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By combining a research technique that dates back 136 years with modern molecular genetics, a Johns Hopkins neuroscientist has been able to see how a mammal’s brain shrewdly revisits and reuses the same molecular cues to control the complex design of its circuits.

Details of the observation in lab mice, published Dec. 24 in Nature, reveal that semaphorin, a protein found in the developing nervous system that guides filament-like processes, called axons, from nerve cells to their appropriate targets during embryonic life, apparently assumes an entirely different role later on, once axons reach their targets. In postnatal development and adulthood, semaphorins appear to be regulating the creation of synapses those connections that chemically link nerve cells.

“With this discovery we’re able to understand how semaphorins regulate the number of synapses and their distribution in the part of the brain involved in conscious thought,” says David Ginty, Ph.D., a professor in the neuroscience department at the Johns Hopkins University School of Medicine and a Howard Hughes Medical Institute investigator. “It’s a major step forward, we believe, in our understanding of the assembly of neural circuits that underlie behavior.”

Because the brain’s activity is determined by how and where these connections form, Ginty says that semaphorin’s newly defined role could have an impact on how scientists think about the early origins of autism, schizophrenia, epilepsy and other neurological disorders.

The discovery came as a surprise finding in studies by the Johns Hopkins team to figure out how nerve cells develop axons, which project information from the cells, as well as dendrites, which essentially bring information in. Because earlier work from the Johns Hopkins labs of Ginty and Alex Kolodkin, Ph.D., showed that semaphorins affect axon trajectory and growth, they suspected that perhaps these guidance molecules might have some involvement with dendrites.

Kolodkin, a professor in the neuroscience department at Johns Hopkins and a Howard Hughes Medical Institute investigator, discovered and cloned the first semaphorin gene in the grasshopper when he was a postdoctoral fellow. Over the past 15 years, numerous animal models, including strains of genetically engineered mice, have been created to study this family of molecules.

Using two lines of mice one missing semaphorin and another missing neuropilin, its receptor postdoctoral fellow Tracy Tran used a classic staining method called the Golgi technique to look at the anatomy of nerve cells from mouse brains. (The Golgi technique involves soaking nerve tissue in silver chromate to make cells’ inner structures visible under the light microscope; it allowed neuroanatomists in 1891 to determine that the nervous system is interconnected by discrete cells called neurons.)

Tran saw unusually pronounced “spines” sprouting willy-nilly in peculiar places and in greater numbers on the dendrites in the neurons of semaphorin-lacking and neuropilin-lacking mice compared to the normal wild-type animals. It’s at the tips of these specialized spines that a lot of synapses occur and neuron-to-neuron communication happens, so Tran suspected there might be more synapses and more electrical activity in the neurons of the mutant mice.

The researchers tested this hypothesis by examining even thinner brain slices under an electron microscope.

The spines of both semaphorin-lacking and neuropilin-lacking mice were dramatically enlarged, compared to those of the smaller, spherical-looking spines in the wild-type mice. In wild types, Tran generally noted a single site of connection per spine. In the mutants, the site of connection between two neurons was often split.

Next, the team recorded the electrical output of mutant and wild-type neurons and found that the mutants, with more spines and larger spines, also had about a 2.5-times increase in the frequency of electrical activity, suggesting that this abnormal synaptic transmission is due to an increase in the number of synapses.

What causes synapses to form or not form in appropriate or inappropriate places is an extremely important and poorly understood process in the development of the nervous system, Kolodkin says, explaining that the neurons his team studies can have up to 10,000 synaptic connections with other neurons. If connections between neurons are not being formed how and where they’re supposed to, then miscommunication occurs and circuits malfunction; as a result, any number of diseases or disorders might develop.

“Seizures can be interpreted as an uncontrolled rapid-firing of certain neural circuits,” Kolodkin asserts. “Clearly there’s a deficit in these animals that has a human corollary with respect to epilepsy. It’s also thought that schizophrenia and autism spectrum disorders have developmental origins of one sort or another. There likely are aspects to the formation of synapses if they’re not in the correct location and in the correct number that lead to certain types of defects. The spine deficits in these mice that are lacking semaphorin or its receptor appear very similar to those that are found in Fragile X, for instance.”

This work was supported by the National Institutes of Health, National Science Foundation, and the Howard Hughes Medical Institute.

Johns Hopkins authors of this paper are Tracy S. Tran, Alex L. Kolodkin, David D. Ginty, Richard L. Huganir, Roger L. Clem, and Dontais Johnson. Other authors are Maria E. Rubio of the University of Connecticut; and Lauren Case and Marc Tessier-Lavigne, of Stanford University.

Source: Johns Hopkins Medicine Continue reading →

Shire plc (LSE: SHP, NASDAQ: SHPGY), the global specialty biopharmaceutical company, reported that it has completed its submission of a New Drug Application (NDA) for velaglucerase alfa, its enzyme replacement therapy in development for the treatment of Type 1 Gaucher disease, with the U.S. Food and Drug Administration (FDA). The Company also announced positive results from the final two Phase III studies of velaglucerase alfa, with both studies reaching all of their primary and secondary endpoints.

“The submission of the NDA for velaglucerase alfa, earlier than previously announced, is an important milestone for Shire, bringing us another step closer to providing a new treatment option for patients with Type 1 Gaucher disease,” said Sylvie Gregoire, President of Shire Human Genetic Therapies. “We are also pleased to report that the data from our final two Phase III trials met our expectations by reaching all of their primary and secondary endpoints, demonstrating consistency with the results recently reported from the first Phase III trial. In addition, we are on-track to submit our European filing for velaglucerase alfa by the end of 2009.”

Shire’s velaglucerase alfa program included the largest and most comprehensive set of Phase III clinical trials conducted to date for Gaucher disease. Over 100 patients at 24 sites in 10 countries around the world have participated in the clinical studies.

“I am impressed by the series of clinical trials that were designed to evaluate velaglucerase alfa at multiple doses and in different patient groups,” said Dr. Christine Eng, Professor of Molecular and Human Genetics, Baylor College of Medicine. “The inclusion of children, who are often the sickest patients, is especially useful. I believe velaglucerase alfa will be an important new treatment option for Type 1 Gaucher disease and I am pleased that there is a mechanism in place for physicians to access this therapy for their patients.”

Velaglucerase alfa is made using Shire’s proprietary technology, in a human cell line. The enzyme produced has the exact human amino acid sequence and has a human glycosylation pattern.

Phase III Studies Overview and Results

All three Phase III studies of velaglucerase alfa demonstrated positive results. The product was generally well-tolerated in both treatment naive and previously treated Gaucher patients. The three studies included: Study 032, which studied velaglucerase alfa in naive patients; Study 039, which was a head-to-head study of velaglucerase alfa and imiglucerase; and Study 034, which was a switch study from imiglucerase to velaglucerase alfa.

As reported on August 3, 2009, Study 032 in naive patients met its primary endpoint which evaluated change in hemoglobin concentrations from baseline.

Study 039 was a 9-month, randomized, double-blind efficacy study in 34 treatment naive patients aged two years and older that compared velaglucerase alfa to imiglucerase. Patients were eligible to participate in the study if they presented with disease-related anemia and had at least one of the following clinical manifestations of Gaucher disease: thrombocytopenia, moderate splenomegaly or a readily palpable enlarged liver. Patients were randomized to receive either velaglucerase alfa or imiglucerase at 60 U/ kg every other week. The primary endpoint was the comparison of increases in hemoglobin concentrations between the velaglucerase alfa and imiglucerase groups. Secondary endpoints were comparisons of increases in platelet counts, decreases in organ volumes, and surrogate markers of Gaucher disease.

In this study of enzyme replacement naive patients, velaglucerase alfa demonstrated robust clinical efficacy that was comparable to imiglucerase in all endpoints.

Study 034 was a 12-month switch study in 40 clinically stable Type 1 Gaucher patients aged two years and older who had been receiving treatment with imiglucerase at doses ranging between 15 U/kg and 60 U/kg every other week for a minimum of 30 consecutive months. This study assessed the safety of patients switched from imiglucerase to velaglucerase alfa administered at the same number of units as their imiglucerase dose. In this study, hemoglobin concentrations, platelet counts, and organ volumes were sustained through 12-months of velaglucerase alfa treatment, and the therapy was generally well-tolerated.

In all three studies, most adverse events were mild to moderate in intensity. Most of the drug-related adverse events were reported in association with velaglucerase alfa infusions, all of which resolved without sequelae.

The development of antibodies to velaglucerase alfa was rare in all three studies, occurring in approximately 1% of patients treated.

The specific data from all three trials will be presented at future scientific meetings.

Background on Gaucher disease

Gaucher disease is an autosomal recessive disorder caused by mutations in the GBA gene which results in a deficiency of the lysosomal enzyme beta-glucocerebrosidase. This enzymatic deficiency causes an accumulation of glucocerebroside, primarily in macrophages. In this lysosomal storage disorder (LSD), clinical features are reflective of the distribution of Gaucher cells in the liver, spleen, bone marrow, skeleton, and lungs. The accumulation of glucocerebrosidase in the liver and spleen leads to organomegaly. Bone involvement results in skeletal abnormalities and deformities as well as bone pain crises. Deposits in the bone marrow and splenic sequestration lead to clinically significant anemia and thrombocytopenia.

Gaucher disease is the most prevalent lysosomal storage disorder, with an incidence of about 1 in 20,000 live births. Gaucher disease has classically been categorized into 3 clinical types. Type 1 is the most common; it is distinguished from Type 2 and Type 3 by the lack of central nervous system involvement. Type 1 Gaucher disease is characterized by variability in signs, symptoms, severity, and progression.

Velaglucerase alfa supplements or replaces beta-glucocerebrosidase, the enzyme that catalyzes the hydrolysis of glucocerebroside, reducing the amount of accumulated glucocerebroside and correcting the pathophysiology of Gaucher disease.

Shire plc

Shire’s strategic goal is to become the leading specialty biopharmaceutical company that focuses on meeting the needs of the specialist physician. Shire focuses its business on attention deficit hyperactivity disorder (ADHD), human genetic therapies (HGT) and gastrointestinal (GI) diseases as well as opportunities in other therapeutic areas to the extent they arise through acquisitions. Shire’s in-licensing, merger and acquisition efforts are focused on products in specialist markets with strong intellectual property protection and global rights. Shire believes that a carefully selected and balanced portfolio of products with strategically aligned and relatively small-scale sales forces will deliver strong results.

“Safe Harbor” Statement Under The Private Securities Litigation Reform Act of 1995

Statements included herein that are not historical facts are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, the Company’s results could be materially adversely affected. The risks and uncertainties include, but are not limited to, risks associated with: the inherent uncertainty of research, development, approval, reimbursement, manufacturing and commercialization of the Company’s Specialty Pharmaceutical and Human Genetic Therapies products, including (without limitation) velaglucerase alfa, as well as the ability to secure and integrate new products for commercialization and/or development; government regulation of the Company’s products; the Company’s ability to manufacture its products in sufficient quantities to meet demand; the impact of competitive therapies on the Company’s products; the Company’s ability to register, maintain and enforce patents and other intellectual property rights relating to its products; the Company’s ability to obtain and maintain government and other third-party reimbursement for its products; and other risks and uncertainties detailed from time to time in the Company’s filings with the Securities and Exchange Commission.

Source: Shire Plc Continue reading →

Research reveals reveals gains or losses of large segments of DNA in healthy people

TORONTO — Scientists at The Hospital for Sick Children (Sick Kids), Brigham and Women’s Hospital (BWH) and Harvard Medical School (HMS) have made the unexpected discovery that significant differences can exist in the overall content of DNA and genes contained in individual genomes. These findings, which point to possible new explanations for individual uniqueness as well as why disease develops, are published in the September 2004 issue of the scientific journal Nature Genetics (available online August 1, 2004).

“Using new genome scanning technologies, we serendipitously found stretches of DNA sometimes hundreds of thousands of chemical bases (nucleotides) long that were present or absent in the genomes of healthy individuals. These large-scale copy variations, or LCVs, frequently overlap with genes and could explain why people are different,” said Dr. Stephen Scherer, co-principal investigator of the study, a Sick Kids senior scientist, and an associate professor in the Department of Molecular and Medical Genetics at the University of Toronto.

“At first we were astonished and didn’t believe our results because for years we had been taught that most variation in DNA was limited to very small changes. Then we heard the Harvard group was making similar observations and ultimately we combined our data and came to the same conclusion,” added Dr. Scherer.

Early information from the Human Genome Project indicated that the DNA in the genome of any two individuals is 99.9 per cent identical with the 0.1 per cent variation arising primarily from some three million single nucleotide changes scattered amongst the chromosomes. The new data from the Sick Kids and Harvard groups revealed 255 regions (comprising more than 0.1 per cent) of the genome where large chunks of DNA are present in different copy numbers between individuals. Over 50 per cent of these alterations lead to changes in gene numbers and at least 14 regions overlapped with known sites associated with human disease.

“Because these newly discovered variants exist in the genomes of healthy individuals, their presence could lead to subtle differences affecting physical or behavioural traits by influencing the expression of specific genes, but they could also predispose to future disease,” said BWH’s Dr. Charles Lee, co-principal investigator and assistant professor at HMS. “For example, the most common LCV involves amylase genes. Our study shows that some people may have 10 copies of this gene while others may have as much as 24 copies of this same gene. It would be really exciting if we found that an increased copy number of these genes was associated with increased susceptibility to pancreatic diseases or cancer. This would allow us to use these LCVs as disease markers.”

The information on identified LCVs has been collated into a publicly accessible database called the Genome Variation Database (projects.tcag/variation) that will be a valuable resource for clinical genetic studies.

Other members of the research team include co-lead authors Dr. Lars Feuk, a Sick Kids postdoctoral fellow and Dr. A. John Iafrate, a postdoctoral fellow at BWH and HMS, and Miguel L. Listewnik (BWH), Patricia K. Donahoe (Massachusetts General Hospital and HMS), and Ying Qi (Sick Kids).

At Sick Kids, the research was supported by Genome Canada through the Ontario Genomics Institute, the McLaughlin Centre for Molecular Medicine, The Centre for Applied Genomics at Sick Kids, and the Sick Kids Foundation. Dr. Feuk is supported by the Swedish Medical Research Council. Dr. Scherer is an Investigator of the Canadian Institutes of Health Research and International Scholar of the Howard Hughes Medical Institute.

At BMH/HMS, the research was supported by the Department of Pathology at Brigham and Women’s Hospital, the Friends of the Dana-Farber Cancer Institute, a Brigham and Women’s Hospital Pathology Department training grant, and the National Institutes of Health.

The Hospital for Sick Children, affiliated with the University of Toronto, is Canada’s most research-intensive hospital and the largest centre dedicated to improving children’s health in the country. Its mission is to provide the best in family-centred, compassionate care, to lead in scientific and clinical advancement, and to prepare the next generation of leaders in child health.

Contact: Laura Greer
laura.greersickkids
416-813-5046
University of Toronto Continue reading →

Existing melanoma classifications have been refined by a team at the
University of California San Francisco according to an article released
on June 2, 2008 in the open access journal PLoS Medicine.

Melanoma, a malignant tumor of melanocytes, are presently classified by
morphological means. The present classification system, while generally
consistent, does not offer information about the treatment methods that
are best suited to that cancer. This team refined these morphological
systems by their causative mutations, creating genetically homogeneous
subgroups. This holds promise to help patients whose tumors have
metastisized find better treatment options.

Jonathan Rees of the University of Edinburgh contributed a related
Research in Translation paper, in which he highlights several omissions
in our knowledge about the etiology of non-acral melanomas.

Improving melanoma classification by integrating genetic and
morphologic features.
Viros A, Fridlyand J, Bauer J, Lasithiotakis K, Garbe C, et al.
PLoS Med 5(6): e120.
Click
Here For Full Length Article

Melanoma: What are the gaps in our knowledge?
Rees JL
PLoS Med 5(6): e122.
Click
Here For Full Length Article

Anna Sophia McKenney

Continue reading →

Cancer Research UK scientists have discovered a missing link in the way cells protect themselves against cancer, according to research published in Genes & Development* today.

Cancer Research UK-funded scientists based at the The Univeristy of Dundee ** and the Agency for Science Technology and Research in Singapore (A*STAR) have discovered how cells switch p53, the tumour-suppressor gene known as the guardian of the genome, on and off. The discovery comes 30 years after it was co-discovered by Professor Sir David Lane, who is also Cancer Research UK’s chief scientist. This has important implications for cancer treatment and diagnosis.

The scientists used a genetic trick to make zebrafish turn green when the p53 gene was switched on to explore the way this gene was regulated.

They found that the p53 gene makes not only the well-established p53 protein, but also an alternative ‘control switch’ variation of the p53 protein – known as an isoform***. It is the isoform that feeds back to regulate the p53 gene. In its active state p53 will trigger cell death – called apoptosis – or arrest cell division to make repairs to DNA.

Normally zebrafish can survive low doses of radiation. But zebrafish which couldn’t make this isoform ‘switch’, died when exposed to low levels of radiation. This proved that the isoform was critical in controlling p53′s normal function to protect cells against the development of cancer – which includes ordering cells to die when they are badly damaged.

Scientists from Professor Sir David’s lab had previously discovered that cells contained more than one isoform of p53 – but they didn’t know how the isoforms were produced or what they did.

Zebrafish carry the same p53 gene as humans.

P53 is damaged or inactive in half of all cancers and has roles in cell development and ageing. In normal cells it is activated in response to cell damage and one of its functions is to order cells to die – a process called apoptosis – when DNA is damaged beyond repair. It is critical that p53 functions normally to prevent genetic mistakes being passed on to daughter cells which can lead to cancer. But until now no-one understood how this gene was controlled.

Professor Sir David Lane, lead author, said: “We are delighted by these findings. Our research is focused on this p53 gene because it is so often damaged in cancer cells.

“The function of p53 is critical to the way that many cancer treatments kill cells since radiotherapy and chemotherapy act in part by triggering cell suicide in response to DNA damage – so understanding more about how this gene is controlled in cells is really important in finding ways to prevent cells from turning cancerous.”

Lesley Walker, Cancer Research UK’s director of cancer information, said: “This is a really exciting study which improves our understanding of how the p53 gene works.

“Cancer Research UK scientists co-discovered p53 30 years ago so discovering how it is regulated will have incredibly important implications in the development of better drugs and ways to diagnose cancer.”

Notes

Click here to hear an interview with David Lane

*Jun Chen et al. p53 isoform 113p53 is a p53 target gene that antagonizes p53 apoptotic activity via BclxL activation in zebrafish. Genes & Development 2009 1 February 2009.
**Work on this study was carried out in labs based in both the University of Dundee and Singapore’s A*STAR Institute of Molecular and Cell Biology (IMCB).
***Protein isoforms Different versions of one protein can be formed. They can be coded for by several genes and stuck together in a slightly different way or coded for by sections of the same gene.

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Researchers at Mayo Clinic Cancer Center, in cooperation with industry partners, have, for the first time, identified tumor specific alterations in the cellular pathway by which the multiple myeloma drug bortezomib (Velcade) works, and they have identified nine new genetic mutations in cancer cells that should increase a patient’s chance of responding to the agent.

The investigators say these findings, presented Sunday, Dec. 10, at the 2006 American Society of Hematology Annual Meeting in Orlando, may help physicians tailor treatment to patients with multiple myleoma, a difficult-to-treat cancer of plasma cells that is the second most common blood cancer in the United States.

“Bortezomib seems to work in about one-third of patients who use it, but we have not been able to predict which ones,” says the study’s lead author, Leif Bergsagel, M.D., a hematologist at Mayo Clinic Arizona. “We now have identified a group that will likely respond because these nine mutations seem to be present in at least 25 percent of newly diagnosed patients.

“Now that we know the pathway the drug targets, and genetic mutations within this pathway that make patients respond better, we are working on a simple way to select those patients who are the best candidates for use of bortezomib,” says Dr. Bergsagel.

In 2003, after only a four-month review, the Food and Drug Administration (FDA) approved use of bortezomib in patients who have failed other treatments for multiple myeloma. Later studies showed it lengthened survival by as much as six months. The drug was the first approved in a new class of agents known as proteasome inhibitors. Proteasomes are large protein groups inside cells that break down other proteins. Agents that inhibit the proteasome cause a buildup of proteins that affect many signaling cascades (various necessary biological processes). Bortezomib was initially thought to exert its activity by disrupting one of two known NF-???B (Nuclear Factor kappa B) pathways which keep cancer cells from self destructing the first-discovered, or canonical, NF-???B pathway.

But through extensive genetic examination of 42 unique multiple myeloma cell lines and tumor samples taken from 68 patients, the investigators defined multiple genetic mutations in the other NF-???B pathway, the so-called non-canonical pathway. “These mutations make the tumor more dependent on that pathway, and consequently more susceptible to bortezomib treatment,” said senior author Rafael Fonseca, M.D., also at Mayo Clinic in Arizona.

“Identifying these mutations in patients will help us decide who should be treated with bortezomib, probably as an initial therapy,” he says. The researchers are developing a test to check for activation of the non-canonical NF-eB pathway in patients.

Now that the mutations have been identified, drug designers may be able to fashion new therapies that are more specific to these genetic alterations and, therefore, less toxic,

Dr. Bergsagel says. “These mutations represent good targets for drug development,” he says.

Other Mayo researchers involved in this study included Marta Chesi, Ph.D.; Scott Van Wier; Jonathan Keats, Ph.D.; Michael Sebag, M.D., Ph.D.; Wee-Joo Chng, M.D.; Roelandt Schop, M.D.; Homer Fogle III; Yuan Xiao Zhu Ph.D.; Chang-Xin Shi, Ph.D.; Tammy Price-Troska; Gregory Ahmann; Kim Henderson; Philip Greipp, M.D.; Angela Dispenzieri, M.D.; Keith Stewart, M.D.; and Rafael Fonseca, M.D. They collaborated with researchers John Carpten, Ph.D.; Angela Baker, Ph.D.; Tae-Hoon Chung, Ph.D.; Michael Barrett, Ph.D.; and Catherine Mancini from TGen, Phoenix, Ariz., and Laurakay Bruhn, Ph.D. from Agilent Labs, Santa Clara, Calif.

To find out more about treatment of blood diseases at Mayo Clinic visit mayoclinic/hematology-rst/treatmentgroups.html. Information regarding Mayo Clinic Cancer Center’s related research is available online at cancercenter.mayo.edu/mayo/research/hematologic_malignancies.

Contact: Elizabeth Zimmermann

Mayo Clinic

View drug information on Velcade. Continue reading →

Discovering the different genes that contribute to a complex disease is like searching in the proverbial haystack for an unknown number of needles — some much smaller than others, often blending into the background, and many of them widely separated from each other. But if some needles are linked to each other by fine threads, you might pull out clumps of them together.

Using a novel approach that combines a statistical tool that identifies genes interacting on the same biological pathways with highly automated gene-hunting techniques that scan the whole genome, an international team of researchers has discovered new genes involved in Crohn’s disease. Crohn’s disease is a chronic and painful condition caused by inflammation of the gastrointestinal tract. The researchers, led by scientists at The Children’s Hospital of Philadelphia, say their approach broadens the power of gene discovery studies to ferret out potential targets for disease treatments.

In a complex disorder such as Crohn’s disease, many different genes interact to cause the illness. Research over the past few years have identified many of the genes with the strongest effects, but many other genes with important roles may produce weaker or ambiguous signals in the large-scale studies, and go overlooked. “Our pathway-based approach aggregates information from multiple sources to detect modest effects from genes associated with each other,” said study leader Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at Children’s Hospital.

The study appeared online in the American Journal of Human Genetics. It will be published in the journal’s print edition on March 13.

Currently the workhorse of gene-hunting is genome-wide association (GWA), which uses automated analytic equipment to sweep through the full range of all 23 human chromosomes and detect the most significant gene variants associated with a given disease. Those variants, each a change in a single DNA base, are called single nucleotide polymorphisms (SNPs).

However, individual GWA studies often do not have the statistical power to detect subtle but important variants that are involved in disease development. By using an algorithm developed by Kai Wang, Ph.D., at the Center for Applied Genomics, Hakonarson’s study team created a pathway-based approach that seeks out interacting or related genes along the same biological pathway. “We applied our pathway-based approach to GWA data for Crohn’s disease, but conducted the search without starting with a hypothesis focused on a specific suspected pathway,” said Hakonarson. “Among hundreds of known biological pathways, the one that surfaced from the analysis as being most significant included genes already known to be relevant to the biology of Crohn’s disease.”

That pathway, the interleukin 12 (IL12) pathway, governs cell receptors involved in the development of Crohn’s disease. Hakonarson added that the IL12 pathway might be more correctly referred to as the IL12/IL23 pathway, since IL12 receptor signaling converges with signaling on another receptor, IL23. Previous work by other researchers had shown that monoclonal antibodies that block the IL12 or IL23 receptor show some clinical success in treating Crohn’s disease.

“As we better understand the gene pathways operating in Crohn’s disease, we are uncovering more potential targets for effective drug treatments,” said pediatric gastroenterologist Robert Baldassano, M.D., a study co-author and the director of the Center for Pediatric Inflammatory Bowel Disease at Children’s Hospital. He added that developing targeted therapies based on gene pathways might allow doctors to tailor treatments to a patient’s genetic profile.

The study team performed the initial analysis in DNA from 1,758 patients with Crohn’s disease and 1,480 control subjects, all of European ancestry. They repeated the study in three additional groups, of both European and African American ancestry, and were able to replicate their results. Their study was the first to use a pathway-based approach to analyze GWA, without deciding beforehand to concentrate on a specific pathway.

For children and adults with Crohn’s disease, who suffer the debilitating effects of chronic gastrointestinal inflammation, the emerging gene data may open the doors to more effective treatments. “Blocking cell receptors at some points on a biological pathway may produce clinical improvements, but with side effects to the immune system,” said Baldassano. “If we can block other molecules further downstream on a pathway, we may achieve better treatments that may be more specific to an individual patient, with fewer side effects.”

Funding for the study came from the National Center for Research Resources of the National Institutes of Health, the Primary Children’s Medical Center Foundation and an Institute Development Award from The Children’s Hospital of Philadelphia.

In addition to the Children’s Hospital researchers, co-authors of the study came from numerous hospitals and universities in the United States, Italy, Scotland and Canada.

Wang et al, “Diverse Genome-wide Association Studies Associate the IL12/23 Pathway with Crohn’s Disease,” The American Journal of Human Genetics, 84, pp. 1-7, March 13, 2009.

About The Children’s Hospital of Philadelphia: The Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking second in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit chop.edu.

The Children’s Hospital of Philadelphia
chop.edu Continue reading →

Small interfering RNA (siRNA), a type of genetic material, can block potentially harmful activity in cells, such as tumor cell growth. But delivering siRNA successfully to specific cells without adversely affecting other cells has been challenging.

University of Iowa researchers have modified siRNA so that it can be injected into the bloodstream and impact targeted cells while producing fewer side effects. The findings, which were based on animal models of prostate cancer, also could make it easier to create large amounts of targeted therapeutic siRNAs for treating cancer and other diseases. The study results appeared online Aug. 23 in the journal Nature Biotechnology.

“Our goal was to make siRNA deliverable through the bloodstream and make it more specific to the genes that are over expressed in cancer,” said the study’s senior author Paloma Giangrande, Ph.D., assistant professor of internal medicine and a member of Holden Comprehensive Cancer Center.

In previous research completed at Duke University, Giangrande’s team showed that a compound called an aptamer can be combined with siRNA to target certain genes. When the combined molecule is directly injected into tumors in animal models, it triggers the processes that stop tumor growth. However, directly injecting the combination into tumors in humans is difficult.

In the new study, the researchers trimmed the size of a prostate cancer-specific aptamer and modified the siRNA to increase its activity. Upon injection into the bloodstream, the combination triggered tumor regression without affecting normal tissues.

Making the aptamer-siRNA combination smaller makes it easier to produce large amounts of it synthetically, Giangrande said.

The team also addressed the problem that large amounts of siRNA are needed since most of it gets excreted by the kidneys before having an effect. To keep siRNA in the body longer and thereby use less of it, the team modified it using a process called PEGlyation.

“If you want to use siRNA effectively for clinical use, especially for cancer treatment, you need to deliver it through an injection into the bloodstream, reduce the amount of side effects and be able to improve its cost-effectiveness. Our findings may help make these things possible,” Giangrande said.

Although the current study focused on prostate cancer, the findings could apply to other cancers and diseases. Giangrande said the next step is to test the optimized aptamer-siRNA compound in a larger animal model.

Other researchers who contributed significantly to the study included James McNamara, Ph.D., and Anton McCaffrey, Ph.D., both UI assistant professors of internal medicine.

Source:
Becky Soglin

University of Iowa Continue reading →

A fundamental process in the transmission of genes from mother to child has been identified by researchers at the Montreal Neurological Institute, McGill University. The new study published in the December issue of the journal Nature Genetics identifies a mechanism that plays a key role in how mutations are transmitted from one generation to the next, providing unprecedented insight into metabolic diseases.

DNA that is only passed on from mothers to their children is stored in mitochondria, a compartment of cells which functions to supply energy to the body. Mutations in mitochondrial DNA (mtDNA) are important causes of over 40 known types of diseases and disorders which primarily affect brain and muscle function, some of which are severely debilitating, with symptoms including stroke, epilepsy, deafness and blindness. One very common mutation in Quebec causes maternally inherited blindness which has now been traced back to a Fille du Roi sent by the king of France in the 1600s to rectify the imbalance of gender in the newly colonized country.

MNI researchers have located a genetic bottleneck that determines the proportion of mutated mtDNA that mothers transmit to their offspring. This is important because there are many copies of mitochondria in cells and their distribution in tissues has a role in the severity and symptoms of the disease. Therefore knowing how mtDNA is transmitted is essential for the understanding and treatment of a range of maternally inherited diseases, and provides an opportunity for genetic counselling and treatment.

“The proportion of mutated DNA copies shifts rapidly and unpredictably from mother to child making it very hard to predict what proportion of mutated DNA will be passed on.” says Dr. Eric Shoubridge, neuroscientist at the MNI and lead investigator in the study. “We now understand that this is partly due to the genetic bottleneck, in which just a small number of the original mtDNA copies from the mother are actually transmitted to the child. This bottleneck occurs during the development of eggs in affected females. Only a small set of the female’s mtDNA is selected to replicate resulting in the individual producing eggs with a wide range of proportions of mutated mtDNA. These eggs give rise to offspring with proportions of mutated mtDNA that differ from each other and are different from the proportion of mutated mtDNA in the mother. This explains why the occurrence and severity of a disease from mutated mtDNA can vary in offspring of an affected mother. The identification and location of the genetic bottleneck in our study strengthens our knowledge of the rules and processes of transmission and improves our capacity for genetic counselling.”

An important application of this study is in the prevention of the disease at the prenatal stage because therapies for sick patients are usually ineffective, and the diseases are often fatal. The study locates the bottleneck as occurring during the process of egg maturation in early postnatal life of a female, supporting the knowledge that mature oocytes or egg cells contain the full set of copies of mtDNA. This evidence makes possible pre-implantation genetic diagnosis, in which an oocyte is screened for harmful mutations prior to fertilization, for in-vitro fertilization for example. This prevents the transmission of harmful mutations and can avoid the termination of a pregnancy in cases where an embryo is carrying a fatal neurological disorder.

This research was supported by the Canadian Institutes of Health Research and the US National Institutes of Health. Eric Shoubridge is an International Scholar of the Howard Hughes Institute.

MNI:

October 2009 marks the 75th anniversary of the MNI. The MNI is a McGill University research and teaching institute, dedicated to the study of the nervous system and neurological diseases. Founded in 1934 by the renowned Dr. Wilder Penfield, the MNI is one of the world’s largest institutes of its kind. MNI researchers are world leaders in cellular and molecular neuroscience, brain imaging, cognitive neuroscience and the study and treatment of epilepsy, multiple sclerosis and neuromuscular disorders. The MNI, with its clinical partner, the Montreal Neurological Hospital (MNH), part of the McGill University Health Centre, continues to integrate research, patient care and training, and is recognized as one of the premier neuroscience centres in the world. At the MNI, we believe in investing in the faculty, staff and students who conduct outstanding research, provide advanced, compassionate care of patients and who pave the way for the next generation of medical advances. Highly talented, motivated people are the engine that drives research – the key to progress in medical care. A new building, the North Wing Expansion, is currently under construction and will house state-of-the-art brain imaging facilities. Once the construction is completed and the new building is fully equipped, the scientific community focused on brain imaging research at the MNI will be without equivalent anywhere in the world.

Source: Anita Kar

Montreal Neurological Institute and Hospital Continue reading →

A group of researchers from the University of Copenhagen and the Biocentre at the Technical University of Denmark have managed to decipher the final part of the immune system’s key codes.

The same researchers already broke the first part of the codes last autumn, and have now put together a comprehensive picture of how the immune system checks for dangers both in and outside our cells.

According to the researchers this new information, produced with the aid of artificial neural networks, means that it should be possible to predict all the immune system’s known, and also as yet unknown codes. This should in turn lead to the development of new targeted treatments, for e.g. cancer and infectious diseases.

Professor S??ren Buus from the Faculty of Health Sciences at the University of Copenhagen has been at the forefront of this research project.

The body’s natural defences uses these key codes in such a way that microorganisms cannot spy on and discover its functions. It this unique protection that has so far made it difficult for scientists to decode the entire human immune system and thus develop precise immunological tools and carry out organ transplants.

Read more on the University of Copenhagen’s Web site: ku.dk/

Source: Sandra Szivos

University of Copenhagen Continue reading →