Category Archives: Gene Medicine

Public release date: 27-Feb-2012
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Contact: Graciela Gutierrez
ggutierr@bcm.edu
713-798-4710
Baylor College of Medicine

HOUSTON (Feb. 27, 2012) ? Antisense oligonucleotides ? short segments of genetic material designed to target specific areas of a gene or chromosome ? that activated an enzyme to "chew up" toxic RNA (ribonucleic acid) could point the way to a treatment for a degenerative muscle disease called myotonic dystrophy, said researchers from Baylor College of Medicine and Isis Pharmaceuticals, Inc., in a report in the journal Proceedings of the National Academy of Sciences.

"This is a proof-of-principle therapy that is very effective in cell culture and mice," said Dr. Thomas A. Cooper, professor of pathology and immunology and molecular and cellular biology at BCM and the report's corresponding author. "The treatment will have to be refined to deliver systemically in people with myotonic dystrophy."

Myotonic dystrophy is the most common muscular disease in adults, affecting mainly the skeletal muscles, heart and central nervous system. It occurs because of a mutation that causes numerous repeats of three letters of the genetic code (CTG) in a gene called DMPK. RNA is made as a step in the cell's production of the protein associated with the gene. The messenger RNA (the chemical blueprint for making a protein) that is produced from the mutated gene also contains the abnormal long repeats that cause the RNA to accumulate in the cell's nucleus. There it sequesters and blocks the function of a protein called Muscleblind-like 1 and activates another protein called CELF1. These proteins antagonize one another and the result is abnormal expression of proteins from many other genes in adult tissues, resulting in disease.

To counteract this, Cooper and his colleagues created antisense oligonucleotides called gapmers, which are simply strands of genetic material that seek out portions of the abnormal RNA repeats and target an enzyme called RNase H to the toxic RNA causing its degradation. They also showed that combining the gapmers with other antisense oligonucleotides that help released the sequestered Muscleblind-like1 can enhance the effect.

"It worked in cultures of cells with the expanded repeats and in mice that model myotonic dystrophy," said Cooper. "We did it in skeletal muscle first because we can inject the material directly into the muscle."

Later, he plans to determine if the material also works in the animals' hearts.

Using the treatment in people will require more fine-tuning, said Cooper. He would like to be able to give the therapy systemically rather than directly into the muscle. They saw some muscle damage and inflammation in the animals they treated.

Antisense oligonucleotide treatments are being tested in Duchenne muscular dystrophy and another disease called spinal muscular atrophy, said Cooper.

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Others who took part in this research include Johanna E. Lee of BCM and C. Frank Bennett of Isis.

Funding for this work came from the National Institutes of Health, the Muscular Dystrophy Association and the Shanna and Andrew Linbeck Family Charitable Fund.

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Antisense oligonucleotides make sense in myotonic dystrophy

Next time you take your medicine, consider that mice likely helped in testing it.

The structure of human and mouse DNA is about 96 percent similar, which makes mice excellent subjects for testing products that could be used on humans. As research has progressed, however, a problem arose within the mice population.

There were very few strains of mice bred for testing, which led to a severe lack of genetic diversity in lab mice. Despite the similarities in DNA structure, the diversity of the mouse population did not match the diversity of the human population, and lab test results in mice could not be safely extrapolated to humans.

In 2001, a program called Collaborative Cross sought to fix this problem. David Threadgill, head of the Genetics Department, works with this group to find ways to diversify lab mouse populations.

"When we started this project, at least a third or half of the mouse genome had no diversity in it, so there were blind spots within the genome, and you couldn't interrogate functions of those parts," Threadgill said.

Threadgill and his colleagues randomly bred eight strains of lab and wild mice, creating a library of test mouse strains with sufficient diversity to mirror the human population.

"We use mice as a surrogate for you, to investigate the causation of human disease," Threadgill said.

Collaborative Cross now has about 1,600 strains of mice, housed and curated at a facility in Chapel Hill. Ten representatives of each strain are kept in the facility's 16,000 cages and are made available to researchers around the world. The mice of Collaborative Cross are currently used in various research projects. From cancer research to infertility studies, these mice of a diverse genetic background enable researchers to investigate the genetic basis of human disease more thoroughly.

Human cell division may mutate into the uncontrolled division of cells, resulting in the development of a cancerous tumor, but researchers can now investigate the causative factors in an expendable mouse population that more closely mirrors the human genome. Because the carriers of these genes, the mice, reproduce very quickly, complete investigations of the behavior and function of genes in relation to the disease in question are possible.

Though Collaborative Cross doesn't just offer mice for direct testing, it also maintains a massive library of genes. Each individual bred through the project has its DNA catalogued in an online resource available to the public. This genome browser is a critical aspect of the project.

It is important in consolidating the work of Collaborative Cross, and offers an excellent reference for any scientist doing work with test mice, according to Threadgill. For example, some diseases are caused by unfavorable combinations of specific genes in an organism's DNA.

"What these mice are telling us is that a lot of human diseases are coming about because of genetic disruption of normal feedback systems," Threadgill said. "There are unique combinations of genetic variation that just don't function well together."

With a resource like the mouse genome library, these unfavorable polymorphisms in genes can be identified, isolated and studied through population analysis.

In the future, Collaborative Cross plans to expand their operation, with new distribution centers around the world and more strains of mice. Being able to perform large scale studies on diverse populations will be even more important as we develop a better understanding of the genetic basis of disease.

For complicated problems, complicated models are needed. According to Threadgill, that's just what Collaborative Cross is developing. 

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Researchers diversify lab mouse gene pool

Sudden infant death syndrome (SIDS) may sometimes have a genetic component, a team of German researchers reports.

DNA analysis from a small group of infants who succumbed to SIDS revealed that many of the male children carried a particular enzyme mutation that may have impaired their ability to breath properly. This was not the case for female SIDS patients.

Study author Dr. Michael Klintschar, director of the Institute for Legal Medicine at Medical University Hannover in Germany, said his team tried to build upon previous research suggesting that "abnormalities in the brain stem, the part of the brain that regulates breathing and other basic functions, lead to SIDS."

"The reasons for these abnormalities are unclear," he noted, "but some scientists believe that the genes inherited by the parents might be one of several factors."

Klintschar and his colleagues found indications that SIDS risk might be higher among male infants who carry a mutation of an enzyme -- called MAOA -- that appears to impede key neurotransmitter function.

"Babies that have this variant inherited might have an impaired breathing regulation," he said. "But the risk conveyed by this gene variant is relatively small compared to other factors, like sleeping position (or exposure to) smoking. Moreover, the findings have to be replicated in another population sample."

The study appears online and in the March issue of Pediatrics.

The authors noted that SIDS is one of the great mysteries in pediatric medicine, with efforts to pin down the root cause for the sudden loss of children under the age of 1 year falling short of a definitive answer.

The new study focused on 156 white infants (99 boys and 57 girls) who were born in the Lower Saxony region of Germany and died while sleeping.

The deaths took place between the second and the 51st week of life, and all remained "unexplained" despite full autopsies, clinical history reviews and analyses of the circumstances of death.

DNA samples were taken from all the deceased, as well as from another 260 male adults between the ages of 18 and 30.

The result: MAOA mutations were more commonly found among male SIDS children than among their healthy male counterparts. This did not hold true with female SIDS children.

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Gene may be culprit in SIDS for boys

FRIDAY, Feb. 24 (HealthDay News) -- Sudden Infant Death Syndrome (SIDS) may sometimes have a genetic component, a team of German researchers reports.

DNA analysis from a small group of infants who succumbed to SIDS revealed that many of the male children carried a particular enzyme mutation that may have impaired their ability to breath properly. This was not the case for female SIDS patients.

Study author Dr. Michael Klintschar, director of the Institute for Legal Medicine at Medical University Hannover in Germany, said his team tried to build upon previous research suggesting that "abnormalities in the brain stem, the part of the brain that regulates breathing and other basic functions, lead to SIDS."

"The reasons for these abnormalities are unclear," he noted, "but some scientists believe that the genes inherited by the parents might be one of several factors."

Klintschar and his colleagues found indications that SIDS risk might be higher among male infants who carry a mutation of an enzyme -- called MAOA -- that appears to impede key neurotransmitter function.

"Babies that have this variant inherited might have an impaired breathing regulation," he said. "But the risk conveyed by this gene variant is relatively small compared to other factors, like sleeping position [or exposure to] smoking. Moreover, the findings have to be replicated in another population sample."

The study appears online and in the March issue of Pediatrics.

The authors noted that SIDS is one of the great mysteries in pediatric medicine, with efforts to pin down the root cause for the sudden loss of children under the age of 1 year falling short of a definitive answer.

The new study focused on 156 white infants (99 boys and 57 girls) who were born in the Lower Saxony region of Germany and died while sleeping.

The deaths took place between the second and the 51st week of life, and all remained "unexplained" despite full autopsies, clinical history reviews and analyses of the circumstances of death.

DNA samples were taken from all the deceased, as well as from another 260 male adults between the ages of 18 and 30.

The result: MAOA mutations were more commonly found among male SIDS children than among their healthy male counterparts. This did not hold true with female SIDS children.

Most mutations appeared to be clustered within a specific time frame of death that correlated with the majority of SIDS fatalities. That is, infants who had died between the age of 46 days and 154 days -- the most prevalent period of SIDS deaths among the study group -- were significantly more likely to carry MAOA mutations than those children who died at ages above 5 months.

The authors concluded that among at least a subset of male SIDS patients, a genetic brain stem abnormality might be the driving force leading to their sudden loss.

"Our study furthers our understanding of the mechanism of SIDS," Klintschar said. "[But] it does not lead directly to a 'cure' of SIDS. And up to now [it] does not enable a lab test to estimate the individual risk of a baby to die from SIDS. But it emphasizes that measures already recommended to prevent SIDS -- using pacifiers, avoid sleeping in the prone position, no smoking during pregnancy -- make sense. Mothers of families with a prior SIDS case in the family should be more careful than others. But in most cases, obeying these recommendations keeps the baby safe."

However, while also an advocate of such basic preventive measures, Dr. Warren Guntheroth, a professor of pediatrics at the University of Washington School of Medicine in Seattle, holds no stock in a genetic basis for SIDS.

"I think it's nonsense," he said. "There's years and years of research that has shown that SIDS is not inherited. Not genetic. The only genetic link I will admit to is that males are definitely more at risk than females. But apart from that, I think fooling around with laboratory studies of genes and saying that that might cause SIDS is a far reach."

So what can parents do?

"Probably one of the most important things is not to put the baby on its tummy for sleep. That reduces risk by 50 percent," Guntheroth said. "Another is the use of the pacifier. Pacifiers, for reasons nobody understands well, reduces the risk. Also, don't overheat the child, by overdressing or putting the infant in a room that is too hot. Finally, cigarettes increase the risk terribly. Living with a parent that smokes is a definite risk factor, so the parent can do themselves and the child a favor by quitting or at least not smoking in the same area as the child."

More information

For more on SIDS, visit the U.S. National Library of Medicine.

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Gene Might Be a Culprit in Sudden Infant Death for Boys

Scientists have identified a new gene that may increase the risk of breast cancer, according to a new study from Finland.

In the study, mutations in this gene, called Abraxas,were linked to cases of hereditary breast cancer.

Researchers have now identified more than 10 genes that increase breast cancer risk; perhaps the most well-known of these are the BRCA1 and BRCA2 genes. But only about 20 percent of women with a family history of breast cancer have mutations in BRAC1 or BRAC2 — meaning in many cases, it's likely other genes are at work.

The mutation does not appear to be common — it was found in 2.4 percent of families with a history of breast cancer. But importantly, the mutation was not found in anyone without breast cancer in the study.

Because the study was conducted in Finland, future studies will need to investigatehow common the mutation is in other countries, said study researcher Roger Greenberg, an associate professor of cancer biology at the University of Pennsylvania School of Medicine.

In the future, women with a family history of breast cancer might be tested for the Abraxas mutation, Greenbergsaid.

Greenberg and colleagues found the Abraxas mutation in three of 125 breast cancer patients from families with a history of the condition. This gene had been suspected to play a role in breast cancer risk because it interacts with BRCA1.

When the researchers looked at an additional 991 breast cancer patients, they found the Abraxas mutation in one woman, who also turned out to have breast cancer in her family. None of the 868 healthy patients in the study had the Abraxas mutation.

The mutated Abraxas gene prevents cells from fixing damaged DNA, increasing the risk that a cell will become cancerous. The gene may increase the risk of other cancers as well. Indeed, one patient in the study was diagnosed with both breast andendometrial cancer, and some patients with the Abraxas mutation had family members with lung cancer, lip cancer and lymphoma.

More research is needed to know exactly how much of an increase in breast cancer risk the Abraxas mutation brings. But Greenberg noted women in the study with this mutation were diagnosed around the same age as those with BRCA1 and BRCA2 mutations — in their mid-40s.

Women with a mutation in BRCA1 or BRCA2 are about five times more likely to develop breast cancer in their lifetimes compared with women who do not have this mutation, according to the National Cancer Institute.

"Identifying more of these mutations will make it easier for patients to know their risk of developing breast cancer," said Dr. Kristin Byrne, chief of breast imaging at Lenox Hill Hospital in New York City, who was not involved in the study. Such genetic information may even help doctors better diagnose breast cancer. Most patients with the Abraxas mutation in the study had a type of breast cancer called lobular carcinoma, which is harder to detect on a mammogram. Knowing that a patient has this mutation might mean doctors use additional screening methods, such as MRI, Byrne said.

The study is published today (Feb. 22) in the journal Science Translational Medicine.

Pass it on: Some cases of hereditary breast cancer may be caused, in part, by mutations in a gene called Abraxas.

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New breast cancer gene found

05-02-2012 04:30 A documentary about Cystic Fibrosis made in 1994. Since this was made a lot of development in treatment has happened. However it is interesting to see how things were and compare them with how things are now. The only thing that hasn't changed is what Cystic Fibrosis is all about and the importance to continue raising much needed funds for the Cystic Fibrosis Research Trust to help find a cure for CF! For more information on CF and how you can help find a cure, visit http://www.cftrust.org.uk

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The Way To Win With Cystic Fibrosis (filmed in 1994). - Video