ScienceDaily (Sep. 30, 2012) Researchers at the University of Cincinnati and Cincinnati Children's Hospital Medical Center have found a new genetic mutation responsible for deafness and hearing loss associated with Usher syndrome type 1.

These findings, published in the Sept. 30 advance online edition of the journal Nature Genetics, could help researchers develop new therapeutic targets for those at risk for this syndrome.

Partners in the study included the National Institute on Deafness and other Communication Disorders (NIDCD), Baylor College of Medicine and the University of Kentucky.

Usher syndrome is a genetic defect that causes deafness, night-blindness and a loss of peripheral vision through the progressive degeneration of the retina.

"In this study, researchers were able to pinpoint the gene which caused deafness in Usher syndrome type 1 as well as deafness that is not associated with the syndrome through the genetic analysis of 57 humans from Pakistan and Turkey," says Zubair Ahmed, PhD, assistant professor of ophthalmology who conducts research at Cincinnati Children's and is the lead investigator on this study.

Ahmed says that a protein, called CIB2, which binds to calcium within a cell, is associated with deafness in Usher syndrome type 1 and non-syndromic hearing loss.

"To date, mutations affecting CIB2 are the most common and prevalent genetic cause of non-syndromic hearing loss in Pakistan," he says. "However, we have also found another mutation of the protein that contributes to deafness in Turkish populations.

"In animal models, CIB2 is found in the mechanosensory stereocilia of the inner ear -- hair cells, which respond to fluid motion and allow hearing and balance, and in retinal photoreceptor cells, which convert light into electrical signals in the eye, making it possible to see," says Saima Riazuddin, PhD, assistant professor in UC's department of otolaryngology who conducts research at Cincinnati Children's and is co-lead investigator on the study.

Researchers found that CIB2 staining is often brighter at shorter row stereocilia tips than the neighboring stereocilia of a longer row, where it may be involved in calcium signaling that regulates mechano-electrical transduction, a process by which the ear converts mechanical energy -- or energy of motion -- into a form of energy that the brain can recognize as sound.

"With this knowledge, we are one step closer to understanding the mechanism of mechano-electrical transduction and possibly finding a genetic target to prevent non-syndromic deafness as well as that associated with Usher syndrome type 1," Ahmed says.

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Gene that causes a form of deafness discovered

04-07-2012 14:06 I created this video with the YouTube Video Editor for our cutting edge science class. Scientific information (or lack thereof) is not necessarily true. No insult was meant by this film. Enjoy!

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The tale of how Simba gets successful GENE THERAPY - Video

Newswise A team of scientists from Johns Hopkins and other institutions report that restoring tiny, hair-like structures to defective cells in the olfactory system of mice is enough to restore a lost sense of smell. The results of the experiments were published online last week in Nature Medicine, and are believed to represent the first successful application of gene therapy to restore this function in live mammals.

An expert in olfaction, Randall Reed, Ph.D., professor of molecular biology and genetics and co-director of the Center for Sensory Biology at the Johns Hopkins Institute for Basic Biomedical Sciences, cautions that researchers are still years away from applying the same therapy in people, and that if and when it comes, it will likely be most effective for those who suffer from anosmia (lack of smell) due to inherited genetic disorders. But our work has already contributed to a better understanding of the cellular factors involved in anosmia, and that will give us insights into other neurological disorders, as well, he says.

The mice used in the current study carried a genetic mutation that destroyed the production of a protein critical for the functioning of cilia in the cells responsible for smell, called olfactory sensory neurons. These specialized cells each display several of the protruding, hair-like structures that contain receptors for odorants. Without functional cilia, the cells become a broken link in the chain of events necessary for proper odor detection in the environment, the researchers explained.

Beginning with a common cold virus, which readily infects the cells of the nasal cavity, researchers replaced some of the viral genes with a corrected version of the defective cilia gene. They then infected smelling-impaired mice with the altered virus, delivering the corrected gene to the olfactory neural cells that needed it.

At the cellular level, scientists saw a restoration of proper chemical signaling between nerve cells after the treated mice were stimulated with various odorants. Perhaps even more indicative of their success, Reed says, was the 60 percent increase in body weight that the mice experienced once they could smell their meals, leading to increased appetite. Many people with anosmia lose weight because aromas play a significant part in creating appetite and food enjoyment.

Researchers are optimistic about the broader implications of this work, Reed notes, because cilia are not only important to olfactory cells, but also to cells all over the body, from the kidney to the eye. The fact that they were able to treat live mice with a therapy that restored cilia function in one sensory system suggests that similar techniques could be used to treat cilia disorders elsewhere.

We also hope this stimulates the olfactory research community to look at anosmia caused by other factors, such as head trauma and degenerative diseases, says senior author Jeffrey Martens, Ph.D., an associate professor of pharmacology at the University of Michigan. We know a lot about how this system works now have to look at how to fix it when it malfunctions.

In addition to Randall Reed from Johns Hopkins, the papers authors include Jeffrey Martens, Jeremy McIntyre, Ariell Joiner, Corey Williams, Paul Jenkins, Dyke McEwen, Lian Zhang and John Escobado from the Martens Lab at the University of Michigan; Erica Davis, I-Chun Tsai and Nicholas Katsanis from Duke University; Aniko Sabo, Donna Muzny and Richard Gibbs from the Baylor College of Medicine; Eric Green and James Mullikin from the National Institutes of Health Intramural Sequencing Center; Bradley Yoder from the University of Alabama-Birmingham; Sophie Thomas and Tania Atti-Bitach from LUniversit Paris Descartes; Katarzyna Szymanska and Colin A. Johnson from St. Jamess University Hospital in Leeds, UK; and Philip Beales from University College London, UK.

The study was funded by the National Institutes of Health: National Institute on Deafness and Other Communication Disorders (#R01DC009606, F32DC011990, R01DC004553, R01DC008295), National Institute of Diabetes and Digestive and Kidney Diseases (#R01DK75996, R01DK072301, R01DK075972, DK074083), National Institute of Child Health and Human Development (#R01HD042601), and National Eye Institute (#R01EY021872). Additional funding sources included LAgence Nationale de la Recherche and the European Communitys Seventh Framework Programme.

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The Nose Knows: Gene Therapy Restores Sense of Smell in Mice

04-07-2012 05:11 Conference by Maria Pia Cosma, ICREA Research Professor, leader of the laboratory Reprogramming and Regeneration, within the Gene Regulation, Stem Cells and Cancer research programme, at the Centre for Genomic Regulation, in Barcelona, Spain. Her research group is dedicated to studying the mechanisms that control the reprogramming of adult cells in order to determine whether this reprogramming contributes to tissue regeneration in higher vertebrates (fish, amphibians, birds and mammals). In recent years, there have been numerous studies of how adult cells of our body can be turn back into stem cells (ie those that have the potential to become any type of adult cell). A skin cell, for example, can be "induced" (converted) into a stem cell again, and then be transformed into a cell of another tissue (muscle, nerve, blood, etc.). This has generated great interest in the field of regenerative medicine. For example, this type of cells called "induced pluripotent stem cells" (IPS) can be used in the treatment of many diseases. But is this really possible? What should we keep in mind according to this approach? Scientists have also discovered that the reprogramming of adult cells can occur naturally in the body, but still do not understand why this happens and, more importantly for the purposes of regenerative medicine, how it happens.

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Cellular reprogramming: a real tool of regenerative medicine? - Video

ScienceDaily (July 2, 2012) Getting under your skin takes on a brave new meaning thanks to Northwestern University research that could transform gene regulation.

A team led by a physician-scientist and a chemist -- from the fields of dermatology and nanotechnology -- is the first to demonstrate the use of commercial moisturizers to deliver gene regulation technology that has great potential for life-saving therapies for skin cancers.

The topical delivery of gene regulation technology to cells deep in the skin is extremely difficult because of the formidable defenses skin provides for the body. The Northwestern approach takes advantage of drugs consisting of novel spherical arrangements of nucleic acids. These structures, each about 1,000 times smaller than the diameter of a human hair, have the unique ability to recruit and bind to natural proteins that allow them to traverse the skin and enter cells.

Applied directly to the skin, the drug penetrates all of the skins layers and can selectively target disease-causing genes while sparing normal genes. Once in cells, the drug simply flips the switch of the troublesome genes to off.

A detailed study of a method that could dramatically redefine the field of gene regulation will be published online during the week of July 2 by the Proceedings of the National Academy of Sciences (PNAS).

Early targets of the novel treatment are melanoma and squamous cell carcinoma (two of the most common types of skin cancer), the common inflammatory skin disorder psoriasis, diabetic wound healing and a rare genetic skin disorder that has no effective treatment (epidermolytic ichthyosis). Other targets could even include wrinkles that come with aging skin.

The technology developed by my collaborator Chad Mirkin and his lab is incredibly exciting because it can break through the skin barrier, said co-senior author Amy S. Paller, M.D., the Walter J. Hamlin Professor, chair of dermatology and professor of pediatrics at Northwestern University Feinberg School of Medicine. She also is director of Northwesterns Skin Disease Research Center.

This allows us to treat a skin problem precisely where it is manifesting -- on the skin, she said. We can target our therapy to the drivers of disease, at a level so minute that it can distinguish mutant genes from normal genes. Risks are minimized, and side effects have not been seen to date in our human skin and mouse models.

A co-senior author of the paper, Mirkin is the George B. Rathmann Professor of Chemistry in the Weinberg College of Arts and Sciences and professor of medicine, chemical and biological engineering, biomedical engineering and materials science and engineering. He also is the director of Northwesterns International Institute for Nanotechnology.

Mirkin first developed the nanostructure platform used in this study in 1996 at Northwestern, and the FDA-cleared technology now is the basis of powerful commercialized medical diagnostic tools. This, however, is the first realization that the nanostructures naturally enter skin and that they can deliver a large payload of therapeutics.

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Breaking the skin barrier: Drugs topically deliver gene therapy via commercial moisturizers for skin disease treatment

July 2, 2012

Lawrence LeBlond for redOrbit.com Your Universe Online

At least three genetic mutations found in the human brain have been linked to enlarged brain size (megalencephaly) and a number of disorders, including cancer, epilepsy and autism, according to new research led by Seattle Childrens Research Institute.

The mutations were found in the genes AKT3, PIK3R2 and PIK3CA. The mutations were also linked to vascular disorders and skin growth disorders, said the researchers. The study, published in the online edition of the journal Nature Genetics on June 24, offers important implications for the future of medicine through the research findings.

Study leaders, geneticist William Dobyns, MD, and Jean-Baptiste Rivire, PhD, discovered through their research additional proof that the genetic makeup of a person is not completely determined at the moment of conception. The new evidence ties in with previous research that recognized that genetic changes can occur after conception, although considered quite rare.

The researchers also discovered the genetic causes of these human diseases, including developmental disorders, may also directly lead to new possibilities for treatment.

AKT3, PIK3R2 and PIK3CA are found in all humans, but only when they are mutated do they lead to the diseases and disorders. PIK3CA is known as a cancer-related gene, and appears to make cancer more aggressive. Boston Childrens Hospital researchers recently found a common link between the PIK3CA gene and a rare condition known as CLOVES syndrome.

James Olson, MD, PhD, a pediatric cancer expert at Seattle Childrens and Fred Hutchinson Cancer Research Center acknowledged the two decades-worth of work that led to the findings.

This study represents ideal integration of clinical medicine and cutting-edge genomics, said Olson, who was not involved in the latest research. I hope and believe that the research will establish a foundation for successfully using drugs that were originally developed to treat cancer in a way that helps normalize intellectual and physical development of affected children.

He noted that the team did an excellent job by deep sequencing exceptionally rare familial cases and unrelated cases to identify the culprit pathway. He further noted that the three genes all encode core components of the phosphatidylinositol-3-kinase/AKT pathway, the culprit pathway, as referenced by his work.

See the article here:
Gene Mutations Associated With Enlarged Brain Size, Disorders

By Jon Bardin, Los Angeles Times / For the Booster Shots blog 7:01 p.m. EST, June 29, 2012

A new vaccine may help prevent the brain stimulation that keeps smokers from being able to quit. (Francine Orr / Los Angeles Times / Jun 29, 2012)

Cant kick cigarettes? A vaccine may one day help by preventing nicotine from reaching its target in the brain, according to research published this week.

Most smoking therapies do a poor job of stopping the habit 70% to 80% of smokers who use an approved drug therapy to quit relapse. Scientists say this is because the targets of existing therapies are imperfect, only slightly weakening nicotines ability to find its target in the brain.

So some scientists have been trying a different approach creation of a vaccine. It would work like this: People would inject the vaccine like a shot, and the vaccine would create nicotine antibodies, molecules that can snatch up nicotine from the bloodstream before it reaches the brain. The vaccine could be used by smokers who want to quit or people who are worried about getting addicted to cigarettes in the future.

Researchers have tried to create vaccines in the past, but the ones theyve come up with have not been particularly effective. The authors of the new study say this may be because previous vaccines just didnt create enough antibodies to get rid of all the nicotine.

The new report, published in the journal Science Translational Medicine, attempts to solve this problem via gene therapy, in which a new gene is inserted into the body to do a particular job.

First the scientists at Weill Cornell Medical College in New York City put a gene that produces a nicotine antibody into mice. The gene was taken into the mices livers, and the liver started producing the antibody. Once produced, the antibody connected with nicotine, trapping it and preventing it from making its way to the brain, where it would otherwise have caused the pleasurable, addictive effects it is so known for.

Because of this trick, the researchers say that the new vaccine should only have to be injected once, and it will work for life, continuing to produce new antibodies in the liver.

The vaccine was effective: When mice were given nicotine intravenously, ones with the vaccine had a 47-fold drop in levels of nicotine in the blood compared with ones that hadnt received the vaccine. The antibody had successfully captured the nicotine in the bloodstream before it could reach the brain.

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Gene therapy for smoking kills pleasure of nicotine

By Brian Alexander

Most people who buy cosmetic lotions and potions know that while the people working behind the department store makeup counters may wear white lab coats, the stuff they sell is more about packaging than science.

But a Northwestern University team is bucking that image, reporting today that theyve created a way to regulate genes affecting the skin -- merely by applying moisturizer.

Not only could their technology pave the way for cosmetics that actually work, but it also might also prove to be a valuable weapon in fighting melanoma, the deadliest form of skin cancer, or diseases like psoriasis, and wounds like the intractable sores that often plague diabetics.

This is a blockbuster in the ways we will treat diseases of the skin, saidChad Mirkin, director of the International Institute for Nanotechnology and the George B. Rathmann Professor of Chemistry at Northwestern said. Were talking about ailments, scarring, wound healing, ways of regulating them or retarding them.

In a research paper published today in the Proceedings of the National Academy of Sciences, Mirkin and his colleagues describe not a drug, exactly, but a way of delivering small sections of nucleic acids (DNA and RNA are nucleic acids) called short interfering RNA, or siRNA, to cells. The cells take up the siRNA, which then alters the way a gene inside each cell can be read by the protein-making system.

The team used gold particles with a diameter of 13 nanometers. (One nanometer is 1-billionth of a meter. A typical strand of human hair is roughly 60,000 nanometers wide.) They coated the particles with siRNA to create what they call spherical nucleic acid nanoparticleconjugates, or SNAs. Millions of SNAs were then added to a commercially available petroleum-based skin moisturizer and the mixture was applied to mice and to lab-grown human skin.

In their key experiment in mice, they used their new system to tamp down the activity of a gene called epidermal growth factor receptor, or EGFR, thats involved in the growth of melanoma. As its name implies, EGFR receives messages from the epidermal growth factor protein. So toning down EGFR will interrupt the message; growth will be reduced or stop.

After mice were treated with the mixture three times per week for three weeks, the expression of the EGFR gene was reduced by 65 percent.

'Impressive' resultsSteve Dowdy, professor of cellular and molecular medicine at the University of California San Diego, and a Howard Hughes Medical Institute investigator specializing in RNA inhibition and ways to deliver siRNAs, called that result impressive.

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Gene healing in a lotion? Researchers are close

Newswise SEATTLE June 28, 2012 A research team led by Seattle Childrens Research Institute has discovered new gene mutations associated with markedly enlarged brain size, or megalencephaly. Mutations in three genes, AKT3, PIK3R2 and PIK3CA, were also found to be associated with a constellation of disorders including cancer, hydrocephalus, epilepsy, autism, vascular anomalies and skin growth disorders. The study, De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes, was published online June 24 in Nature Genetics.

The discovery offers several important lessons and hope for the future in medicine. First, the research team discovered additional proof that the genetic make-up of a person is not completely determined at the moment of conception. Researchers previously recognized that genetic changes may occur after conception, but this was believed to be quite rare. Second, discovery of the genetic causes of these human diseases, including developmental disorders, may also lead directly to new possibilities for treatment.

AKT3, PIK3R2 and PIK3CA are present in all humans, but mutations in the genes are what lead to conditions including megalencephaly, cancer and other disorders. PIK3CA is a known cancer-related gene, and appears able to make cancer more aggressive. Scientists at Boston Childrens Hospital recently published similar findings related to PIK3CA and a rare condition known as CLOVES syndrome in the American Journal of Human Genetics.

Physician researcher James Olson, MD, PhD, a pediatric cancer expert at Seattle Childrens and Fred Hutchinson Cancer Research Center who was not affiliated with the study, acknowledged the two decades-worth of work that led to the findings. This study represents ideal integration of clinical medicine and cutting-edge genomics, he said. I hope and believe that the research will establish a foundation for successfully using drugs that were originally developed to treat cancer in a way that helps normalize intellectual and physical development of affected children. The team knocked it out of the park by deep sequencing exceptionally rare familial cases and unrelated cases to identify the culprit pathway. The genes AKT3, PIK3R2 and PIK3CAall encode core components of the phosphatidylinositol-3-kinase (P13K)/AKT pathway, the culprit pathway referenced by Olson.

The research provides a first, critical step in solving the mystery behind chronic childhood conditions and diseases. At the bedside, children with these conditions could see new treatments in the next decade. This is a huge finding that provides not only new insight for certain brain malformations, but also, and more importantly, provides clues for what to look for in less severe cases and in conditions that affect many children, said William Dobyns, MD, a geneticist at Seattle Childrens Research Institute. Kids with cancer, for example, do not have a brain malformation, but they may have subtle growth features that havent yet been identified. Physicians and researchers can now take an additional look at these genes in the search for underlying causes and answers.

Researchers at Seattle Childrens Research Institute will now delve more deeply into the findings, with an aim to uncover even more about the potential medical implications for children. Based on what weve found, we believe that we can eventually reduce the burden of and need for surgery for kids with hydrocephalus and change the way we treat other conditions, including cancer, autism and epilepsy, said Jean-Baptiste Rivire, PhD, at Seattle Childrens Research Institute. This research truly helps advance the concept of personalized medicine.

Drs. Dobyns, Rivire and team made this discovery through exome sequencing, a strategy used to selectively sequence the coding regions of the genome as an inexpensive but effective alternative to whole genome sequencing. An exome is the most functionally relevant part of a genome, and is most likely to contribute to the phenotype, or observed traits and characteristics, of an organism.

BACKGROUND ON RESEARCHERS

Seattle Childrens Research Institute conducted this study in collaboration with teams from University of Washington Genome Sciences Department, FORGE (Finding of Rare Disease Genes) Canada Consortium, Cedars Sinai Medical Center and University of Sussex.

Dr. Dobyns, who is also a UW professor of pediatrics, is a renowned researcher whose life-long work has been to try to identify the causes of childrens developmental brain disorders such as megalencephaly. He discovered the first known chromosome abnormality associated with lissencephaly (Miller-Dieker syndrome) while still in training in child neurology at Texas Childrens Hospital in 1983. That research led, 10 years later, to the discovery by Dobyns and others of the first lissencephaly gene known as LIS1.

Continue reading here:
Study Finds New Gene Mutations That Lead to Enlarged Brain Size, Cancer, Autism, Epilepsy

ScienceDaily (June 29, 2012) A research team led by Seattle Children's Research Institute has discovered new gene mutations associated with markedly enlarged brain size, or megalencephaly. Mutations in three genes, AKT3, PIK3R2 and PIK3CA, were also found to be associated with a constellation of disorders including cancer, hydrocephalus, epilepsy, autism, vascular anomalies and skin growth disorders.

The study was published online June 24 in Nature Genetics.

The discovery offers several important lessons and hope for the future in medicine. First, the research team discovered additional proof that the genetic make-up of a person is not completely determined at the moment of conception. Researchers previously recognized that genetic changes may occur after conception, but this was believed to be quite rare. Second, discovery of the genetic causes of these human diseases, including developmental disorders, may also lead directly to new possibilities for treatment.

AKT3, PIK3R2 and PIK3CA are present in all humans, but mutations in the genes are what lead to conditions including megalencephaly, cancer and other disorders. PIK3CA is a known cancer-related gene, and appears able to make cancer more aggressive. Scientists at Boston Children's Hospital recently published similar findings related to PIK3CA and a rare condition known as CLOVES syndrome in the American Journal of Human Genetics.

Physician researcher James Olson, MD, PhD, a pediatric cancer expert at Seattle Children's and Fred Hutchinson Cancer Research Center who was not affiliated with the study, acknowledged the two decades-worth of work that led to the findings. "This study represents ideal integration of clinical medicine and cutting-edge genomics," he said. "I hope and believe that the research will establish a foundation for successfully using drugs that were originally developed to treat cancer in a way that helps normalize intellectual and physical development of affected children. The team 'knocked it out of the park' by deep sequencing exceptionally rare familial cases and unrelated cases to identify the culprit pathway." The genes -- AKT3, PIK3R2 and PIK3CA -- all encode core components of the phosphatidylinositol-3-kinase (P13K)/AKT pathway, the "culprit pathway" referenced by Olson.

The research provides a first, critical step in solving the mystery behind chronic childhood conditions and diseases. At the bedside, children with these conditions could see new treatments in the next decade. "This is a huge finding that provides not only new insight for certain brain malformations, but also, and more importantly, provides clues for what to look for in less severe cases and in conditions that affect many children," said William Dobyns, MD, a geneticist at Seattle Children's Research Institute. "Kids with cancer, for example, do not have a brain malformation, but they may have subtle growth features that haven't yet been identified. Physicians and researchers can now take an additional look at these genes in the search for underlying causes and answers."

Researchers at Seattle Children's Research Institute will now delve more deeply into the findings, with an aim to uncover even more about the potential medical implications for children. "Based on what we've found, we believe that we can eventually reduce the burden of and need for surgery for kids with hydrocephalus and change the way we treat other conditions, including cancer, autism and epilepsy," said Jean-Baptiste Rivire, PhD, at Seattle Children's Research Institute. "This research truly helps advance the concept of personalized medicine."

Drs. Dobyns, Rivire and team made this discovery through exome sequencing, a strategy used to selectively sequence the coding regions of the genome as an inexpensive but effective alternative to whole genome sequencing. An exome is the most functionally relevant part of a genome, and is most likely to contribute to the phenotype, or observed traits and characteristics, of an organism.

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New gene mutations that lead to enlarged brain size, cancer, autism, epilepsy identified

ScienceDaily (June 29, 2012) A recent study led by researchers at Boston University School of Medicine (BUSM) revealed that the FOXO1 gene may play an important role in the pathological mechanisms of Parkinson's disease.

These findings are published online in PLoS Genetics, a peer-reviewed open-access journal published by the Public Library of Science.

The study was led by Alexandra Dumitriu, PhD, a postdoctoral associate in the department of neurology at BUSM. Richard Myers, PhD, professor of neurology at BUSM, is the study's senior author.

According to the Parkinson's Disease Foundation, 60,000 Americans are diagnosed with Parkinson's disease each year and approximately one million Americans are currently living with the disease.

Parkinson's disease is a complex neurodegenerative disorder characterized by a buildup of proteins in nerve cells that lead to their inability to communicate with one another, causing motor function issues, including tremors and slowness in movement, as well as dementia. The substantia nigra is an area of the midbrain that helps control movement, and previous research has shown that this area of the brain loses neurons as Parkinson's disease progresses.

The researchers analyzed gene expression differences in brain tissue between 27 samples with known Parkinson's disease and 26 samples from neurologically healthy controls. This data set represents the largest number of brain samples used in a whole-genome expression study of Parkinson's disease to date. The novel aspect of this study is represented by the researchers' emphasis on removing possible sources of variation by minimizing the differences among samples. They used only male brain tissue samples that showed no significant marks of Alzheimer's disease pathology, one of the frequently co-occurring neurological diseases in Parkinson's disease patients. The samples also had similar tissue quality and were from the brain's prefrontal cortex, one of the less studied areas for the disease. The prefrontal cortex does not show neuronal death to the same extent as the substantia nigra, although it displays molecular and pathological modifications during the disease process, while also being responsible for the dementia present in a large proportion of Parkinson's disease patients.

Results of the expression experiment showed that the gene FOXO1 had increased expression in the brain tissue samples with known Parkinson's disease. FOXO1 is a transcriptional regulator that can modify the expression of other genes. Further examination of the FOXO1 gene showed that two single-nucleotide polymorphisms (SNPs), or DNA sequence variations, were significantly associated with age at onset of Parkinson's disease.

"Our hypothesis is that FOXO1 acts in a protective manner by activating genes and pathways that fight the neurodegeneration processes," said Dumitriu. "If this is correct, there could be potential to explore FOXO1 as a therapeutic drug target for Parkinson's disease."

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FOXO1 gene may play important role in Parkinson's disease

Public release date: 28-Jun-2012 [ | E-mail | Share ]

Contact: Jenny Eriksen Leary jenny.eriksen@bmc.org 617-638-6841 Boston University Medical Center

(Boston) A recent study led by researchers at Boston University School of Medicine (BUSM) revealed that the FOXO1 gene may play an important role in the pathological mechanisms of Parkinson's disease. These findings are published online in PLoS Genetics, a peer-reviewed open-access journal published by the Public Library of Science.

The study was led by Alexandra Dumitriu, PhD, a postdoctoral associate in the department of neurology at BUSM. Richard Myers, PhD, professor of neurology at BUSM, is the study's senior author.

According to the Parkinson's Disease Foundation, 60,000 Americans are diagnosed with Parkinson's disease each year and approximately one million Americans are currently living with the disease.

Parkinson's disease is a complex neurodegenerative disorder characterized by a buildup of proteins in nerve cells that lead to their inability to communicate with one another, causing motor function issues, including tremors and slowness in movement, as well as dementia. The substantia nigra is an area of the midbrain that helps control movement, and previous research has shown that this area of the brain loses neurons as Parkinson's disease progresses.

The researchers analyzed gene expression differences in brain tissue between 27 samples with known Parkinson's disease and 26 samples from neurologically healthy controls. This data set represents the largest number of brain samples used in a whole-genome expression study of Parkinson's disease to date. The novel aspect of this study is represented by the researchers' emphasis on removing possible sources of variation by minimizing the differences among samples. They used only male brain tissue samples that showed no significant marks of Alzheimer's disease pathology, one of the frequently co-occurring neurological diseases in Parkinson's disease patients. The samples also had similar tissue quality and were from the brain's prefrontal cortex, one of the less studied areas for the disease. The prefrontal cortex does not show neuronal death to the same extent as the substantia nigra, although it displays molecular and pathological modifications during the disease process, while also being responsible for the dementia present in a large proportion of Parkinson's disease patients.

Results of the expression experiment showed that the gene FOXO1 had increased expression in the brain tissue samples with known Parkinson's disease. FOXO1 is a transcriptional regulator that can modify the expression of other genes. Further examination of the FOXO1 gene showed that two single-nucleotide polymorphisms (SNPs), or DNA sequence variations, were significantly associated with age at onset of Parkinson's disease.

"Our hypothesis is that FOXO1 acts in a protective manner by activating genes and pathways that fight the neurodegeneration processes," said Dumitriu. "If this is correct, there could be potential to explore FOXO1 as a therapeutic drug target for Parkinson's disease."

###

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BUSM researchers identify role of FOXO1 gene in Parkinson's disease

Cant kick cigarettes? A vaccine may one day help by preventing nicotine from reaching its target in the brain, according to research published this week.

Most smoking therapies do a poor job of stopping the habit 70% to 80% of smokers who use an approved drug therapy to quit relapse. Scientists say this is because the targets of existing therapies are imperfect, only slightly weakening nicotines ability to find its target in the brain.

So some scientists have been trying a different approach creation of a vaccine. It would work like this: People would inject the vaccine like a shot, and the vaccine would create nicotine antibodies, molecules that can snatch up nicotine from the bloodstream before it reaches the brain. The vaccine could be used by smokers who want to quit or people who are worried about getting addicted to cigarettes in the future.

Researchers have tried to create vaccines in the past, but the ones theyve come up with have not been particularly effective. The authors of the new study say this may be because previous vaccines just didnt create enough antibodies to get rid of all the nicotine.

The new report, published in the journal Science Translational Medicine, attempts to solve this problem via gene therapy, in which a new gene is inserted into the body to do a particular job.

First the scientists at Weill Cornell Medical College in New York City put a gene that produces a nicotine antibody into mice. The gene was taken into the mices livers, and the liver started producing the antibody. Once produced, the antibody connected with nicotine, trapping it and preventing it from making its way to the brain, where it would otherwise have caused the pleasurable, addictive effects it is so known for.

Because of this trick, the researchers say that the new vaccine should only have to be injected once, and it will work for life, continuing to produce new antibodies in the liver.

The vaccine was effective: When mice were given nicotine intravenously, ones with the vaccine had a 47-fold drop in levels of nicotine in the blood compared with ones that hadnt received the vaccine. The antibody had successfully captured the nicotine in the bloodstream before it could reach the brain.

The work is still preliminary, and the authors admit the technology is far from ready for human use; it has only been used in rodents so far. But given the results, and the continued public health effect of smoking, it may not be too long before all those boxes of Nicorette are replaced with a single trip to the doctors office.

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New gene therapy for smoking kills the pleasure of nicotine

Featured Article Academic Journal Main Category: Smoking / Quit Smoking Also Included In: Immune System / Vaccines Article Date: 28 Jun 2012 - 2:00 PDT

Current ratings for: New Smoking Vaccine Using Gene Therapy Being Developed

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In a study reported in the journal Science Translational Medicine this week, Researchers at Weill Cornell Medical College in New York City show how a single dose of the vaccine protected mice, over their lifetime, against nicotine addiction.

The addictive properties of the nicotine in tobacco smoke is a huge barrier to success with current smoking cessation approaches, say the authors in their paper.

Previous work using gene therapy vaccination in mice to treat certain eye disorders and tumors, gave them the idea a similar approach might work against nicotine.

The new anti-nicotine vaccine is based on an adeno-associated virus (AAV) engineered to be harmless. The virus carries two pieces of genetic information: one that causes anti-nicotine monoclonal antibodies to be created, and the other that targets its insertion into the nucleus of specific cells in the liver, the hepatocytes.

The result is the animal's liver becomes a factory continuously producing antibodies that gobble up the nicotine as soon as it enters the bloodstream, denying it the opportunity to enter the brain.

The researchers write:

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New Smoking Vaccine Using Gene Therapy Being Developed

Forget patches: gene therapy could suppress cigarette cravings by preventing the brain from receiving nicotine. The treatment is effective in mice, but with gene therapy still not fully tested in people, human trials and treatments are a long way off.

For drug users who really can't quit, vaccination might one day be an option, and several groups have attempted to develop such treatments.

But nicotine vaccines have mostly flopped. This is because nicotine is a very small molecule, so the immune system has difficulty recognising the drug and making antibodies that bind it. Physicians can inject antibodies directly into a patient, but this treatment quickly becomes expensive because the antibodies don't last long.

Ronald Crystal of Weill Cornell Medical College in New York and his team decided to bypass that problem by putting the gene for a nicotine antibody right into the body.

They selected the strongest antibody against nicotine from a mouse and isolated the gene that produced it. They then placed this gene into a carrier called adeno-associated virus (AAV), which is widely used for gene therapy.

When the researchers injected the virus and its cargo into nicotine-addicted mice, the rodents' livers took up the virus, began making antibodies and pumped them into the bloodstream. The researchers injected two cigarettes' worth of nicotine into AAV-infected mice. The antibodies were able to bind 83 per cent of the drug before it reached the brain.

Without their drug, the mice's behaviour changed. Nicotine usually causes mice to "chill out", Crystal says, but the researchers found that the treated mice stayed active and their heart rates stayed normal when they received nicotine.

Eighteen weeks later, the mice's livers were still making the antibody, suggesting that the therapy might render nicotine useless to smokers for long periods.

Jude Samulski at the University of North Carolina at Chapel Hill, who was part of the team that developed AAV as a gene therapy vector, says he's "ecstatic" that the vector has come so far. He calls the research "a gorgeous piece of work" that has "leapfrogged" the difficulties faced by vaccines.

But he has doubts about whether gene therapy is well-tested enough to be used to treat nicotine addiction. So far, AAV has been clinically tested in people with HIV or terminal cancer where potential benefits far outweigh the risks. "It's ahead of its time. In 10 years there may be enough safety data," he says. "Quitting smoking might be easier."

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Gene therapy curbs nicotine addiction in mice

By Elizabeth Lopatto - 2012-06-27T18:00:00Z

An experimental vaccine againstnicotine, delivered using gene therapy, prevents the substance from reaching the brain and may make quitting easier for smokers, a study using mice indicates.

A single dose of vaccine allowed the liver to produce antibodies that stopped most of the nicotine from getting to the brain, according to a study in the journal Science Translational Medicine. The concentration of nicotine in the brains of treated mice was just 15 percent of that in untreated ones.

Of the more than 4,000 chemicals in cigarette smoke, it is nicotine that leads to addiction, the researchers wrote. Keeping the substance away from the brain might stymie nicotines addictive power by preventing smokers from enjoying their cigarettes, giving them no incentive to relapse, said Ronald Crystal, one of the studys researchers.

This looks really terrific if youre a mouse, but the caveat is that they arent small humans, said Crystal, the chairman of genetic medicine at Weill Cornell Medical College in New York, in a telephone interview.

The gene therapy delivers the vaccine to the liver using a virus engineered not to be harmful. The gene sequence for the antibodies is inserted into liver cells, which then begin to create antibodies to nicotine.

The antibody is floating around like Pac-Man in the blood, Crystal said. If you give the nicotine and the anti- nicotine gobbles it up, it doesnt reach the brain.

The idea of vaccines against nicotine has emerged before, in the form of injections used to trigger an immune response. Those methods proved ineffective, according to the researchers. They turned to gene therapy to trigger production of antibodies.

About 20 percent of U.S. adults are smokers, and most relapse shortly after quitting.

We dont have very effective therapies, Crystal said. The problem is even with the drugs we have now, 70 percent of people go back to smoking within 6 months of trying to quit.

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Gene Therapy Against Nicotine May Someday Help Smokers Quit

Public release date: 27-Jun-2012 [ | E-mail | Share ]

Contact: Brian Lin brian.lin@ubc.ca 604-822-2234 University of British Columbia

An international team led by human genetic researchers at the University of British Columbia and Vancouver Coastal Health has identified the latest gene associated with typical late-onset Lewy body Parkinson's disease (PD), with the help of a Canadian Mennonite family of Dutch-German-Russian ancestry.

Twelve of the 57 members of the Saskatchewan family who participated in the study had previously been diagnosed with PD.

UBC Medical Genetics Prof. Matthew Farrer, who led the research, notes that unequivocal confirmation of the gene's linkage with PD required DNA samples from thousands of patients with PD and healthy individuals. He refers to the new discovery as the "missing link," as it helps to unify past genetic discoveries in PD.

"A breakthrough like this would not be possible without the involvement and support of the Saskatchewan Mennonite family who gave up considerable time, contributed clinical information, donated blood samples, participated in PET imaging studies and, on more than one occasion following the death of an individual, donated brain samples," says Farrer, Canada Excellence Research Chair in Neurogenetics and Translational Neuroscience and the Dr. Donald Rix BC Leadership Chair in Genetic Medicine.

"We are forever indebted to their generosity and contribution to better understanding and ultimately finding a cure for this debilitating disease."

The mutation, in a gene called DNAJC13, was discovered using massively parallel DNA sequencing. Conclusive evidence came from the identification of the gene mutation in several other families across many Canadian provinces, including British Columbia.

"This discovery is not only significant for researchers, but also for those families carrying this genetic mutation and afflicted with this disease in that it offers hope that something good might yet result from their suffering," says Bruce Guenther, President of the Mennonite Brethren Biblical Seminary Canada, a community leader and spokesperson for the family that participated in the study.

"The family involved is very grateful for the research team's respectful, collaborative and sensitive approach, and we hope that this enables the discovery of more effective treatments, and hopefully eventually a cure."

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Parkinson's disease gene identified with help of Mennonite family: UBC-VCH research

Public release date: 26-Jun-2012 [ | E-mail | Share ]

Contact: Aaron Lohr alohr@endo-society.org 240-482-1380 The Endocrine Society

Prenatal exposure to bisphenol A, or BPA, a chemical found in many common plastic household items, can cause numerous genes in the uterus to respond differently to estrogen in adulthood, according to a study using a mouse model. The results will be presented Tuesday at The Endocrine Society's 94th Annual Meeting in Houston.

The study, led by Hugh Taylor, MD, professor and chief of the reproductive endocrinology section at Yale University School of Medicine, observed "major and permanent changes in gene expression" in female mice exposed to BPA as a fetus. Taylor said these differences were apparent only after estrogen exposure, either naturally at puberty or with estrogen treatment.

"Hyperresponsiveness to estrogens is a potential mechanism to explain the increased incidence of estrogen-related disorders seen after exposure to endocrine disrupters like BPA," Taylor said.

BPA has estrogen-like properties and has been linked to breast cancer and many female reproductive disorders that are sensitive to estrogen. These problems include uterine fibroids (benign tumors), endometriosis and endometrial hyperplasia, an abnormal thickening of the lining of the uterus that can lead to uterine cancer.

Taylor and his co-workers gave pregnant mice either BPA or an inactive substance for about two weeks beginning on the ninth day of pregnancy. After the mice gave birth, the scientists removed and tested the uterus of half of the female offspring before sexual maturation, looking for changes in gene expression. The other half of the female offspring had removal of their ovaries at 6 weeks of age, followed by treatment with estradiol, an estrogen. They then underwent uterine removal and testing after puberty at 8 weeks of age.

Before sexual maturation, gene expression was "remarkably similar" among control micethose that were not exposed to BPA in the womband the mice that were prenatally exposed to BPA, Taylor said. Of 45,000 genes screened, only 18 showed twofold or greater changes in expression, the authors reported.

After estrogen exposure at puberty, the gene expression profile had changed greatly in BPA-exposed offspring, with 365 genes showing altered expression, according to the study abstract. Of these genes, 208 also showed aberrations in the usual pattern of DNA methylation, a biochemical process that regulates gene expression. At least 14 of the 208 genes have known estrogen response elements, areas that indicate that they are directly regulated by estrogen through its receptor.

Among the BPA-exposed mice, another 316 genes showed altered response to estradiol at puberty. This included several genes that have not previously demonstrated an exaggerated response to estradiol treatment or genes that have not been known to be regulated by estrogen, Taylor said.

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BPA exposure in pregnant mice changes gene expression of female offspring

Public release date: 26-Jun-2012 [ | E-mail | Share ]

Contact: Mary Ellen Peacock maryellen.peacock@nationwidechildrens.org 614-355-0495 Nationwide Children's Hospital

Scientists now have clues to how a gene mutation discovered in families affected with congenital heart disease leads to underdevelopment of the walls that separate the heart into four chambers. A Nationwide Children's Hospital study appearing in PLoS Genetics suggests that abnormal development of heart cells during embryogenesis may be to blame.

When babies are born with a hole in their heart (either between the upper or lower chambers), they have a septal defect, the most common form of congenital heart disease. Although it's not clear what causes all septal defects, genetic studies primarily utilizing large families have led to the discovery of several causative genes.

Vidu Garg, MD, the study's lead author, previously reported that a single nucleotide change in the GATA4 gene in humans causes atrial and ventricular septal defects along with pulmonary valve stenosis. In mice, the GATA4 gene has been shown to be necessary for normal heart development and its deletion leads to abnormal heart development.

"While GATA4 has been shown to be important for several critical processes during early heart formation, the mechanism for the heart malformations found in humans with the mutation we previously reported is not well understood," said Dr. Garg, a pediatric cardiologist in The Heart Center and principal investigator in the Center for Cardiovascular and Pulmonary Research at The Research Institute at Nationwide Children's Hospital.

To better characterize the mutation, Dr. Garg and colleagues generated a mouse model harboring the same human disease-causing mutation. They saw heart abnormalities in the mice that were consistent with those seen in humans with GATA4 mutations. Upon further examination, they found that the mutant protein leads to functional deficits in the ability for heart cells to increase in number during embryonic development.

"Our findings suggest that cardiomyocyte proliferation deficits could be a mechanism for the septal defects seen in this mouse model and may contribute to septal defects in humans with mutations in GATA4," said Dr. Garg, also a faculty member at The Ohio State University College of Medicine. "This mouse model will be valuable in studying how septation and heart valve defects arise and serve as a useful tool to study the impact of environmental factors on GATA4 functions during heart development."

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New mouse model helps explain gene discovery in congenital heart disease

MAYNARD, Mass.--(BUSINESS WIRE)--

Allegro Diagnostics today announced the formation of its Clinical and Scientific Advisory Board. Allegro has developed a molecular testing platform that utilizes gene expression of normal epithelial cells in the respiratory tract to detect early signs of lung cancer.

Our advisory board is comprised of some of the most respected and prolific clinicians, researchers and pioneers in the fields of pulmonary medicine, lung cancer and cancer diagnostics, said Michael D. Webb, President and Chief Executive Officer of Allegro Diagnostics. These individuals will play a central role in advising Allegro on its research and development efforts, as well as on the product development strategy for the BronchoGen genomic test, which is approaching commercialization.

The members of the advisory board are:

About the Allegro Platform

Allegro Diagnostics molecular testing platform utilizes gene expression of normal epithelial cells in the respiratory tract to detect early signs of lung cancer. The field of injury principle on which the platform is based refers to the common molecular response that occurs throughout the respiratory tract in current and former smokers with lung cancer. These changes can be detected in a gene expression signature from non-malignant airway cells and indicate the presence of malignancy remotely in the lung. Allegro has applied this platform to generate multiple product candidates.

About Allegro Diagnostics

Allegro Diagnostics is a molecular diagnostics company focused on the development and commercialization of innovative genomic tests for the diagnosis, staging and informed treatment of lung cancer and other lung diseases. Allegro has developed a molecular testing platform that utilizes a genomic biomarker to detect early signs of lung cancer in current and former smokers. The companys lead product is the BronchoGen genomic test for use in combination with standard bronchoscopy for the diagnosis of lung cancer. http://www.allegrodx.com

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Allegro Diagnostics Appoints Clinical and Scientific Advisory Board Comprised of Experts in Pulmonology, Lung Cancer ...