Cholesterol-Regulating Genes Identified By Scientists

Scientists at the European Molecular Biology Laboratory (EMBL) and the University of Heidelberg, Germany, have come a step closer to understanding how cholesterol levels are regulated. In a study published in the journal Cell Metabolism, the researchers identified 20 genes that are involved in this process. Besides giving scientists a better idea of where to look to uncover the mechanisms that ensure cholesterol balance is maintained, the discovery could lead to new treatments for cholesterol-related diseases.



"This finding may open new avenues for designing targeted therapies, for example by looking for small molecules that could impact these genes," says Heiko Runz, whose group at the University Clinic Heidelberg carried out the research together with Rainer Pepperkok's lab at EMBL.



High levels of cholesterol in the bloodstream are a major risk factor for atherosclerosis and coronary heart disease, one of the leading causes of death in developed countries today. Nevertheless, cholesterol is an important cellular component: 90% of the cholesterol in our bodies is inside our cells, where it does not cause any harm. Blood cholesterol levels are partly regulated by cells taking up cholesterol from the bloodstream, a process Runz and his colleagues are helping to unveil.



The researchers deprived isolated human cells of cholesterol and then looked at the whole genome to find the genes that react to changes in cholesterol levels by altering their expression. This large-scale approach pointed to hundreds of genes which might be involved in cholesterol regulation. To check which genes really were involved, the scientists used a technique called RNA interference to systematically turn each of the candidate genes off. With a microscope they then observed what effect switching off different genes had, both on cholesterol uptake and on the total amount of cholesterol inside cells.



Of the 20 genes the scientists identified as involved in regulating cholesterol levels and uptake, 12 were previously unknown. The remainder were known to have some link to lipid metabolism - how the body breaks down fat - including two genes that when mutated may cause heart disease, but which were only now shown to also play a part in bringing cholesterol into cells in the first place.



The scientists are now trying to discover exactly how the novel genes regulate cholesterol levels inside cells, as well as looking at patients to determine whether these genes (or alterations in them) do constitute risk factors, and investigating if and how they could be useful drug targets.



This discovery could help fight not only heart disease, but also other conditions, as one of the genes identified appears to influence the behaviour of NPC1, a protein involved in the neuro-degenerative Niemann-Pick disease.



The research was conducted under the Molecular Medicine Partnership Unit (MMPU), a collaboration between EMBL and Heidelberg University. "It is very convenient to have such a close partnership here in Heidelberg", says Rainer Pepperkok from EMBL, adding, "it allowed us to use the sophisticated techniques and technology from EMBL to answer questions that first arose at the University clinic, whose clinical aspects will now help in the follow-up."

Cleveland Clinic To Lead First Head-to-Head Comparison Of The Two Most Potent Statins

Cleveland Clinic researchers will
coordinate the first head-to-head comparison of the two most powerful
statin medications. The trial intends to begin enrollment as early as next
week. Statins are the world's most commonly prescribed drugs and widely
used to treat patients with elevated cholesterol levels.


The two drugs, atorvastatin (Lipitor) and rosuvastatin (Crestor), lower
LDL ("bad") cholesterol and raise HDL ("good") cholesterol. But which drug
is best for patients with heart disease? This study will seek to answer
this important scientific question by measuring the rate of regression of
coronary disease using intravascular ultrasound (IVUS), a technique that
directly measures the amount of plaque in the coronary arteries.



The SATURN study (Study of Coronary Atheroma by InTravascular
Ultrasound: Effect of Rosuvastatin Versus AtorvastatiN) will compare the
ability of these two statins to stop the progression of atherosclerosis,
the main cause of cardiovascular disease, over a two year treatment period.



SATURN, a multicenter, double-blind Phase IIIb trial, will use IVUS
imaging to study approximately 1,300 patients at 150 hospitals in 20
countries worldwide. The trial is expected to be completed in 2011.
Cleveland Clinic cardiologist Stephen J. Nicholls, M.D., PhD., will lead
the trial.



Cleveland Clinic researchers have conducted two previous studies with
IVUS looking at statins and the rate of atherosclerosis regression.
Researchers have found a significant benefit with statins by intensively
lowering LDL- cholesterol and the inflammatory marker C-reactive protein
(CRP) and by raising levels of HDL cholesterol. SATURN aims to determine if
differences in the ability of the different statins to lower LDL and raise
HDL can promote regression (reduction in the amount of plaque in the
coronary arteries).



About Cleveland Clinic



Cleveland Clinic, located in Cleveland, Ohio, is a not-for-profit
multispecialty academic medical center that integrates clinical and
hospital care with research and education. Cleveland Clinic was founded in
1921 by four renowned physicians with a vision of providing outstanding
patient care based upon the principles of cooperation, compassion and
innovation. U.S. News & World Report consistently names Cleveland Clinic as
one of the nation's best hospitals in its annual "America's Best Hospitals"
survey. Approximately 1,800 full-time salaried physicians and researchers
at Cleveland Clinic and Cleveland Clinic Florida represent more than 100
medical specialties and subspecialties. In 2006, there were 3.1 million
outpatient visits to Cleveland Clinic. Patients came for treatment from
every state and from more than 80 countries. There were more than 53,000
hospital admissions to Cleveland Clinic in 2006. Cleveland Clinic's Web
site address is clevelandclinic.


Cleveland Clinic

clevelandclinic



View drug information on Crestor.

Joint effects of cardiac risk factors mean more then just double trouble

High blood pressure and high LDL-cholesterol add up to more than just double trouble for heart health, a Penn State College of Medicine study reports.


"The whole is larger than the sum of the parts when it comes to the combined risk of heart attack from high blood pressure and high LDL-cholesterol," said Duanping Liao, M.D., Ph.D., associate professor of health evaluation sciences, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center, and lead investigator of the study. "Our study showed that about 21 percent of middle-aged Americans might have both risk factors, implying that these findings could have significant public health implications with regard to controlling both hypertension and high cholesterol in reducing cardiovascular disease."


Liao's study is one of the few to identify people with these joint risk factors and evaluate on a long-term basis the relationship between the clustering of the risk factors and the incidence of myocardial infarction, or heart attack. The study was presented today (Aug. 30, 2004) at the European Society of Cardiology Congress in Munich, Germany.


Cardiovascular disease remains the No. 1 killer in the United States with about 1 million Americans dying of the disease each year. High blood pressure, or hypertension, and high LDL (low-density lipoprotein) cholesterol are highly prevalent and well-established risk factors for cardiovascular disease.



The study team used data from 14,500 people in the Atherosclerosis Risk in Communities (ARIC) study who were free of coronary disease at initial examination and were followed for an average of nine years. Started in 1987, the ARIC is an ongoing, long-term, observational study of cardiovascular and pulmonary diseases sponsored by the National Heart, Lung, and Blood Institute of the National Institutes of Health.

The ARIC study initially included about 16,000 men and women between the ages of 45 and 64 from four U.S. communities (Washington County, Md., Forsyth County, N.C., selected suburbs of Minneapolis, Minn., and Jackson, Miss.). Participants were given questionnaires and were examined every three years. Follow-up occurs yearly by telephone to maintain contact with participants and to assess participants' health status.


The study showed that those without high blood pressure or high cholesterol showed an incidence for heart attack of 23 per 10,000 person-years, which is roughly 23 cases per 10,000 persons per year. Because these people lacked any risk factors, the incidence of 23 is considered background risk and is subtracted from the total number of heart attacks for those with risk factors present. After deducting background risk, those with high blood pressure had an incidence of 16 and those with elevated LDL-cholesterol had an incidence of 12. The expected incidence for those with both high blood pressure and elevated LDL-cholesterol would be the sum of those two risks, or 28. In fact, the actual incidence of heart attack for those with both risk factors was 51.


"The observed disease rate due to the combination of these two risk factors was significantly higher than what was expected," Liao said. "In terms of excess risk, 31 percent of the risk of developing heart attack among people with both high blood pressure and elevated LDL-cholesterol was attributable to the synergistic interaction of these two risk factors."


In terms of relative risk, the findings showed that those with high blood pressure, elevated LDL-cholesterol or both have a 1.95, 1.70 and 3.31 times higher risk of having a heart attack than those without either of the two conditions.


"This study highlighted the need for physicians to consider treating both high blood pressure and high cholesterol in persons with both risk factors," Liao said, "because the patient's risk of developing a heart attack is beyond simple addition of each risk factor acting alone."


In addition to Liao, the study team included: Jingping Mo, M.D., Ph.D., Global Epidemiology, Pfizer Inc.; and Yinkang Duan, M.D., M.S., Megan Darnell, M.S., Hung-Mo Lin, Ph.D., Zhengmin Qian, M.D., Ph.D., Department of Health Evaluation Sciences, Penn State College of Medicine, Penn State Hershey Medical Center.


The study was partially supported by a research grant from Pfizer Inc., New York.


CONTACT: Valerie Gliem

vgliempsu

814-865-9481

717-531-8604

Penn State

Think Treatments For Cancer, Diabetes Don't Grow On Trees? Think Again

Supported by thousands of years of use, a new wave of polymolecular botanical drugs (PBDs), backed by strong biomedical research and clinical trials, are growing in acceptance as a viable new drug category for the treatment and prevention of a wide spectrum of diseases from cancer to obesity.



Leading researchers in drug development from the National Cancer Institute, Wake Forest University, the University of California, the Scripps Centre for Integrative Medicine, King's College in London UK, and many Canadian Universities will be among the twenty panellists at a Toronto forum on November 15th. Speakers will highlight recent discoveries, discuss current and future research, and chart regulatory landscapes for the promising field of polymolecular drug development. Treatment areas include diabetes, cholesterol management, and cancer.



Research findings will be presented illustrating the advances in the development of polymolecular drugs and their growing recognition as potential mainstream therapies to not only treat illness, but to prevent it. Since polymolecular drugs are composed of multiple components, they often produce biological and/or clinical efficacy through multiple mechanisms of action rather than through a single pathway, as conventional drugs do. An added advantage of this new class of drugs is the synergy between their components, which allows for lower concentrations of each individual ingredient with no reduction in efficacy. As a result they are, as a category, safer and more tolerable than conventional drugs.



Discussion will also focus on recent successes in standardization, which overcome the greatest challenge of botanical medicine and allow for assurances of consistency, safety, and efficacy.



The list of speakers at the forum will include:
Dr. Erminia Guarneri, founder and medical director of the Scripps Center for Integrative Medicine, who will deliver the keynote address, titled Personalized, Predictive, Pro-Active Health: Treating the Whole Person, Body, Mind & Spirit
Dr. Pierre Haddad, Professor at the University of Montreal presenting on novel anti-obesity and anti-diabetic properties of plants originating from the Boreal forest of Canada.
Dr. Peter Hyland: Professor, King's College, UK, presenting on novel standardization methods for polymolecular drugs.
Dr. Auro del Giallo, ABC Foundation School of Medicine, San Paulo Brazil presenting on polymolecular drugs and their role in treating cancer related fatigue
Dr. Jeffrey White, MD, Director, Office of Cancer Complementary and Alternative Medicine, National Cancer Institute, NIH, DHHS presenting on the US National Cancer Institute and its botanical research

Academic and clinical researchers, business development professionals and government agencies involved in the drug development field have been invited to attend and learn about this emerging field of health and therapeutics, and to network with other professionals in the field.



Learn more about the November 15th meeting in Toronto by visiting the MaRS Discovery District website. A webinar of the event will be posted after the event.

Explaining An Important Genetic Cardiovascular Risk Factor

New findings reported in the September issue of Cell Metabolism, a Cell Press publication, appear to explain why people who carry specific and common versions of a single gene are more likely to have high cholesterol and to suffer a heart attack. Studies in mice show that the gene, known as sortilin (SORT1), controls the release of LDL (a.k.a. "bad") cholesterol from the liver into the bloodstream.



The findings suggest that SORT1 may be a good target for new cholesterol-lowering drugs, according to the researchers.



"The vast majority - some 95 percent - of cardiovascular disease is the result of environmental factors modified by genes," said Anders Nykjaer of Aarhus University in Denmark. "Some people can eat a diet enriched in fat, be overweight, and not develop cardiovascular disease. Others can't." SORT1 appears to be one of those important genetic variables, and now the researchers have a pretty good idea why that might be.



The researchers had earlier studied SORT1 in a completely different context. The gene also plays a role in the nervous system. So they were intrigued by the results of genome-wide association studies, which look for associations between common variation in the human genome and diseases or traits, showing that a particular stretch of sequence on chromosome 1 was linked to cardiovascular risk. That sequence covered three genes, including SORT1. (It was not immediately clear which of those three genes was responsible for the rise in cardiovascular risk.)



To investigate SORT1's role further, the researchers created a mouse that lacked SORT1 altogether. That mouse showed 20 percent lower blood cholesterol levels when fed a high-fat Western diet than did normal mice. Importantly, this reduction in cholesterol translated into an approximately 50 to 60 percent reduction in the buildup of plaque in the animals' artery walls. Mice with higher-than-normal levels of SORT1, on the other hand, had higher cholesterol.



If the mice fared better without SORT1 at all, what is it good for? "Everybody says that LDL cholesterol is a bad guy, but you can't do without cholesterol," Nykjaer explains. Cholesterol is a key ingredient in cell membranes and in steroid hormones, for instance. SORT1 facilitates the release of cholesterol into the bloodstream, making that fat available to body tissues that need a certain amount of it.



The problem comes in when you start eating a diet loaded with fat and cholesterol. "Overall, it's good to have sortilin if you don't eat that much," Nykjaer said. "Now, it might be better not to have it all."



Based on the findings, Nykjaer said it might be helpful for people to know what version of SORT1 they carry. Almost a quarter of all people carry the "bad" version of the gene. But he would sooner suggest that everyone live a healthier lifestyle, given that cardiovascular disease is influenced by many factors.



Perhaps the most important implication of the study, he says, is that SORT1 might be a good target for drugs that could block excess cholesterol in the liver, keeping it out of the bloodstream and protecting the heart.



"Lowering LDL cholesterol is considered one of the most efficient strategies to reduce the risk of coronary artery disease," the researchers wrote in conclusion. "Identification of regulators in lipoprotein metabolism such as sortilin will help to develop therapeutic strategies aimed at reducing plasma LDL cholesterol, the single most predictive cardiovascular risk factor."



Notably, loss of SORT1 doesn't result in a buildup of bad cholesterol in the liver, as one might expect, Nykjaer said. That's because the blocked path to the bloodstream engages other molecular players that dump cholesterol from the liver into bile. In other words, he says, the liver appears to protect itself by ridding the body of that cholesterol.



The researchers include Mads Kjolby, Aarhus University, Aarhus, Denmark; Olav M. Andersen, Aarhus University, Aarhus, Denmark; Tilman Breiderhoff, Max-Delbruck-Center for Molecular Medicine, Berlin, Germany; Anja W. Fjorback, Aarhus University, Aarhus, Denmark; Karen Marie Pedersen, Aarhus University, Aarhus, Denmark; Peder Madsen, Aarhus University, Aarhus, Denmark; Pernille Jansen, Aarhus University, Aarhus, Denmark; Joerg Heeren, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Thomas E. Willnow, Max-Delbruck-Center for Molecular Medicine, Berlin, Germany; and Anders Nykjaer, Aarhus University, Aarhus, Denmark.

RNA Treatment Lowers Cholesterol in Mice

Alnylam Pharmaceuticals, Inc, a leading therapeutic RNA interference (RNAi) company, today announced the first in vivo demonstration ever published of RNAi-mediated gene silencing in mammals by a method that potentially can be applied to systemic RNAi therapeutics for human disease. The research, published in Nature, represents a significant advance in the development of systemic RNAi therapeutics. Systemic delivery through the bloodstream potentially enables RNAi therapeutics to target virtually any gene involved in the cause of human disease, opening up the prospect for broad application of RNAi therapeutics to treat a wide range of diseases.


In the published research, Alnylam scientists demonstrated in vivo silencing of the gene for apolipoprotein B (apoB), a protein involved in cholesterol metabolism, and a consequent reduction in blood cholesterol levels. This was achieved using a specially engineered short interfering RNA (siRNA) that was given intravenously by a clinically relevant route of administration. siRNAs are the molecules within cells that trigger RNAi.


To enable the synthetic siRNA used in the study to reach and enter appropriate cells, this siRNA incorporated proprietary chemical modifications designed to provide it with "drug-like" properties. Intravenous injection of the modified siRNA into mice resulted in silencing of apoB messenger RNA (mRNA) in liver and intestine, and reduced blood levels of both apoB protein and total cholesterol. In parallel experiments, the ability of siRNAs to silence the human apoB gene in a transgenic mouse model was also demonstrated. The apoB gene is highly relevant clinically and to date has not been amenable to targeting with traditional small molecule, protein, or antibody therapies.


"We have meaningfully advanced the field of RNAi in this first ever demonstration of RNAi mediated by systemically delivered siRNAs, providing tangible evidence of the broad potential for RNAi therapeutics," said Hans- Peter Vornlocher, Ph.D., Vice President of Research at Alnylam Europe AG. "We are excited that our research progress has been recognized by the prestigious journal Nature, as Alnylam continues our leading-edge therapeutic research to harness RNAi for a whole new class of medicines."


In this robust and well controlled study, Alnylam scientists generated the first in vivo evidence that a siRNA triggers RNAi-mediated degradation of its target mRNA in mice. Specific cleavage of the apoB mRNA at the predicted site was demonstrated, using sophisticated analytical methods. This confirmation of the specific mechanism of action of siRNAs reinforces their therapeutic potential to harness the natural catalytic process of RNAi for the treatment of disease.


"This significant research is a major step forward as we seek to develop systemic RNAi therapeutics for the broad-based application of RNAi to important diseases such as cardiovascular disease, diabetes, obesity, hepatitis, cancer, and many infectious diseases," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam Pharmaceuticals. "Alnylam remains committed to applying our scientific expertise and proprietary technologies to advance both direct and systemic applications of RNAi, including the continued improvement of systemic RNAi technology for human therapeutics."















Conference Call Information


Alnylam will discuss these results during its regularly scheduled earnings conference call, which will take place today, November 10, 2004, at 4:30 pm EST. The call may be accessed by dialing 800-260-8140 (domestic) or 617-614- 3672 (international) five minutes prior to the start time, and providing the passcode 34345993.


A replay of the call will be available from 6:30 pm EST on November 10, 2004 until November 17, 2004. To access the replay, please dial 888-286-8010 (domestic) or 617-801-6888 (international), and provide the access code 61185381. A live audio webcast of the call will also be available on the "Investors" section of the Company's website, alnylam. An archived webcast will be available on the Alnylam website approximately two hours after the event, and will be archived for 14 days thereafter.


About RNAi


RNA interference, or RNAi, is a naturally occurring mechanism within cells for selectively silencing and regulating specific genes that is potentially the basis for a new class of therapeutic products. Since many diseases are caused by the inappropriate activity of specific genes, the ability to silence and regulate such genes selectively through RNAi could provide a means to treat a wide range of human diseases. The discovery of RNAi has been heralded by many as a major breakthrough, and the journal Science named RNAi the top scientific achievement of 2002, as well as one of the top ten scientific advances of 2003.


About Alnylam


Alnylam is a biopharmaceutical company seeking to develop and commercialize novel therapeutics based on RNA interference, or RNAi. Growing from its foundation as the world's first company focused on RNAi therapeutics, the company's leadership in the field of RNAi is supported by its preeminent founders and advisors and its strengths in fundamental patents, technology, and know-how that underlie the commercialization of RNAi therapeutics. Alnylam is developing a pipeline of RNAi products using Direct RNAi(TM) to treat ocular, central nervous system, and respiratory diseases and Systemic RNAi(TM) to treat a broad range of diseases, including oncologic, metabolic, and autoimmune diseases. The company's global headquarters are in Cambridge, Massachusetts. For additional information, please visit alnylam.


Forward-Looking Statements


Various statements in this release concerning our future expectations, plans, prospects and future operating results constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including risks related to: our approach to discover and develop novel drugs, which is unproven and may never lead to marketable products; our ability to obtain additional funding to support our business activities; our dependence on third parties for development, manufacture, marketing, sales and distribution of our products; the successful development of products, all of which are in early stages of development; obtaining regulatory approval for products; competition from others using technology similar to ours and others developing products for similar uses; obtaining, maintaining and protecting intellectual property utilized by our products; our dependence on collaborators; and our short operating history; as well as those risks more fully discussed in the "Certain Factors That May Affect Future Results" section of our Form 10-Q filed with the Securities and Exchange Commission. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. We do not assume any obligation to update any forward-looking statements.


Contact


Lilian Stern, Stern Investor Relations, Inc., Telephone: 1-212-362-1200


Media Contacts:


In USA, Kathryn Morris, KMorrisPR, Telephone: 1-845-635-9828


In Europe, Michael Sinclair, Halsin Partners, Telephone: 44-(0)870-747- 0800


alnylam

New Research Claims Cholesterol Drug Could Reduce Risk Of Amputations In People With Diabetes

People with diabetes who were prescribed the cholesterol-lowering drug fenofibrate reduced their risk of minor amputations by 36 per cent, according to new research.


Researchers in Australia, Finland and New Zealand looked at almost 10,000 people aged between 50 and 75 with Type 2 diabetes. About half of them were given fenofibrate while the other half were given placebos.


New discovery


The study, first published in 2005, aimed to see if fenofibrate prevented heart disease, which it did not. But in this new analysis, experts found patients on fenofibrate had a 36 per cent lower risk of a first amputation than those on the placebo.


The risk of minor amputations in people without large vessel arterial disease was nearly 50 per cent lower in the group taking fenofibrates, but the risk of a major amputation was not substantially different between the two groups. Taller people were also more likely to have amputations.


Fenofibrates can cause side effects including abdominal pain, nausea, pancreas and lung problems.


Leading research forward


"This large trial suggests that the drug fenofibrate could play a role in the reduction of below-the-ankle amputations in people with Type 2 diabetes," said Dr Victoria King, Research Manager at Diabetes UK.


"We know that approximately 100 people a week in the UK lose a toe, foot or lower limb due to diabetes.


"Managing blood glucose levels by keeping them within acceptable limits can cut the risk of diabetes-related amputations, and trials like this one guide us towards further ways of reducing the risk of diabetes associated amputations."

Source
Diabetes UK


View drug information on Fenofibrate.