TI Pharma Annual Report

Studies show that 1 in 5 people suffer from chronic pain. Therefore, Project Manager Dr. Laura Heitman, assistant professor of Medical Chemistry at the University of Leiden, launched – together with professor Ad IJzerman, Principal Investigator – the Top Institute Pharma project “Target Residence Time” in January 2010. “We want to develop better medication to combat chronic pain,” Heitman explains. Chronic pain often has an underlying cause like cancer or rheumatism, but unlike acute pain, does not give off warning signals. It can also be extremely aggravating to the patient.

“Our team works together with a diverse group of research partners, and we’re all interested in CCR2.” CCR2 is a receptor protein which gives off signals – in this case, from the outside to the inside of a cell. CCR2 is found on cell membranes in the central nervous system. Their natural ligand, CCL2, attaches to CCR2 if, for example, there is an infection, to send pain signals through the central nervous system. Heitman specialized in receptors during her doctoral research. “We are going to manufacture small molecules that bind really well to CCR2, thus taking the place of CCL2. A molecule that binds in CCL2’s place for a prolonged period of time will hinder the signaling process and thus the occurrence of chronic pain.”

“In 2010 we were mainly concerned with collecting the right cell lines, making the first small molecules and designing experiments. Now the real scientific work begins,” says Heitman. “The most important goal of the research is to get these synthetic molecules to stay on the receptors for a long time, because if their stay is too short there won’t be any pharmacological effect. We’re also working on selectivity to minimize the chance of side effects.”

Next to Leiden, VU University Amsterdam and the Global Biotechnology company Vertex Pharmaceuticals are partners in this project. “The VU is specialized in chemokine receptors like CCR2. Vertex can conduct experiments in a relevant pain model to test our laboratory’s findings in vivo right away; for these reasons, this is a typical Top Institute Pharma project. It builds a bridge between fundamental research and industry.”

Partners: University of Leiden, VU Amsterdam, Vertex Pharmaceuticals

click here to watch a video presentation by Laura Heitman.

In 2010, researchers in a Top Institute Pharma project discovered proteins which guide the growth of nerve fibers in the brain. This startling finding can be significant for the treatment of Parkinson’s patients. Parkinson’s is a neurodegenerative disease in which dopamine neurons and their extensions, the nerve fibers, vanish from the midbrain. This causes defects in motor skills and sometimes in cognitive function. Patients are usually between the ages of 50 and 60 years old. In this age group, Parkinson’s affects 1 out of 50 people.

"Our findings can lead to large improvements in transplantation therapy,” explains researcher Dr. Jeroen Pasterkamp of UMC Utrecht. “Transplanted nerve fibers do not always extend into the areas where they’re needed. With this new information, we hope to steer those inserted nerve fibers in the right direction, thereby repairing the system in the right place and, in so doing, improving the course of the disease."

A consortium of researchers, including academic and industrial partners, collaborate in research in Top Institute Pharma. “The advantage of this is that you have at your disposal a lot of expertise which lies outside of your own field. We make use of this added value at all levels required for translational research, from patient to molecule,” Pasterkamp says. The added advantage of working with industrial partners is having access to their particular perspective on scientific findings. “They can immediately see whether it is useful to pursue your findings, and whether a treatment can perhaps be realized.”
The discovery of the guidance proteins does not mean that this successful project, which started four years ago, is finished. “The research is being continued,” explains Pasterkamp, “because we ultimately want to find out whether we can combat the disappearance of the nerve fibers.”

Partners: Abbott, DNage, EMC, LUMC, NIN, UMCU, UU, VU Amsterdam, VUMC

In 2010, scientists from Dr. Joost Verhaagen’s research group, part of The Netherlands Institute for Neuroscience in Amsterdam, made significant headway in the search for a treatment for Alzheimer’s disease. In the frontal lobes of Alzheimer’s patients, researchers discovered a set of almost 500 genes which behave differently in people without Alzheimer’s. Verhaagen, the Principal Investigator of the Top Institute Pharma project, explains: “These genes exhibit different expression levels and are possibly the cause behind the changes we find in patients’ brains.” The discovery of these differences in genetic expression are the first steps towards a treatment.

The researchers immediately undertook action to find the “key genes” in the set. “Key genes are those genes that are involved in the major molecular processes in the development of Alzheimer’s. We want to filter out a selection of 7 or 8 of these key genes. We’ll then manipulate these selected genes in the brain tissue to see if they have a protective or neutralizing effect. This will help make gene therapy or a pharmacological approach possible.”

Through cooperation with various partners, Top Institute Pharma projects give scientists access to advanced molecular techniques, such as the microarray technique used in this project. The partnership with the Netherlands Brain Bank allowed the scientists to study and compare preserved human brain tissue.

“This is an important project,” says Verhaagen. “Many people over 80 develop Alzheimer’s. It’s a horrible disease which causes people to lose their memories and live in a state of unawareness; what’s more, there is still no effective treatment available. We’re therefore not focusing on combating symptoms, but on developing an actual regenerative or preventative treatment that will keep the brain tissue intact as long as possible.”

Partners: Abbott, DNage, EMC, LUMC, NIN, UMCU, UU, VU Amsterdam, VUMC

“The system we’ve built for Mondriaan is operational, and we have collected information from 400,000 people. That was our biggest success in 2010,” says Marc Rietveld, MSc, of UMC Utrecht, one of the Mondriaan project managers. This Top Institute Pharma project aims to collect the patient medication histories from those organizations which own the data, such as general practitioners, pharmacies, hospitals and healthcare insurance companies, then to link this information and make it available to academic and industrial researchers. “We aim to advance drug research and make drugs safer, more effective and cheaper, and obviously all of this while adhering to privacy laws.” They accomplish this by using the services of a so-called “Trusted Third Party” (TTP), an independent organization which links the data and makes it anonymous before delivering it back to the Mondriaan system.

UMC Utrecht’s Professor Rick Grobbee, who is the Principal Investigator of the project, explains: “Data files are often in the possession of people who feel closely connected to that information. They don’t want to lose control over it. Therefore, we will always take the time to speak to those people, to explain that they will stay in control of their data.” This approach is working, and larger owners of patient data, like the Network of General Practitioners in Utrecht, are making their information available to The Mondriaan Project. Grobbee is also pleased with the results of the software development: “Our automated system is unique. The software is a technical masterpiece; not only is the system able to handle many different kinds of data and data formats, but it handles the transfer of this data to and from the TTP and collects it in a standardized format to then deliver to researchers.”

The Mondriaan Project started in 2007 and has been on track since. “We are now in the last phase: completing the system,” Grobbee explains. “Next to maintaining intensive contact with our academic and industrial partners, we also work closely with other organizations like the Foundation for Pharmaceutical Statistics.”

“Our aim is to have Mondriaan operating as a self-sufficient databank by the end of the project,” Rietveld says. “We are going to be a kind of middleman between owners and users of healthcare data.” Grobbee continues: “And if there are problems with a drug, we want to be able to answer questions from the government or industry quickly, and substantiate these answers with hard facts.” Studies show that this is particularly important to patients with chronic illnesses. “But of course it’s important for all patients in the Netherlands that medicines are safe, reliable and affordable,” Grobbee explains. “The nice thing about this is that it doesn’t cost these patients anything extra, since all data in the Mondriaan system originates from the existing healthcare infrastructure in the Netherlands.”

Partners: GSK, RUG, Sanofi Aventis, UMCG, UMCU, UU

“At Top Institute Pharma, we feel that it is important to involve patients in scientific research,” explains Dr. Jay Iyer, program manager at Top Institute Pharma. She and Dr. Els Berns, project leader and professor at Erasmus MC Rotterdam, published an opinion piece in the Financieel Dagblad in 2010 in which they outlined the value of involving patients in cancer research. “It is important that patients gain more insight into their diseases and the methods of treatment, and that researchers take into account the needs of patients in their research,” Iyer continues.

Breast cancer researcher Berns explains: “Patients in the Netherlands who are diagnosed with cancer often go to the internet to find information about their disease and new treatment methods. But more often than not, they cannot find the right information. It is important to guide them towards reliable sites, and to teach them more about the disease and research.”

Top Institute Pharma’s portfolio is full of projects in which patients and scientists can come together to discuss drug development for cancer and other diseases.

In 2010, Top Institute Pharma looked at how patient organizations could help determine the direction of research in new projects. Considering that many projects focus on the early, often “pre-clinical” phase of research to develop new drugs, this is a challenge. In drug development (and to a lesser extent diagnostic development), it takes a long time before concrete results turn into new medications.

“In joining patients and researchers, it’s not just the patient who comes away with valuable information about his or her disease and possible new methods of treatment. The researcher also gains new insights,” Berns argues.

Top Institute Pharma opened a new Value Creation Call at the start of 2011, where scientists are encouraged to include patient organizations in their research. “We have invited patient organizations to our Spring Meeting in April,” says Iyer. At this annual Top Institute Pharma event, representatives from a few patient organizations will interact with scientists on specific topics.

Moreover, the Education & Training program at Top Institute Pharma includes a course where researchers learn about the needs of patients in a drug development simulation. Such information can contribute to the design of clinical studies and marketing strategies, and can motivate researchers to explore different conditions in their experiments to try to address patient concerns.

click here to watch a video presentation by Els Berns.