Complementary Medicine News

Researchers have identified a protein they say appears to be a primary player in maintaining normal functioning of an important class of neurons – those brain cells that produce, excrete and then reabsorb dopamine neurotransmitters. These molecules command numerous body functions, ranging from management of behavior and mood to control of movement, and one day may hold the key to why and how some people develop Parkinson’s and other brain diseases.

In the Journal of Neuroscience, the scientists say that this protein, which they call the Nurr-1 interacting protein (NuIP), interacts with, and helps regulate the activity of the Nurr1 gene. That gene has long been known to be essential to development and maintenance of dopaminergic neurons.

Efforts to control Nurr-1 have been underway by pharmaceutical drug developers, because these neurons are the ones that die in Parkinson’s disease and which are, conversely, over-active in schizophrenia. Now NuIP may also provide a good drug target for these and other neurological disorders caused by faulty dopamine transmission, says the study’s lead investigator, Howard J. Federoff, M.D., Ph.D., Executive Vice President for Health Sciences and Executive Dean of the School of Medicine at Georgetown University Medical Center.

“We do not know yet whether this is true, but one can speculate that small molecules that may either facilitate, stabilize, or otherwise regulate the action of NuIP on Nurr1 may be relevant in a therapeutic context,” says Federoff, a neuroscientist who did much of this research at the University of Rochester School of Medicine and Dentistry before coming to Georgetown in 2007. His three other co-authors are from Rochester.

In this study, the researchers specifically set out to find potential “partners” of Nurr1 because no molecule had yet been found that could positively activate the Nurr1 gene or the protein receptor it produces. Crystal structures of the Nurr1 receptor show it to have an area where another protein could bind to it, but this “domain” is too small for usual binding partners, such as steroids.

Using a library of potential molecules in laboratory samples of brain cells from a developing mouse, the researchers identified a new family of gene products that interacts with and regulates the activity of Nurr1. These gene products are all derived from the NuIP gene.

They then discovered that loss of NuIP function led to decreased numbers of cells in culture and to a decreased expression of the dopamine transporter on these neurons.

The mechanism underlying the ability of NuIP to positively regulate the activity of Nurr1 is not yet clear, but the researchers suspect that “as yet unknown upstream signals impinge on NuIP which, in turn, instructs Nurr1 to become activated and thus facilitates the expression of a set of genes involved in dopamine neuron phenotypic maturation,” Federoff says. “That means they become more like a dopamine neuron which manufactures, releases, and the takes up the neurotransmitter.”

“The relevance of NuIP to Parkinson’s disease has not been established but it is tempting to speculate that it participates in the maintenance of the mature phenotype of midbrain dopaminergic neurons which are rendered vulnerable in this neurological disease,” Federoff says.

The study was supported by grants from the Department of Defense.

About Georgetown University Medical Center

Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through our partnership with MedStar Health). Our mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis — or “care of the whole person.” The Medical Center includes the School of Medicine and the School of Nursing and Health Studies, both nationally ranked, the world-renowned Lombardi Comprehensive Cancer Center and the Biomedical Graduate Research Organization (BGRO), home to 60 percent of the university’s sponsored research funding.

Source: Karen Mallet

Georgetown University Medical Center Continue reading →

UroToday – Whilst the two major risk factors for bladder cancer are smoking and occupational exposure to chemicals, there is also evidence of a genetic component to its aetiology. Candidate gene studies have mostly focussed on genes involved in adduct metabolism and DNA repair, including a recent consortium-based meta-analysis (Stern et al., Cancer Res 2009, 69:6857-64), which included 10 SNPs in seven DNA repair genes in 13 studies. Weak but consistent associations were found for ERCC2 Asp312Asn, NBN Glu185Gln and XPC Ala499Val.

In contrast to candidate gene studies, genome wide association studies (GWAS) adopt a hypothesis-free approach to the detection of genetic variations associated with common diseases, which has resulted in the discovery of previously unsuspected aetiological pathways. Recently, two genome wide association studies in bladder cancer have been published and a third is awaited with interest.

The first genome-wide association study in bladder cancer was published by Kiemeney et al. in September 2008 (Nat Genet 2008 40:991-5) and included 1803 cases and 34336 controls in phase I and 2165 cases and 3800 controls in phase II. In phase I, no single SNP reached the genome-wide significance threshold, but the ten most significant SNPs (all p Continue reading →

Abnormal heart rhythms – arrhythmias – are killers. They strike without warning, causing sudden cardiac death, which accounts for about 10 percent of all deaths in the United States.

Vanderbilt investigators have discovered a new molecular mechanism associated with arrhythmias. Their findings, reported in The Journal of Clinical Investigation, could lead to novel arrhythmia treatments.

“The current antiarrhythmic drugs do not prolong life,” said Bj?¶rn Knollmann, M.D., Ph.D., associate professor of Medicine and Pharmacology and the senior author of the current report. “There’s a large need for new approaches to antiarrhythmic therapy.”

In their quest to understand how irregular heart rhythms arise – as a way to find new molecular targets for treatment – Knollmann and his colleagues have focused on the role of calcium inside heart muscle cells.

Calcium is central to the contractile cycle. After it is released from its storage sites in heart muscle cells, it interacts with proteins called troponins, part of the cell’s myofilament contractile apparatus. The interaction of calcium with troponins regulates myofilament activation and contraction.

Mutations in troponin genes had been linked to inherited forms of hypertrophic cardiomyopathy (HCM), which carries a high risk of sudden cardiac death. HCM is perhaps most famous as a cause of sudden cardiac death in young athletes, but it can affect individuals of any age.

In previous studies, Knollmann’s team demonstrated that troponin mutations associated with HCM increase the sensitivity of the troponins to calcium – they bind calcium more readily, which activates the myofilaments more easily and results in stronger contractions.

Increased myofilament calcium sensitivity has also been found in acquired heart diseases, such as heart failure, that have a high incidence of sudden cardiac death, Knollmann said. He and his colleagues proposed that increased myofilament calcium sensitivity contributes to arrhythmia susceptibility.

The researchers examined the heart rhythms of mice expressing various troponin mutants that cause HCM and showed that the mice develop ventricular tachycardia (a particular arrhythmia). The risk for this arrhythmia was directly related to the degree of calcium sensitization caused by the troponin mutation: the higher the calcium sensitivity, the greater the arrhythmia risk.

The investigators then tested whether or not a calcium-sensitizing drug – infused into the mouse heart – would cause arrhythmias. It did.

“We could make a normal heart prone to arrhythmias simply by changing the sensitivity of the myofilaments to calcium,” Knollmann said.

Calcium-sensitizing drugs are used clinically in Europe and Japan to treat heart failure (because they increase the strength of contraction), but they have not been approved for use in the United States. The current studies suggest that these agents would increase the risk of arrhythmias.

In addition to demonstrating that a calcium-sensitizing drug could cause arrhythmias, Knollmann and colleagues showed that an agent that desensitizes the myofilaments – makes them less “willing” to bind calcium – prevented arrhythmias. The drug they used is limited to in vitro testing, but the studies validate the concept of calcium desensitization as a way to prevent or block arrhythmias.

“The next step is to look for agents that have a desensitizing effect and then try them therapeutically, first in our mouse models, and then potentially further along to patients,” Knollmann said.

“We’re excited about these studies because we believe that we have identified a novel mechanism that renders the heart susceptible to arrhythmias and a new therapeutic target for familial hypertrophic cardiomyopathy and other arrhythmia syndromes.”

The first author of the current report, Franz Baudenbacher, Ph.D., assistant professor of Biomedical Engineering and Physics, played a key role in studying the electrical changes that caused the arrhythmias. Using optical imaging, he and colleagues in the Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE) measured how electrical excitation traveled across the hearts expressing troponin mutants or treated with calcium-sensitizing agents. These experiments defined the electrical underpinnings of the arrhythmias.

The National Institutes of Health, the American Heart Association and VIIBRE supported the research.

Source: Leigh MacMillan

Vanderbilt University Medical Center Continue reading →

Virginia Commonwealth University School of Medicine researchers have discovered a gene involved with the production of sperm that may contribute to male infertility and lead to new approaches to male contraception.

One in six couples trying to conceive a baby is affected by infertility, according to the American Fertility Association – and in about half of these cases, a male factor is present. Sperm defects are often found to be the main cause or a contributing cause.

Sperm are produced in the testicles through a three-step process called spermatogenesis. During the final stage, known as spermiogenesis, a lot of changes take place, including the packaging of DNA into the sperm head and the formation of the sperm tail, which propels the sperm cell toward the egg.

In the study, published online in the Early Edition of the Proceedings of the National Academy of Sciences the week of Sept. 14, the team reported that male mice lacking a protein called meiosis expressed gene 1, or MEIG1, were sterile as a result of impaired spermiogenesis – the process that encompasses changes in the sperm head and the formation of the tail.

According to Jerome F. Strauss III, M.D., Ph.D., dean in the VCU School of Medicine, and Zhibing Zhang, M.D., Ph.D., assistant professor in the VCU Department of Obstetrics and Gynecology, the team also found that MEIG1 associates with the Parkin co-regulated gene protein, or PACRG protein, and that testicular PACRG protein is reduced in MEIG1-deficient mice. PACRG is thought to play a key role in assembly of the sperm tail, and the reproductive phenotype of PACRG -deficient mice mirrors that of the MEIG1-mutant mice.

“We discovered that MEIG1 is essential for male fertility. Moreover, our findings reveal a critical role for the MEIG1/PACRG partnership in the function of a structure that is unique to sperm, the manchette. The absence of a normal manchette in mice lacking MEIG1 totally disrupts the maturation process of sperm,” said Strauss.

“In addition to having an impact on fertility, the discovery identifies a new target for drug discovery for a much needed reversible male method of contraception,” he said.

This work was supported by a grant from the National Institutes of Health.

Strauss and Zhang, who are affiliate faculty members in the VCU Department of Biochemistry and Molecular Biology, collaborated with VCU researchers Xuening Shen, M.D., and David R. Gude, Ph.D. Also contributing to this work were Bonney M. Wilkinson, Ph.D., and Monica J. Justice, Ph.D., from the Baylor College of Medicine; Charles J. Flickinger, Ph.D., and John C. Herr, Ph.D., with the University of Virginia; and Edward M. Eddy, Ph.D., with the National Institute of Environmental Health Sciences.

Source:
Sathya Achia Abraham

Virginia Commonwealth University Continue reading →

Immortality and uncontrolled cell division are the fundamental differences between cancer cells and normal cells.

A widely held explanation for these differences is that the biological clocks in cancer cells are damaged and can’t regulate cell division in the fashion that they do in normal cells.

This assumption is challenged by the results of the first experiment that has continuously monitored variations in the rate of cell division of cultured mammalian cells for extended periods. The results are reported this week in a paper published in the online Early Edition of the Proceedings of the National Academy of Sciences.

The experiment discovered that one line of immortal cells have functioning biological clocks but their internal clocks have no effect on the rate at which they divide and grow. (Immortal cells have the same basic properties as cancer cells but are created in the laboratory where they are used for a wide variety of purposes.)

“The current assumption has been that the biological clocks in cancer cells have been disabled,” says Julie Pendergast, a research associate who participated in the study. “We determined that the immortalized cells in our experiment had functioning biological clocks but these clocks don’t control the process of cell division. That is the paradigm shifting aspect of our study.”

If confirmed by follow-up studies, this insight could aid in the development of new cancer therapies.

“This strengthens the possibility that the biological clock pathway could be an effective target for anti-cancer drugs,” says Shin Yamazaki, the research professor of biological sciences at Vanderbilt who directed the project. “For example, if a drug could be found that restores the control of the biological clock over cancer cell division, it could reduce tumor growth.”

Biologists have observed that cell division in normal cells in species ranging from unicellular organisms to humans peaks at specific times of the day and consider this as indirect evidence that the process is regulated by their internal biological clocks. Cells in the human mouth, for example, tend to divide in the evening, just before nightfall.

“There is a general evolutionary explanation for this,” says research associate Julie Pendergast who participated in the study. “Ultraviolet light is one of the primary causes of mutations. Cells are particularly vulnerable to mutations during cell division. So organisms with cells that divide at night have a selective advantage.”

In addition, there has been a considerable amount of indirect evidence that mitosis (division) in cancer cells is not under 24-hour control. For example, “experiments have found that cells turn cancerous when certain circadian clock genes have been knocked out,” says Yamazaki. The results of other experiments that have periodically sampled cancer cell division rates also support this possibility.

Yamazaki designed and built a special system to monitor cell division in real time. He and his colleagues designed a special “reporter” molecule incorporating a gene that produces an enzyme that makes green light. They figured out how to insert this reporter into a cell’s genome so that it produces the luminescent enzyme when the cell divides. This allows them to use a camera to continuously measure variations in the rate of cell division over long periods of time.

For the current experiment, the researchers inserted their special reporter into immortalized rat fibroblasts formed from connective tissue taken from rats. They selected this cell line because it was known to have working circadian clocks.

They have obtained consistent results in preliminary studies of lung cancer cells.

The other participants in the study were Professor Yoshihiro Ohmiya at the Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan and post-doctoral researcher Mijung Yeom, now at the Acupuncture and Meridian Science Research Center, Kyung Hee University in Seoul, South Korea.

The research was supported by funds from the National Institutes of Health, Research Foundation for Opto-Science and Technology, the NEDO Project and Takeda Science Foundation.

Source: Vanderbilt University Continue reading →

A genomic study of cerebrospinal fluid (CSF) has added a new gene to the list of potential genetic contributors to Alzheimer’s disease, a national research team led by Indiana University School of Medicine scientists has reported.

The research team conducted a genome-wide analysis of potential CSF biomarkers that could be used for early detection of Alzheimer’s disease, using samples from 374 participants in the national Alzheimer’s Disease Neuroimaging Initiative (ADNI).

“This study was one of the first genome-wide analyses of biomarkers in cerebrospinal fluid, which has direct access to the brain and allows you to look at biochemical features that might be more directly tied to the disease,” said Andrew J. Saykin, Psy.D., Raymond C. Beeler Professor of Radiology and Imaging Sciences and director of the IU Center for Neuroimaging. The study was reported in the online edition of Neurology, the journal of the American Academy of Neurology.

In the genome-wide association study, researchers looked for genetic variations that could be related to CSF levels of three proteins – beta amyloid, tau and phosphorylated tau – that are linked to damage seen in brains of Alzheimer’s patients.

The primary novel finding was that a gene known as enhancer of polycomb homolog 2 (EPC2) was associated with total levels of the tau protein in the cerebrospinal fluid. This gene, which has not previously surfaced in other studies looking for Alzheimer-related markers, has been associated with a gene deletion syndrome that includes mental retardation, short stature and epilepsy.

EPC2 is also involved in the formation of a DNA structure, heterochromatin, that plays a role in the activation and control of gene activity. That process, called epigenetics, refers to the alteration of gene expression by factors beyond the instructions in the DNA itself, including environmental factors.

“The association of CSF tau and the EPC2 gene suggests a possible epigenetic mechanism that warrants follow-up in other samples. These epigenetic processes, in which genome function can be modified through interacting with the internal or external environment, are suspected of playing a role in neurodegenerative diseases such as Alzheimer’s,” said Dr. Saykin, who leads the Alzheimer’s Disease Neuroimaging Initiative genetics component.

The co-first authors of the study were Sungeun Kim, Ph.D., assistant research professor of radiology and imaging sciences, and Shanker Swaminathan, Ph.D. candidate in medical and molecular genetics, at IU School of Medicine, which is located on the campus of Indiana University-Purdue University, Indianapolis. Other investigators from IU include Li Shen, Ph.D., assistant professor of radiology and imaging sciences, Shannon L. Risacher, Ph.D. candidate in medical neuroscience, Kwangsik Nho, Ph.D., post doctoral fellow and Tatiana Foroud, Ph.D., P. Michael Conneally Professor of Medical and Molecular Genetics and director of the Hereditary Genomics Division.

The research team also included collaborating scientists from the University of Pennsylvania School of Medicine; University of California, Irvine; The Translational Genomics Research Institute in Phoenix; Pfizer Inc.; University of California, San Diego; and the Mayo Clinic College of Medicine. Michael W. Weiner, MD, of the University of California, San Francisco and the Department of Veterans Affairs Medical Center, San Francisco, is the principal investigator of the ADNI.

The Alzheimer’s Disease Neuroimaging Initiative is funded by the National Institute on Aging (NIA), a component of the National Institutes of Health (NIH), with additional support from pharmaceutical and related industries and not-for-profit organizations including the Alzheimer’s Association. The initiative combines clinical, brain imaging (MRI and PET scans) and genetic data with other measurements including CSF and plasma to search for biomarkers that could be used for early diagnosis of Alzheimer’s disease and design of more efficient clinical trials.

Source:

IU School of Medicine Continue reading →

Scientists at the University of Illinois have discovered an antifreeze-protein gene in cod that has evolved from non-coding or ‘junk’ DNA. Since the creation of these antifreeze proteins is directly driven by polar glaciation, by studying their evolutionary history the scientists hope to pinpoint the time of onset of freezing conditions in the polar and subpolar seas. Professor Cheng will present her latest results at the Annual Main Meeting of the Society for Experimental Biology in Canterbury on Tuesday the 4th April [session A2].

Fish such as cod that live in subzero polar waters have evolved to avoid freezing to death by using special antifreeze proteins that work by binding to ice crystals to prevent the crystals growing larger and causing problems. Most of these antifreeze proteins evolve by natural selection from existing proteins when the DNA coding for them duplicates itself and changes over time to give new functions. However, Professor Christina Cheng and her group have found the gene for the cod antifreeze protein has come from a non-coding region of their DNA known as “junk DNA”.

“This appears to be a new mechanism for the evolution of a gene from non-coding DNA”, says Professor Cheng, “3.5 billion years of evolution of life has produced many coding genes and conventional thinking assumes that new genes must come from pre-existing ones because the probability of a random stretch of DNA somehow becoming a functional gene is very low if not nil. This cod antifreeze gene might be an exception to this because it consists of a short repetitive sequence that only needs to be duplicated four times to give a fully functioning protein”.

Contact: Vicky Just
v.justlancaster.ac
Society for Experimental Biology Continue reading →

Researchers at the University of North Carolina at Chapel Hill have shown that disruption of the circadian clock – the internal time-keeping mechanism that keeps the body running on a 24-hour cycle – can slow the progression of cancer.

The study disputes some of the most recent research in the field indicating that alteration of this daily cycle predisposes humans and mice to cancer. The UNC researchers found that genetically altering one of four essential “clock” genes actually suppressed cancer growth in a mouse model commonly used to investigate cancer. The findings could enable clinicians to reset the internal clock of each cancer cell to render it more vulnerable to attack with chemotherapeutic drugs.

“Adjusting the clock in this way could certainly be a new target for cancer treatment,” said senior study author Aziz Sancar, M.D., Ph.D., a member of the UNC Lineberger Comprehensive Cancer Center and Sarah Graham Kenan Professor of Biochemistry and Biophysics in the UNC School of Medicine. Sancar is also a member of the National Academy of Sciences, the Turkish Academy of Sciences and the American Academy of Arts and Sciences.

“Our study indicates that interfering with the function of these clock genes in cancer tissue may be an effective way to kill cancer cells and could be a way to improve upon traditional chemotherapy,” Sancar said. His findings appear February 2, 2009 in the online early edition of the Proceedings of the National Academy of Sciences.

Previous research has shown that the disruption of the body’s natural circadian rhythms affects people’s health. One of the largest epidemiological studies ever performed, the Nurses’ Health Study, found that nurses who worked the night shift had a higher incidence of breast cancer than those who worked days. Another study of flight attendants whose internal biological clocks had been wrecked by travel on transatlantic flights produced similar findings.

Yet when scientists, including Sancar, began to tinker with the molecular mechanisms within the internal clocks of animal models, they did not always see such an effect. Circadian rhythms in humans and in mice are controlled by “clock genes,” four of which are absolutely essential. In a study four years ago, Sancar found that deleting the clock gene cryptochrome in mice did not increase the incidence of cancer as had previously been expected.

While altering the clock gene did not cause cancer in otherwise normal mice, Sancar and his colleagues wanted to see if it would accelerate the development of tumors in a mouse model that is already predisposed to cancer. Therefore, in this study they modified the cryptochrome gene in mice that also had defects in a gene called P53, which is mutated in nearly half of human cancers. The researchers found that disturbing the internal clock in these mice did not speed up the onset of cancer, but instead had the opposite effect – it extended their lives by 50 percent.

The researchers then wanted to know how interfering with the cryptochrome gene had reduced the incidence of cancer. By closely examining the series of biological events in the disease’s development, they determined that the mutation of this clock gene reactivates the intracellular signals that can eliminate cancerous cells. Sancar said this tactic essentially makes cancer cells more likely to commit cell suicide – through a process known as apoptosis – in response to the stresses of UV radiation or chemotherapy.

“These results suggest that altering the function of this clock gene, at least in the 50 percent of human cancers associated with p53 mutations, may slow the progression of cancer,” Sancar said. “In combination with other approaches to cancer treatment, this method may one day be used to increase the success rate of remission.”

The research was supported by the National Institutes of Health. Study co-authors from Sancar’s UNC laboratory include the lead author and postdoctoral fellow Nuri Ozturk, Ph.D.; Jin Hyup Lee, a graduate student; and postdoctoral fellow Shobhan Gaddemeedhi, Ph.D.

The study follows the recent publication earlier this month of another paper from Sancar’s laboratory in the Proceedings of the National Academy of Sciences. It suggested that chemotherapy treatment for cancer is most effective at certain times of day because that is when a particular enzyme system – one that can reverse the actions of chemotherapeutic drugs – is at its lowest levels in the body.

Click here to read the news release about the previous study.

Source: Leslie Lang
University of North Carolina School of Medicine Continue reading →

The University of North Carolina at Chapel Hill’s newest “library” is not the kind that will entice an average book
lover, but it eventually will please thousands of plant scientists around the world. Through such researchers’ work, it will
undoubtedly contribute to improving crops that humans around the planet depend on every day, its developers say.

Named Phytome, the unique library is a compilation of voluminous genetic data on 39 plant species. The list includes almost
all the world’s most valuable crops, among them rice, wheat, corn and potatoes.

“But it’s also much more than just a repository of genetic information,” said Dr. Todd J. Vision, assistant professor of
biology in UNC’s College of Arts and Sciences.

“It allows plant researchers to ask complex questions that involve comparisons across different genes and species, such as
‘what genes with known function are related to this gene with unknown function?’ or ‘what biochemical functions have been
gained or lost in different species,’” Vision said.

Answers to those kinds of questions will lead to plants that yield more food and resist damage from diseases and insects more
successfully, he said. They also can lead to better and cheaper medicines and plant products like cotton, paper and rubber.

“A persistent challenge of genomics is how to capture, analyze and distribute the massive amounts of data being churned out
at record levels from ongoing genome projects,” he said. “Creating useful and accessible tools like this is critical to the
field. Even if researchers have access to all the genomic data and all the methods necessary to analyze it, it takes a lot of
human and computer effort to put those two things together in one user-friendly package like Phytome.”

Phytome went online at www.phytome in the fall after two years work and already is being used by basic and applied
scientists worldwide. The first version of the database contains information on more than 730,000 unique protein sequences in
more than 25,000 protein families.

Analysis of that data required 460 days of computer processing time, but it was condensed into a few short weeks by use of
parallel computing, Vision said.

Currently, scientists know the complete genetic makeup of only a handful of plants although humans are economically dependent
on dozens of different ones, he said. It would be far too expensive and time-consuming, however, to characterize the genomes
of all of them experimentally.

“Many plants are impractical to work with experimentally because they have genomes full of material that serves no known
function,” Vision said. “For example, the lily genome is roughly 40 times the size of the human genome.”

Nevertheless, the gene content of lilies can be predicted reasonably well by looking at a related plant with a small genome,
like rice, he said. To breed better crops, it’s important to be able to leverage the information from the tractable model
systems that scientists already know so much about.

“We will continue to add new features to Phytome over the next few years,” Vision said. “Perhaps the most important will be
the ability to compare the genetic maps of multiple species simultaneously and predict the gene content in regions of plant
genomes that have not yet been deciphered.”

Besides Vision, others involved in the development of Phytome are Dr. Stefanie Hartmann, a postdoctoral researcher in
biology; Dihui Lu, a graduate student in information and library science; and computer programmer Jason Phillips.

The National Science Foundation is supporting the project with a five-year, $1 million grant it awarded to UNC in 2002.

“This is a unique resource for scientists trying to understand the genes contributing to variation in traits of economic
importance in crops,” Vision said.

Contact: David Williamson
919-962-8596
University of North Carolina at Chapel Hill
unc.edu Continue reading →

Genzyme Corporation (NASDAQ: GENZ) announced two-year follow-up data from patients enrolled in the phase 2 clinical trial for its investigational oral therapy for Gaucher disease type 1 known as eliglustat tartrate (formerly Genz-112638). Continued improvements were observed across all endpoints, including bone disease, at the two-year timepoint, compared with baseline. The two-year results were presented for the first time today at the Lysosomal Disease Network WORLD Symposium in Miami, Fla.

Eliglustat tartrate, a capsule taken orally, is being developed to provide a convenient treatment alternative for adult patients with Gaucher disease type 1, and to offer a broader range of treatment options for patients and physicians to achieve individual therapeutic goals. Genzyme’s Cerezyme® (imiglucerase for injection), the standard of care for patients with Gaucher disease type 1, is administered through intravenous infusions.

Genzyme reported last year that the phase 2 trial had met its primary composite endpoint: a clinically meaningful response in at least two of three endpoints (improvements in spleen size, hemoglobin and platelet levels) in individual patients after the 52-week study period. Twenty-two of 26 study participants completed at least one year of treatment, and 20 patients completed two years of treatment. The study is continuing with 19 patients in their third year. Medical centers in North America, South America, Europe and the Middle East participated in this study.

Continued improvement was observed through two years for patients who received eliglustat tartrate:

- Spleen volumes decreased from baseline by a mean of 52 percent and liver volumes decreased from baseline by 24 percent.

- Hemoglobin levels increased from baseline by a mean of 2.1 grams per deciliter.

- Platelet counts increased from baseline by a mean of 81 percent.

- Chitotriosidase levels decreased from baseline by a median of 63 percent (only 18 month data are available to date), among the 17 patients with chitotriosidase. Chitotriosidase is commonly monitored by physicians as a biomarker of Gaucher disease burden and response to treatment.

“We remain committed to building our Gaucher health portfolio by developing clinically meaningful solutions to support individualized care for this community,” said Genzyme Senior Vice President Geoff McDonough, MD. “We have set a high threshold for success for eliglustat tartrate, and are very encouraged by the results we continue to observe.”

According to the ICGG Gaucher Registry, an international multi-center program sponsored by Genzyme that tracks the routine clinical outcomes for patients with Gaucher disease, irrespective of treatment status, over 80 percent of Gaucher patients have radiologic evidence of bone disease. The data presented today also included pre-planned analyses that suggest eliglustat tartrate may positively impact some indicators of bone disease through two years of follow up. These indicators include bone mineral density, as measured by dual energy x-ray absorptiometry (DXA), and the proportion of dark marrow on magnetic resonance imaging (MRI). Dark marrow reflects the infiltration of diseased cells into the bone marrow. Specifically:

- Bone mineral density (BMD) in the lumbar spine showed clinically and statistically significant improvements (Z score = +0.60, T score = +0.56) in 16 patients with available data at baseline, one and two years. Four out of six of these patients who were below the normal range at baseline improved to have normal BMD Z scores at two years.

- In the 18 patients with dark marrow visible on MRI at baseline, six improved by one year, an additional two improved by two years and 10 remained stable.

“Bone disease is a primary cause of morbidity for patients with Gaucher disease,” continued Dr. McDonough. “These data suggest that eliglustat tartrate may have a significant effect on bone mineral density, which could make a positive impact on the lives of patients.”

Eliglustat tartrate was generally well tolerated. The most common adverse events (AEs) reported in greater than 10 percent of patients by two years included viral infections (six patients), urinary tract infections, increased blood pressure, and abdominal pain (three patients each). Eight drug-related AEs, including one serious event, were reported in six patients. All were mild in severity.

Genzyme has begun enrollment in two global, multi-center, phase 3 trials of eliglustat tartrate. The first trial, ENCORE, is a randomized, open-label study for adult patients with Gaucher disease type 1 designed to compare eliglustat tartrate to Cerezyme. Adult patients who have previously received Cerezyme for at least three years and have reached their therapeutic goals may qualify for this trial. The second trial, ENGAGE, is a randomized, double-blind, placebo-controlled study for patients with a confirmed diagnosis of Gaucher disease type 1. Patients who have not been treated in the last 12 months for Gaucher disease may qualify for this study. Over 30 centers in more than 20 countries are participating in these trials. Genzyme is also initiating a trial comparing once-daily dosing of eliglustat tartrate with twice-daily dosing.

About Gaucher disease

Gaucher disease is an inherited condition affecting fewer than 10,000 people worldwide. People with Gaucher disease do not have enough of an enzyme, ??-glucosidase (glucocerebrosidase) that breaks down a certain type of fat molecule. As a result, lipid engorged cells (called Gaucher cells) amass in different parts of the body, primarily the spleen, liver and bone marrow. Accumulation of Gaucher cells may cause spleen and liver enlargement, anemia, excessive bleeding and bruising, bone disease and a number of other signs and symptoms. The most common form of Gaucher disease, type 1, does not affect the brain or nervous system.

About eliglustat tartrate

Eliglustat tartrate, a novel glucosylceramide analog given orally, is designed to partially inhibit the enzyme glucosylceramide synthase, which results in reduced production of glucosylceramide. Glucosylceramide is the substance that builds up in the cells and tissues of people with Gaucher disease. In preclinical studies, the molecule, developed with James A. Shayman, MD, from the University of Michigan, has shown high potency and specificity. Based on its mechanism of action, which is independent of genotype, eliglustat tartrate may be a potential therapy for all patients with Gaucher disease type 1. Initiation of the Phase 2 and 3 studies of eliglustat tartrate in Gaucher disease followed completion of an extensive pre-clinical research effort and a Phase 1 program that involved more than 120 subjects in three separate studies. Safety analysis of the phase 2 trial demonstrated that eliglustat tartrate was well tolerated. The most common adverse events (AEs) by two years included viral infections, urinary tract infections, increased blood pressure and abdominal pain.

Cerezyme important safety information

Approximately 15 percent of patients have developed IgG antibodies, and these patients have a higher risk of hypersensitivity reaction. Therefore periodic monitoring is suggested; caution should be exercised in patients with antibodies or prior symptoms of hypersensitivity. Symptoms suggestive of hypersensitivity occurred in 6.6 percent of patients, and include anaphylactoid reaction, pruritus, flushing, urticaria, angioedema, chest discomfort, dyspnea, coughing, cyanosis and hypotension. Reactions related to Cerezyme administration have been reported in less than 15 percent of patients. Each of the following events occurred in less than two percent of the total patient population. Reported adverse events include nausea, vomiting, abdominal pain, diarrhea, rash, fatigue, headache, fever, dizziness, chills, backache and tachycardia. Adverse events associated with the route of administration include discomfort, pruritus, burning, swelling or sterile abscess at the site of venipuncture. For full prescribing information, please visit genzyme.

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