That facilitates synaptic plasticity. It facilitates the ability of people to form new memories — to form new connections between different neurons — and maintain those memories. So, it’s an essential function,” Dr. Dunckley said.
However, sometimes the tau protein becomes hyperphosphorylated, a condition in which the tau creates neurofibrillary tangles, one of the signature indicators of Alzheimer’s.
“When tau protein is hyperphosphorylated, the microtubule comes apart — basically destroying that bridge — and the neurons can no longer communicate with each other,” Dr. Dunckley said.
TGen investigators created sophisticated tests to look at all 572 known and theoretical kinases within human cells. They identified 26 associated with the phosphorylation of tau. Of these 26, three of them — EIF2AK2, DYRK1A and AKAP13 — were found to cause hyperphosphorylation of tau, permanently dismantling the microtubule bridges.
“This paper shows, for the first time, these three kinases affect Alzheimer’s disease-relevant tau hyperphosphorylation, in which most of the tau protein is now driven into a permanently phosphorylated form,” Dr. Dunckley said.
Dr. Eric Reiman, clinical director of TGen’s Neurogenomics Division and executive director of the Banner Alzheimer’s Institute, explained that tau holds together the skeleton inside neurons. When phosphate molecules stick to tau proteins, the skeleton falls apart and the neurons begin to retract their synaptic branches and die, leading to memory loss and thinking problems.
In this study, researchers used a molecular tool called siRNA to screen the entire human genome, said Dr. Reiman, a co-author of the scientific paper. This tool enabled the TGen-led team to discover which proteins, when genetically turned off, prevent phosphate molecules from sticking to tau. The three kinases, or proteins, that appear to contribute to the formation of brain tangles, can now be targeted by protein-inhibitor drugs.
“This study used a powerful tool to discover three proteins that may be involved in tangle formation. If safe and well-tolerated tangle-busting medications can be developed, they offer great promise in the treatment of Alzheimer’s disease,” said Dr. Reiman, who also is Director of the Arizona Alzheimer’s Consortium.
The next step will be to identify drug compounds that can negate the effects of the three kinases linked to tau hyperphosphorylation.
“The reason that we did this study was to identify therapeutic targets for Alzheimer’s disease, whereby we could modify the progression of tau pathology,” Dr. Dunckley said. “This was a screen to identify what the relevant targets are. Now, we want to match those targets to treatments.”
TGen’s collaborators in the study included: the Department of Neurology at the Mayo Clinic in Jacksonville, Fla.; the Center for Alzheimer’s Research at the Sun Health Institute in Sun City, Ariz.; Banner Alzheimer’s Institute in Phoenix, Ariz.; the Department of Psychiatry at the University of Arizona; and the Arizona Alzheimer’s Consortium, a group of nine institutes that cooperatively study Alzheimer’s disease.
source: sciencedaily.com
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Sleep with the Fishes Zebrafish larvae are a surprisingly compatible stand-in for humans as researchers test the next generation of insomnia drugs.
Last Updated on Thursday, 6 May 2010 11:44 Written by Editor Thursday, 6 May 2010 11:44
There’s a new guinea pig in the search for sleep-related drugs: the zebrafish. Researchers at Harvard University have developed a screening tool that tests the effects of thousands of compounds on zebrafish behavior in an effort to discover new pathways that govern sleep. The research, published this week in the journal Science, may result in new drugs to treat insomnia and other sleep-related disorders.
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| Sleepy head: Harvard scientists are using zebrafish as a model to find drug candidates for insomnia and other sleep disorders. Pictured above is the head portion of a zebrafish larva. The zebrafish brain is labeled in green. Credit: Albert Pan and Alexander Schier |
Alexander Schier and his colleagues at Harvard developed an automated system to assess 60,000 distinct sleep-related behaviors in zebrafish, a tropical fish often used in scientific research. After screening 5,600 small molecules on the larvae, the team discovered 463 significant sleep-altering compounds, many of which have been known to have similar effects in humans.
“We didn’t expect as much conservation of the effects of drugs between humans and zebrafish,” says Schier, professor of molecular and cellular biology. “This was a proof of principle that many of the pathways found in humans are conserved in fish.”
Schier says such behavioral similarities may make zebrafish an ideal model for studying how and why humans sleep, mysteries that are largely unsolved. It’s still unclear what molecular mechanisms control sleep and wakefulness. Pinpointing these pathways, and finding drugs to block or promote them, is a major focus for many pharmaceutical companies–sleep drugs generate $7 billion in annual profits in the United States. However, the drug development process is tedious and expensive. Schier believes that testing drug candidates in zebrafish could be a cheap and straightforward alternative to conventional drug screening.
Typically, to test a drug, researchers first study its effects in cultured cells, looking to see if the drug binds successfully to a target receptor or molecule. They then advance the drug to animal experiments, testing behavioral effects in live subjects. But drugs that have certain effects in cultured cells often have unexpected side effects–or no effect–in a live animal.
“The advantage of zebrafish is that you can keep large numbers of animals in a very small space, and raise many, many animals relatively cheaply,” says Schier. Unlike flies and worms, which are often used in the early stages of pharmaceutical research, fish are vertebrates. “Much can be found in zebrafish that is relevant to mammals,” he says.
To screen the drugs, researchers pipetted single zebrafish larvae into a tiny well of a 96-well tray. Each well was injected with a drug, with one drug tested on 10 different larvae. They placed the tray in a recording chamber with infrared and white LED lights and a camera connected to computer software. After lining the tray up with a corresponding grid on the computer screen, researchers programmed the timing of light to simulate day and night. The camera recorded each fish’s activity over two days, and video tracking software plotted out each fish’s movements per second.
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| Z’s for zebrafish: Zebrafish larvae (above) are naturally transparent. Scientists hope to one day study the effects of sleep drugs on the brain and spinal cord, which can be seen in the image above as a long white structure stretching left to right. Credit: Albert Pan and Alexander Schier |
Using clustering algorithms, Schier and his colleagues grouped fish into 60,000 distinct behavioral profiles, depending on various constraints. “When you turn off the light, how often are they active? When they are inactive, how long? That’s what we observe in the fish,” says Schier. “You can measure many different parameters, and that allows you to profile different drugs.”
Anti-inflammatories, such as cytokines, nonsteroidal anti-inflammatory drugs, and cyclosporine, had a surprising effect. Normally, these drugs induce sleep when taken to combat infection such as the flu. However, Schier found that when given to normal, healthy zebrafish, these compounds, or immunomodulators, made fish more active during the day.
“In disease, immunomodulators have been implicated in sleep,” says Schier. “We propose that maybe there’s some baseline function for these immunomodulators during normal sleep and wake cycles.”
Such findings could help researchers identify new molecular players involved in sleep and wakefulness. Irina Zhdanova, associate professor of anatomy and neurobiology at Boston University Medical School, studies the physiological mechanisms of circadian rhythms and sleep in zebrafish. Zhdanova says there are many sleep-related drugs on the market with substantial side effects; these effects might be avoided with better screening tools.
“The huge scope of drugs tested [by Schier's group] shows that zebrafish-based tests can be effectively used to at least prescreen multiple classes of existing drugs and new candidate substances,” says Zhdanova. “[That is] certainly very helpful.”
In the future, Schier says, zebrafish could also be used as a model for testing drugs for human psychiatric diseases like schizophrenia and autism. The idea is to identify genes associated with the human disease, and try to engineer the same genetic defect in zebrafish. Researchers could then look for certain behavioral changes as a result, such as a fish’s sensitivity to touch, or its reaction to visual cues.
“Hopefully there would be a connection between the gene affected, and change in behavior, and one would try to correct the change in behavior by adding particular drugs,” says Schier. “That’s a bit science fiction at the moment, but it is possible.”
source:technologyreview.com
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Hunt for Dioxin Substitutes to Fight Autoimmune Diseases
Last Updated on Thursday, 6 May 2010 11:41 Written by Editor Thursday, 6 May 2010 11:41
(HealthNewsDigest.com) – CORVALLIS, Ore. – Scientists at Oregon State University are hunting for substitute chemicals for a toxic dioxin to fight diseases that are triggered by haywire immune systems attacking the body.
The dioxin, known as TCDD, has been shown to suppress the immune system in animals and prevent type 1 diabetes in mice. OSU researchers hypothesize that it could do the same in people. But they aren’t considering it as a treatment because it has produced bad side effects in animals and can cause chloracne, a disfiguring skin disease in humans.
Instead, they’re looking for safer alternatives that would function like TCDD, which is perhaps best-known for its presence in the jungle-decimating Agent Orange herbicide used during the Vietnam War.
If successful, the chemicals might be able to prevent and treat autoimmune diseases like rheumatoid arthritis, multiple sclerosis, psoriasis and type 1 diabetes.
“Immunosuppressive drugs are already used to treat these diseases, but they can create their own problems,” said Nancy Kerkvliet, an OSU immunotoxicologist who is helping conduct the research. “Consequently, the new way of thinking is to use a mixture of drugs at lower doses to reduce the side effects caused by higher dosages of individual drugs. Through our research, we’re hoping to discover new drugs that will expand the choices of drugs that can be used.”
To help with that effort, the American Recovery and Reinvestment Act of 2009 provided Kerkvliet and her team with $1.8 million.
Kerkvliet has been studying dioxins for three decades. She published a paper last year in the journal Immunotherapy that showed that in mice TCDD can prevent type 1 diabetes, which occurs when the immune system attacks the pancreas and kills the cells that produce insulin. The mice used in the study develop type 1 diabetes spontaneously because of genetic defects in their immune system. However, of the 12 mice that were treated with TCDD, none developed the disease. Eight of the 11 mice that weren’t treated with it developed diabetes by 28 weeks of age.
Kerkvliet said that TCDD’s effect on the immune system of mice works like this: First, it binds to a protein called the aryl hydrocarbon receptor (AhR) found inside a cell. The united TCDD and AhR then pass into the nucleus, latch onto DNA and turn certain genes on or off. Kerkvliet’s research suggests that this process produces regulatory T cells, which then shut down the immune system’s response. This then suppresses the development of diabetes, she said.
To help her find alternatives for TCDD, cancer biologist Siva Kolluri and his crew are screening 50,000 chemical compounds in search of ones that will bind to AhR and induce regulatory T cells. So far, they’ve tested about 5,000 in cell-based assays for their ability to activate AhR, Kolluri said.
“There have been some promising hits,” he said. “We need to make sure that they work only through this receptor. We also have to make sure they’re not toxic. We don’t want them to have any of the bad effects that TCDD has.”
Later, Kerkvliet and her team will test the compounds in mice to see if they prevent type 1 diabetes. If they do, Kerkvliet believes that it would be likely that they would also fight other autoimmune diseases because most of these diseases are also controlled by regulatory T cells. Of course, any chemicals that are successful in treating laboratory animals would eventually have to be studied in humans to see if the effects are the same.
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Science & Health > Chemistry > Zebrafish point the way Screening method finds new roles for drugs in sleeping, waking
Last Updated on Thursday, 6 May 2010 11:33 Written by Editor Thursday, 6 May 2010 11:33
A robust new technique for screening drugs’ effects on zebrafish behavior is pointing Harvard University scientists toward unexpected compounds and pathways that may govern sleep and wakefulness in humans.Among the scientists’ more intriguing findings, described in the journal Science, are that various anti-inflammatory agents in the immune system, long known to induce sleep during infection, may also shape normal sleep/wake cycles.
The new research identifies several compounds with surprising effects on sleep and wakefulness in zebrafish. But it also suggests that despite the evolutionary gap between zebrafish and mammals, they may be strikingly similar in the neurochemistry underlying their rest/wake cycles, meaning that these same compounds may prove effective in people.
“Many current drug discovery efforts rely on screening conducted outside the body,†said Alexander F. Schier, professor of molecular and cellular biology at Harvard. “Although such screens can be successful, they cannot recreate the complex neuroscience of entire organisms. These limitations are particularly acute for behavior-altering drugs, because brain activity cannot be modeled in a Petri dish or test tube.â€
Together with postdoctoral fellows Jason Rihel and David Prober, Schier and other collaborators used their automated screening technique to monitor sleep and wakefulness in zebrafish for two days following administration of 5,600 compounds, creating more than 60,000 distinct behavioral profiles. By applying clustering algorithms to organize the molecules, the researchers identified 463 drug candidates that significantly altered rest and wakefulness, many of which had not previously been known to have such effects.
“For instance, we found that a diverse set of anti-inflammatory compounds increased wakefulness during the day, with much less effect at night,†Schier said. “Although these compounds have long been known to promote sleep during infection, this is an indication that the molecules that regulate the immune system may also play a role in setting normal daytime activity levels.â€
Anti-inflammatory agents found to affect sleep/wake cycles included cytokines, nonsteroidal anti-inflammatory drugs, and the immunosuppressant cyclosporine. Schier and colleagues also found calcium channel inhibitors that increased rest with minimal effects on waking behavior and a class of potassium channel blockers found in a wide variety of drugs — including antimalarials, antipsychotics, and antihistamines — that selectively increased wakefulness at night without affecting total rest.
“Behavioral profiling reveals nuanced relationships between drugs and their targets,†Schier said. “It can characterize large classes of compounds and reveal differences in effectiveness, potential side effects, and combinatorial properties that might not otherwise be detected.â€
Schier and his colleagues plan to expand their zebrafish screening to include many more uncharacterized compounds and to assay behaviors that, in humans, are associated with psychiatric disorders.
Schier’s co-authors on the Science paper are Jason Rihel, David A. Prober, Anthony Arvanites, Kelvin Lam, Steven Zimmerman, Sumin Jang, and Lee L. Rubin, all at Harvard; Stephen J. Haggerty of the Broad Institute of Harvard and MIT and Massachusetts General Hospital (MGH); David Kokel of MGH; and Randall T. Peterson of the Broad Institute, MGH, and Harvard Medical School.
The work was funded by the Life Sciences Research Foundation, the Helen Hay Whitney Foundation, the National Institutes of Health, the Stanley Medical Research Institute, the Harvard Stem Cell Institute, and the McKnight Endowment Fund for Neuroscience.
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