Category Archives: Gene Medicine

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.

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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

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

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

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.

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Study Finds New Gene Mutations That Lead to Enlarged Brain Size, Cancer, Autism, Epilepsy

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.

Read more:
New gene therapy for smoking kills the pleasure of nicotine