Kerentech

Professor Andrew Loudon from the University of Manchester

Researchers funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Medical Research Council (MRC) have successfully used a drug to reset and restart the natural 24 hour body clock of mice in the lab.

The ability to do this in a mammal opens up the possibility of dealing with a range of human difficulties including some psychiatric disorders, jet lag and the health impacts of shift work, like obesity.

Research was led by Professor Andrew Loudon from the University of Manchester and Dr Mick Hastings of the MRC Laboratory of Molecular Biology in Cambridge, working with a multi-disciplinary team of scientists from Pfizer led by Dr Travis Wager, and was published in PNAS.

Professor Loudon said “It can be really devastating to our brains and bodies when something happens to disrupt the natural rhythm of our body clocks. This can be as a result of disease or as a consequence of jet lag or frequent changing between day and night shifts at work.

Professor Janet Allen, BBSRC Director of Research

Most living creatures and plants have an internal body timing system – called the circadian clock. This is a complex system of molecules in every cell that drives the rhythmicity of everything from sleep in mammals to flowering in plants.

Light and the day and night cycle are very important for resetting the clock and the fine adjustments are made through the action of several enzymes, including one called casein kinase 1, which has been the centre of this research

Professor Loudon continued “The circadian clock is linked to the 24 hour day-night cycle and the major part of the clock mechanism ‘ticks’ once per day. If you imagine each ‘tick’ as represented by the rise and fall of a wave over a 24 hour period, as you go up there is an increase in the amount of proteins in the cell that are part of the clock mechanism, and as you go down, these substances are degraded and reduce again. What casein kinase 1 does is to facilitate the degradation part.

“So you can imagine that the faster casein kinase 1 works, the steeper the downward part of the wave and the faster the clock ticks – any change in casein kinase 1 activity, faster or slower, would adjust the ‘ticking’ from 24 hours to some other time period. Consider that if your body suddenly starts working on a 23 hour or 25 hour clock, many of your natural processes, such as sleeping and waking could soon become out of step with day and night.”

Dr Michel Goedert, Head of the Neurobiology Division at Medical Research Council Laboratory of Molecular Biology

The team found a drug that slows casein kinase 1 down and used it in mice where the circadian rhythm has ceased i.e. the clock has stopped ticking all together. In live mice and also in cells and tissue samples from mice, they were able to re-establish the ticking of the clock by using the drug to inhibit the activity of casein kinase 1.

Professor Loudon concluded “We’ve shown that it’s possible to use drugs to synchronise the body clock of a mouse and so it may also be possible to use similar drugs to treat a whole range of health problems associated with disruptions of circadian rhythms. This might include some psychiatric diseases and certain circadian sleep disorders. It could also help people cope with jet lag and the impact of shift work.”

Professor Janet Allen, BBSRC Director of Research said “The most effective way to develop drugs to treat a health problem is to understand the basic biology that underpins what is going on in our bodies. In this case, by understanding the basic biology of the enzyme controlling biological clocks the research team have been able to identify potential drug-based solutions to a range of issues that affect many people’s health and quality of life.”

Dr Michel Goedert, Head of the Neurobiology Division at Medical Research Council Laboratory of Molecular Biology said “We’re all familiar with jet-lag and that sense of being disoriented in time. What is probably less widely understood is how this effect can impact on those with certain mental illnesses. It is crucial to find out what can go wrong at the molecular and cellular level in the brain if we are to determine what treatments will work for patients. If further studies in humans confirm what this study has shown in mice, this could eventually lead to an entirely new approach to treating mental illnesses such as bipolar disorder.”

Dr. Wager, Associate Research Fellow, Pfizer said “It is amazing what can be accomplished when first-rate academic groups and pharmaceutical discovery units team up. Leveraging each other’s talents we now have a deeper understanding of the role casein kinase plays within biological systems. Having the ability to entrain or re-entrain an arrhythmic system opens the door to new treatment option for circadian rhythm disorders. Targeting the inhibition of casein kinase with small molecules may lead to the discovery of novel drugs for the treatment of bipolar depression and other circadian rhythm disorders. The burden of these disorders is enormous and new treatment options are needed.”

University of Maryland, Baltimore BioPark Building II

University of Maryland Baltimore leaders are asking the city’s architecture review board to approve a $675 million expansion of the UMB BioPark–a move that would triple the size of the planned project. At the moment the site has two research buildings with 470,000 square feet of space, and a third building will open its doors later this year. The BioPark already counts Alba Therapeutics, Gliknik, FASgen, Biomere, and Fyodor Biotechnologies among its tenants, according to the Baltimore Business Journal.

Two years ago, Maryland Governor Martin O’Malley announced plans to invest $1.3 billion in the state’s bioscience industry by the year 2020. The state’s biotech leaders hope the massive expansion will help it compete with biotech powerhouses like San Francisco and Boston for tenants.

Construction of yet another multi-tenant building is expected to begin later this year, and BioPark planners are on the hunt for tenants for the new space. “If I said we were putting every ounce of energy into finding tenants for that building, it would be an understatement,” Jane Shaab, the biopark’s senior vice president, told the Journal. “That is the focus right now.” The BioPark expansion will boast 11 research buildings upon completion in 2020.

By: Erik Greb

Jose Carlos Gutierrez-Ramos, SVP Research and Development, Biotherapeutics, Pfizer

This week, Pfizer (New York) created a new research unit within its Worldwide Research and Development division that will focus on rare diseases. The new unit will expand the company’s presence in rare-disease research and seek to discover medicines for diseases that affect fewer than 200,000 patients. Pfizer’s Rare Disease Research Unit will pursue treatments in all therapeutic areas, and the company will collaborate with patient-advocacy groups as it develops the unit’s research plan. The establishment of the new research unit is part of Pfizer’s strategy to use its scientific and technological resources to find new treatments for patients with large unmet medical needs.

Edward Mascioli, most recently the founder and CEO of private-equity firm Dapis Capital, will lead the Rare Diseases Research Unit. Mascioli gained clinical-development experience as vice-president of clinical affairs at Peptimmune (Cambridge, MA) and as senior medical director at Parexel International (Waltham, MA). Mascioli, who also has a background in business development, will be based in Cambridge, Massachusetts, and will report to Jose Carlos Gutierrez-Ramos, Pfizer’s senior vice-president of biotherapeutics research and development.

“We are very excited about our new Rare Diseases Research Unit,” said Gutierrez-Ramos in a company press release. “We are coupling Pfizer’s existing experience in rare diseases such as hemophilia with our advanced protein technologies, resources, and world-class scientific team to focus on becoming a driving force in rare-disease research. Pfizer has a long history in discovering, developing, and commercializing medicines that treat rare diseases and we are hopeful that this research unit will lead to additional new medicines for patients suffering from devastating illnesses for which there is no cure.”

The National Organization for Rare Disorders (NORD) is “very happy that Pfizer is establishing a Rare Diseases Research Unit,” said Peter L. Saltonstall, the group’s president and CEO, in the Pfizer press release. “Approximately 30 million Americans, 30 million Europeans, and millions more around the world have rare diseases and, for most of those people, there is no specific treatment. As the voice of the US rare-disease patient community, NORD applauds Pfizer’s commitment to expanding its research with the goal of developing new treatments for this medically underserved population.”

Although more than 6000 diseases are classified as orphan diseases, fewer than 10% of them are directly targeted by specific drugs. The pharmaceutical industry traditionally has invested little in rare-disease research, and its scientific advances in this field have proceeded slowly as a result.

Pfizer’s interest in rare diseases was first manifest in December 2009, when the company licensed the worldwide rights to taliglucerase alfa, a product that treats the genetic disorder Gaucher disease, from Protalix Biotherapeutics (Karmiel, Israel). With that deal, Pfizer became a competitor of Genzyme (Cambridge, MA), which markets Cerezyme as a treatment for Gaucher disease.

One of the persistent frustrations in cancer treatment has been the way that tumors can evade our immune systems as they grow and multiply inside our bodies.

Even though cancer cells have special surface markers, known as antigens, the body often doesn’t seem to be able to mount a full-fledged attack against the tumors, and the longer they last, the more they seem to suppress the immune response.

Yet it doesn’t have to be that way, says a dedicated band of scientists in universities and companies around the globe. In fact, they say, we may be on the verge of being able to vaccinate people against cancer in the same way we do with infectious diseases.

“I think we really are on the cusp of a revolution in cancer immunology,” said Andres Salazar, CEO of Oncovir, a Washington, D.C., company that makes an immune system booster for cancer vaccines. “We hope to make patients allergic to their cancers.”

The first commercial cancer vaccine out of the gate is likely to be sipuleucel-T, a vaccine against advanced prostate cancer being made by Dendreon Corp. of Seattle, Wash.

Not far behind in the pipeline is Stimuvax, a vaccine being made by Merck in Germany that targets a cancer marker known as MUC1, which is present in many different tumors.

That is the same target that UPMC researcher Olivera Finn has developed her own vaccine against.

Dr. Finn’s vaccine, which has been in development for several years, has already shown limited success in advanced pancreatic cancer patients.

But because she believes these vaccines will work best in people who do not yet have cancer, she and UPMC researcher Robert Schoen are testing the vaccine now in patients who have precancerous polyps in their colons, to see if it prevents the onset of colorectal cancer.

While she is still a couple years away from being able to report results, Dr. Finn knows the vaccine has created a strong immune response in the patients and has had few side effects.

The hope? “If we immunize early on, the cells that become abnormal might actually be eliminated by a strong immune response,” she said.

James Gulley, a leading vaccine researcher at the National Cancer Institute, agrees with that approach. He said there is growing evidence that the immune system doesn’t work as well against cancers that are more advanced, which “leads me to believe the best time to try vaccines thus might be before the tumor gets too large.”

That is also the goal of a new cancer vaccine trial being started here for patients with gliomas, a type of brain cancer.

That experiment, being run by UPMC neurosurgeon Hideho Okada, will administer the first vaccine ever developed for low-grade gliomas, which includes an immune system booster called Hiltonol.

These cancers are especially insidious, Dr. Okada said, because they often grow slowly for several years and the patients look and feel healthy. Then suddenly, they convert into an aggressive form of brain cancer that kills the patients.

“A low-grade tumor is not a benign tumor,” he said. “Unfortunately, a diagnosis with a low-grade glioma today is still a death sentence” — something he hopes the new vaccine can reverse.

The trial will be small to start with, involving 18 patients with new cancers and nine with recurrent tumors.

“We believe that immunotherapy could be long-lasting,” Dr. Okada said. “The actual drug doesn’t have to be present in the system, unlike chemotherapy, and the slow-growing nature of these gliomas gives us sufficient time to vaccinate and revaccinate patients.

“Our goal is to educate the immune system so that it recognizes the cancer-specific antigens.”

A key part of that will be the Hiltonol booster made by Dr. Salazar’s company.

The substance, named for co-inventor Hilton Levy, mimics the DNA of a virus, and seems to deliver a “warning signal” that fires up the immune system, Dr. Salazar said. It is being used now in about 12 different cancer vaccine trials, he said, including Dr. Okada’s.

Hiltonol is made of double-stranded DNA, “which doesn’t normally occur in mammalian cells,” he said, “but is a product of viral replication, so when mammalian cells see it, they say, “There’s a difference here. ”

Besides monitoring the patients who had colon polyps, Dr. Finn has also reported encouraging results with her vaccine in specially bred mice.

The mice have human genes that make them prone to get inflammatory bowel disease, which is a known risk factor for colorectal cancer. In fact, if they are left untreated, she said, about 80 percent of the mice will go on to get cancer.

When her team administered the MUC1 vaccine to the mice, though, not only did far fewer of them get inflammatory bowel disease, but almost none of them went on to get cancer.

The encouraging results of MUC1 vaccines aren’t confined to animals.

The version that is now being tested by Merck showed a 17-month survival advantage for advanced lung cancer patients who got the vaccine vs. those who didn’t in an earlier trial.

While the current testing has been suspended temporarily because one patient got encephalitis, the man whose company invented the vaccine is encouraged by the progress it has made.

Robert Kirkman, president of Oncothyreon, the Seattle, Wash., company that developed the vaccine, said he understands the logic of testing cancer vaccines on patients who aren’t as sick, but said that presents a financial challenge.

If vaccines were to be tested on a large group of patients with earlier stage cancer, it could mean following them for up to 10 years to see if the therapy was effective, and that would be enormously expensive.

If his company’s vaccine, Stimuvax, demonstrates a relative survival benefit for patients with later-stage cancers and can then be approved as a commercial product, he said, “it’s likely the work will then be done to show it works in earlier-stage disease, but it’s much easier to do that after you’ve got a revenue-generating product.”

The National Cancer Institute’s Dr. Gulley said he thinks there may be a middle ground between what is “biologically plausible and financially feasible” for testing cancer vaccines on human patients.

There is evidence that cancer vaccines take longer to show beneficial results than other kinds of therapies, he said, partly because the immune system needs time to gear up to fight the tumor.

In doing human trials of vaccines, he said, “if I were to err on one side or the other, I’d err on the side of what’s biologically plausible.” Too often in cancer treatment, “everyone’s looking for the big payoff with little effort, and that’s exactly the wrong thing to do.”

One other possible benefit of vaccines: They may make it possible for some people to live with their cancers for many years, even if the malignancies aren’t completely wiped out.

With Dr. Okada’s brain tumor patients, for instance, it would be a major advance if a vaccine could just stop their tumors from becoming aggressive and life-threatening.

Even with the addition of newer forms of chemotherapy in recent years, doctors who treat gliomas have only been able to extend average life spans by about three months over the past couple of decades.

“So if I could even make brain cancer a chronic disease like hypertension or diabetes,” he said, “I would be ecstatic.”

Three separate research programs in Seattle were awarded about $5 million each by Washington state’s Life Sciences Discovery Fund.

Winning grants were:

— Stephen Friend of Sage Bionetworks, of Seattle. His program focus, according to the fund, is “to more accurately and comprehensively model biological systems through their network of interactions to develop safer and more effective drugs and diagnostic tests.”

— Thomas Matula of the University of Washington. His program focus, according to the fund, is “to develop, translate and commercialize new ultrasound techniques for molecular imaging and therapy.”

— Peggy Porter of Fred Hutchinson Cancer Research Center. Her program focus, according to the fund, is “to facilitate cancer treatment through comprehensive biological collection and distribution.”

Fund officials said 19 proposals were submitted before the three winners were chosen.

Started in 2008, the fund draws $35 million a year for 10 years from a settlement with tobacco companies. It’s administered by an 11-member board of trustees. The governor appoints seven trustees, and four are appointed by legislators

Hadassah Hospital researchers develop new cell growth method which may help heal Parkinson’s disease, diabetes

Sarit Rosenblum

Fetal stem cells. Considerable scientific interest

A breakthrough made by Israeli researchers may pave the way for healing chronic illnesses: Researchers from Jerusalem’s Hadassah Hospital have developed a new method for producing large amounts of human fetal stem cells.

Fetal stem cells can transform into any type of cell in the human body. The cells attract considerable scientific interest due to the estimate that in the future they could be used as an endless source of cells, which will be transplanted and improve the performance of organs in a wide variety of degenerative diseases.

The medical world hopes to be able to use fetal stem cells to heal Parkinson’s disease, diabetes, reticular degeneration and other illnesses. In addition, the cells may be used in the future to grow human organs which would replace damaged organs like kidneys and liver.

Up to now, stem cells would be multiplied in colonies of one cell layer attached to a flat substrate. In their study, the Israeli researchers showed that human fetal stem cells can be produced and multiplied while floating in liquid substrate.

“The study’s findings are an important step ahead of an automatic and controlled creation of the large amounts of cells needed for transplant and other industrial and research purposes,” says Prof. Benjamin Rubinoff, director of the Hadassah Human Embryonic Stem Cell Research Center, who headed the team of researchers.

New research from Switzerland provides insight into how tumors remain undetected by the body’s immune system by mimicking lymph nodes.

Prof. Melody Swartz

“The tumor tricks the body into thinking it is healthy tissue,” lead author Melody Swartz, head of the Laboratory of Lymphatic and Cancer Bioengineering, said in a news release about the study, published online March 25 in Science.

According to Swartz and her colleagues at the Ecole Polytechnique Federale de Lausanne, the findings could lead to better treatments for cancer.

In the study, the researchers focused on a protein that is typically found in lymph nodes and discovered that certain tumors can secrete the protein, making them appear to be lymph nodes. This disguise allows the tumors to manipulate immune cells known as T-cells, just like lymph nodes do, the study authors explained.

The findings have “important implications for tumor immunotherapy,” Jacqui Shields, another researcher, explained in the news release

Periodic breathing cessation during slumber can lengthen seniors’ lives.

Sleep apnea syndrome – in which sufferers stop breathing momentarily many times during the night – has for many years been regarded as a major risk factor for clogging of the coronary arteries and other heart diseases. But now, Technion-Israel Institute of Technology President Prof. Peretz Lavie – a psychologist and one of the country’s leading sleep medicine experts – and his wife and fellow researcher cell biologist, Dr. Lena Lavie, have found that in elderly people, moderate apnea may in fact extend their lives rather than shorten it.

The Lavies’ research, based on the study of 611 individuals with a mean age of 70 and a follow-up period of about five years, has just been published in the Journal of Sleep Research of the European Sleep Research Society. The reasoning has been confirmed separately by German researchers at Heinrich Heine University in Dusseldorf, who published their findings in the journal Chest of the American College of Chest Physicians.

Prof. Lavie has published more than 340 scientific articles and eight books in the field of sleep research, including The Enchanted World of Sleep, which is suited for the layman and translated to 15 languages. Lena, a senior researcher in the Technion, has collaborated with him on sleep research focusing on understanding the cellular and biochemical impacts of the breathing cessations.

Many sleep apnea patients go to bed at night connected to a continuous positive airway pressure (CPAP) device, which is not very comfortable but pushes through a mask pressurized air – insufficient during breathing cessation – under pressure into their lungs. This does not cure sleep apnea but can reduce the complications.

Intermittent hypoxia – the lack of adequate oxygen – initiates a cascade of events involving oxidative stress and inflammatory processes leading to atherosclerosis. But surprisingly, the new research found that in contrast to young and middle-age patients, who showed significantly higher mortality than their counterparts in the general population, elderly patients with mild or moderate apnea showed significantly lower mortality than in the general population.

The researchers suggest that the hearts of elderly sleep apnea patients get blood from a larger number of arteries – called collaterals – that develop by angiogenesis due to the lack of oxygen supply, than the hearts of patients without sleep apnea. This additional blood supply protects them if they suffer a heart attack, the Lavies write.

The Haifa researchers based their hypothesis on previous results from the Haifa group demonstrating that sleep apnea patients have in their blood high levels of a protein called vascular endothelial growth factor (VEGF). This protein is responsible for the growth of new blood vessels, and its production is triggered by a drop in blood oxygen levels.

The Technion team also showed that there are very large individual differences in the effect of hypoxia on the production of this protein. The research group found that individuals who could produce a large amount of protein when exposed to hypoxia had more blood vessels around their hearts in comparison with individuals who could not produce the protein.

Dr. Stephan Steiner and his colleagues from the cardiology department in Heinrich Heine University reported data that provided strong support to the Lavies’ hypothesis. Steiner and his colleagues compared the number and size of the heart collaterals measured by catheterization in patients with and without sleep apnea and reported that patients with sleep apnea had significantly more collaterals than patients without sleep apnea, even though there were no differences between the groups in age, weight, heart condition or use of medication.

The German research in Chest was accompanied in the same issue by an editorial that was written by the Lavies. “If confirmed, these findings may have important clinical implications regarding treatment of the syndrome. Moreover,” they continued, “such findings – if combined with individual gene analysis – may provide new treatment strategies for cardiovascular protection.”

Israeli researchers find pregnancy can be mimicked to regenerate tissue.

Dr Joshua Cohen

BOSTON -  New products to treat neglected diseases have received marketing approval from regulatory agencies at a steadily increasing rate in recent years as R&D funding for those diseases has increased, according to a recently completed study by the Tufts Center for the Study of Drug Development.

According to the study, the annual rate of new product approvals worldwide for neglected diseases increased from an average of 1.8 in 1975-99 to 2.6 in 2000-09.

Neglected diseases include malaria, kinetoplastids, diarrheal diseases, helminths (e.g. roundworm), bacterial pneumonia and meningitis, and typhoid and paratyphoid fever.

“During this past decade, a significant increase in R&D funding for neglected diseases has led to marketing approval for 26 drugs and vaccines,” said Joshua Cohen, senior research fellow at Tufts CSDD and author of the study.

He added, “While increased approvals are necessary to improve access, policymakers need to ensure that safe, effective, and easy-to-administer products are adopted by health care systems and providers on a consistent basis, that they are affordable, and that they reach the people who need them.”

The Tufts CSDD analysis examined the results of a widely circulated 2002 study, which reported that only 16 of 1393 new chemical entities marketed between 1975 and 1999 targeted tropical diseases and tuberculosis. Tufts CSDD found that the more accurate count was 33. However, the earlier study prompted governments, nonprofit foundations, and private-public partnerships to increase funding for neglected diseases, from less than $100 million annually a decade ago to more than $2.5 billion annually today.

The new analysis, reported in the November/December Tufts CSDD Impact Report, released today, also found that:

*  Drugs to treat HIV/AIDS and malaria accounted for 81% of approvals during 2000-09.

*  Vaccines have displaced drugs as the main products being developed for neglected diseases, accounting for 76% of all products in development to treat neglected diseases.

*  Public-private partnerships accounted for 46% of all new product development to treat neglected diseased during 2000-09, up from 15% in the 1975-99 period.

About the Tufts Center for the Study of Drug Development

The Tufts Center for the Study of Drug Development (http://csdd.tufts.edu) at Tufts University provides strategic information to help drug developers, regulators, and policy makers improve the quality and efficiency of pharmaceutical development, review, and utilization. Tufts CSDD, based in Boston, conducts a wide range of in-depth analyses on pharmaceutical issues and hosts symposia, workshops, and public forums, and publishes the Tufts CSDD Impact Report, a bi-monthly newsletter providing analysis and insight into critical drug development issues.