More Success With Gene Therapy for Blindness

WEDNESDAY, Feb. 8 (HealthDay News) -- As a child, Tami Morehouse had vision problems. She struggled to read the blackboard at school, and homework took hours.

Yet, she made it through high school and college, and became a social worker. Although she was never able to drive, she learned to ride a bike.

But in her 30s, with three young children, her vision took a turn for the worse. "I'd be reading a book and the words faded away," she said.

Morehouse was going blind, the result of Leber congenital amaurosis (LCA), a rare inherited eye disease that causes a progressive loss of vision. "As my kids needed me more and more, I was able to do less and less," Morehouse said.

That changed in 2009, when she was one of 12 people to undergo an experimental treatment using gene therapy in one eye. Now, scientists report even more progress, having successfully treated the second eye of three patients, including Morehouse. The new results are published Feb. 8 in Science Translational Medicine.

LCA is caused by a faulty gene, RPE65, that fails to produce an enzyme needed by the retina, the tissue in the back of the eye that converts light images into nerve signals that get sent to the brain.

Lack of the enzyme causes toxic byproducts to build up in the retinal cells, gradually killing them.

"It's inevitable and progressive, and people watch as they are losing more and more of their vision," said Dr. Jean Bennett, an ophthalmology professor at University of Pennsylvania Perelman School of Medicine and co-leader of the research team that pioneered the treatment. "By the time they're teenagers or young adults, they are severely impaired."

The treatment involved injecting a virus genetically engineered to carry a normal version of gene RPE65 into the retinal cells.

About two weeks later, with the eyes now producing the enzyme, the patients -- adults and children -- saw a marked improvement in their vision.

"They all gained vision in a very meaningful way," said Bennett, also a scientist at Children's Hospital of Philadelphia. "Children can read books, ride their bikes to their friends' houses -- things which they never could do before."

Initially, researchers only injected one eye because of safety concerns, Bennett explained. The fear was that the first injection would prime the immune system to recognize the virus and attack it when it was injected into the second eye. That would cause inflammation in the eye, potentially leading to more vision loss.

But animal studies showed that didn't happen, and so they decided it was safe to try the second eye in adults.

"It's amazing," Morehouse said. "I just feel so different. I used to wake up in the morning, so afraid and so anxious, that I would look over at the alarm clock and see nothing."

Prior to the treatments, she could see light and dark, but most of the world was hazy and gray. By night time, when her eyes were tired, she could see very little.

Today, her vision is still significantly impaired. She needs help finding her way to a table in a restaurant, for example, and reading isn't really possible. Yet, she can tell when someone is approaching, and she can make out a smile.

"Seeing my daughter walk across the basketball court. Seeing my son step up to the plate when he's playing ball -- it's phenomenal," Morehouse said.

Researchers verified that patients could see more by performing functional MRI scans before and after the second eye treatment. The brain imaging showed much more response to visual stimuli after their second eye was done.

At 47, Morehouse was the oldest patient. The prior study taught researchers that children improved the most, probably because their retinal cells had suffered less damage.

Now that researchers have established the procedure is safe in adults, they've started using gene therapy on the second eyes of children with the condition, Bennett said.

Though more research needs to be done and there are "technical" issues to be overcome, "we want to be able to use this approach in developing similar treatments for other more common blinding diseases," she said.

Dr. Richard Lewis, a clinical correspondent for the American Academy of Ophthalmology, called the results "exciting." Not only did the results show that treating the second eye is safe and effective, but that vision in the first eye also appears to improve as well.

"This is setting us up for the next step, which is to take the 5-year-old, the 8-year-old, or even the 6-month-old who has the mutation in this particular gene, and replace the enzyme using gene replacement therapy before permanent damage is done," said Lewis, who is a professor of ophthalmology at Baylor College of Medicine's Cullen Eye Institute in Houston.

More information

The Foundation Fighting Blindness has more on LCA.

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More Success With Gene Therapy for Blindness

Gene Therapy Proves Effective In Treating Blindness

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Main Category: Eye Health / Blindness
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Article Date: 09 Feb 2012 - 0:00 PST

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Researchers from the Perelman School of Medicine at the University of Pennsylvania and The Children's Hospital of Philadelphia have conducted a recent study, published in Science Translational Medicine which focuses on gene therapy for congenital blindness. The scientists were able to improve sight in 3 adult patients who had previously been treated in one eye. The researchers used the same treatment on the second eye of the patients, and they were able to see in low-light situations and also find their way around. There were no conflicting effects reported.

The scientists report that the first and second treatments had no immune reactions which cancelled the genes administered. This has happened in previous studies of gene therapy on different diseases. This study in particular focused on addressing Leber congenital amaurosis (LCA), a retinal disease that results in complete loss of vision by the time the person is an adult.

Jean Bennett, M.D., Ph.D, F.M Kirby, professor of Ophthalmology at Penn., said:

"Patients have told us how their lives have changed since receiving gene therapy. They are able to walk around at night, go shopping for groceries and recognize people's faces - all things they couldn't do before. At the same time, we were able to objectively measure improvements in light sensitivity, side vision, and other visual functions."

During their research, researchers used neuroimaging to flash a dimly blinking checkerboard pattern in front of the patient's eye which had recently been treated. They found that a part of the brain responsible for vision brightened as a result of the functional magnetic resonance imaging (MRI).

Manzar Ashtari, Ph.D., of The Children's Hospital of Philadelphia, and the co-leader of the study says:

"This finding is telling us that the brain is responding to the eye's sensitivity to dim light".

The team administered patients with a vector, a genetically engineered adeno-associated virus, which was carrying a normal version of the gene named RPE65, which is mutated in one form of LCA. LCA is an accumulation of hereditary retinal diseases, in which a gene mutation challenges production of an enzyme necessary for light receptors in the retina.

Before this study, the researchers conducted a trial in Octorber of 2009, using the same gene therapy. The study involved 12 volunteers with LCA. Four of these patients were under the age of 11 when they were treated for the blindness. They only treated one eye in the patients - whichever eye was able to see better, and the study had evident results - 6 patients were able to see better, and were no longer considered "legally blind". Even though the testing on animals proved that re-administering the treatment in the second eye was safe, the researchers were skeptical that the vector in the eye which had not been treated could possibly result in inflammatory responses that could take away the benefits from the eye that wasn't treated.

The eye is somewhat separate from the body's immune system, therefore the concern was not high in terms of the inflammatory responses, however, further testing needed to be done in practice.

Bennett commented:

"Our concern was that the first treatment might cause a vaccine-like immune response that could prime the individual's immune system to react against a repeat exposure."

Like the first study, Albert M. Maguire, M.D, a study co-author, and professor of Opthalmology at Penn, administered the vector in the eye which was untreated previously, in 3 patients at The Children's Hospital of Philadelphia. These patients had received treatment 3 years prior. The authors then proceeded to observe the patients for 6 months after they had been readministered with the vector. The greatest advancements were in terms of light sensitivity, including the pupil's acknowledgments to light when it was seen in a range of different intensities. Out of the 3 patients, 2 were able to find their way through an obstacle course in very low-light situations.

The study showed no significant problems, and they actually discovered something they were not looking for. The fMRI findings demonstrated improvement in brain responses in the first treated eye, not just the newly treated one. The researchers say this is probably because the eyes were able to parallel each other in zooming in on the objects they were trying to see.

The authors say that it is important for further research to be done in order to ensure that gene therapy is an effective and safe way to treat retinal disease in humans.

Bennett concludes:

"However, the findings bode well for treating the second eye in the remaining patients from the first trial - including children, who may have better results because their retinas have not degenerated as much as those of the adults. What's more, the research holds promise for using a similar gene therapy approach for other retinal diseases."

The Children's Hospital of Philadelphia and The Center for Cellular and Molecular Therapeutics (CCMT) sponsored both trials and constructed the vector which carried the corrective gene. The director of CCMT, Katherine A. High, M.D., and pioneering gene therapy researcher, was the co-author of both studies.

CCMT, the Foundation Fighting Blindness, the National Institutes of Health, Research to Prevent Blindness, Hope for Vision, the Paul and Evanina Mackall Foundation Trust at the Scheie Eye Institute, the F.M Kirby Foundation, and anonymous donors funded this study.

Written By Christine Kearney
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

Visit our eye health / blindness section for the latest news on this subject. AAV2 Gene Therapy Readministration in Three Adults with Congenital Blindness
Jean Bennett,, Manzar Ashtari, Jennifer Wellman, Kathleen A. Marshall, Laura L. Cyckowski, Daniel C. Chung,, Sarah McCague, Eric A. Pierce, Yifeng Chen, Jeannette L. Bennicelli, Xiaosong Zhu, Gui-shuang Ying, Junwei Sun, J. Fraser Wright, Alberto Auricchio, Francesca Simonelli,, Kenneth S. Shindler, Federico Mingozzi2, Katherine A. High, and Albert M. Maguire
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Gene Therapy Proves Effective In Treating Blindness

Gene Therapy Helps People With Inherited Blindness See

Treating Two Eyes Safe and Effective, New Study Confirms

By Salynn Boyles
WebMD Health News

Reviewed by Laura J. Martin, MD

Feb. 8, 2012 -- Functionally blind for many years, Tami Morehouse calls the gene therapy that partially restored her sight nothing short of a miracle.

Morehouse was the first of 12 patients with a rare congenital retinal disease to receive the experimental treatment in one eye three years ago, and she is one of just three who has now had the gene therapy in both eyes.

The 47-year-old Ohio social worker and mother of three says before having the treatment she worried everyday that she would lose what little sight she had left.

"This treatment literally gave me a much brighter future," she says. "My world just lit up and I saw things much more clearly. Soon after the second treatment I went out to dinner with my husband and I looked down and thought, 'Oh my gosh, I can see the glass sitting in front of me.'"

Gene Therapy Targets Eye Mutation

The study Morehouse took part in was among the first to show that gene therapy can improve vision in people with inherited blindness.

The updated findings prove that treating both eyes is safe and beneficial, says researcher Jean Bennett, MD, PhD, of the University of Pennsylvania.

Patients received injections of healthy copies of a dysfunctional gene into their eyes in an effort to get the cells to work better.

The injections worked so well that Bennett and colleagues plan to treat the second eyes of the remaining five children and four adults who took part in the original study.

"There was some concern that the first injection would set up an immune response, causing the body to reject the second injection," Bennett says. "If that happened, the benefits to the first [treated] eye could be threatened."

But that is not what happened.

After having the injections in their second eye, the three patients were better able to see in dim light, and two of the three were able to navigate obstacles in low-light situations.

Half of Patients No Longer Legally Blind

All of the patients had an inherited, degenerative retinal disease called Leber congenital amaurosis (LCA), which is caused by a mutation in the RPE65 gene and generally progresses to blindness by mid-adulthood.

Morehouse says her vision became worse with each of her three pregnancies.

By the time she reached her early 40s, she saw little light or color, and most objects looked like "dark, hazy, blurry blobs," she says.

The treatment involved injections of a genetically engineered virus that carried a normal version of the RPE65 gene.

After the first injections, the vision of six of the 12 study participants improved to the point that they were no longer classified as legally blind.

"One of the children who took part in the original study was riding a bicycle within a year," says study co-author Manzar Ashtari, PhD, of the Children's Hospital of Philadelphia. "This is a child who used a cane and held on to adults to guide him before having the treatment."

Gene Therapy Might Prevent Blindness

The hope is that similar therapies targeting other mutations can be used to treat a large number of inherited diseases that cause blindness.

Katherine A. High, MD, of Children's Hospital of Philadelphia, who also worked on the study, says there are now 200 known genetic mutations that cause vision loss.

Because LCA is a degenerative disease, there is also hope that the treatment may one day be used in very young children, or even babies, before vision loss has occurred.

"For many genetic diseases -- not just this one -- early intervention will hold the key to optimal outcomes," High says.

Morehouse is most excited by this promise.

"If this treatment or treatments like this one can keep children from losing their vision in the first place and spare them the struggles that I had growing up, that is truly a miracle," she says.

SOURCES: Bennett, J. Science Translational Medicine, Feb. 8, 2012.Jean Bennett, MD, PhD, F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania at Philadelphia.Manzar Ashtari, PhD, department of radiology, Children's Hospital of Philadelphia.Katherine A. High, MD, Children's Hospital of Philadelphia.News release, Science Translational Medicine.News release, Children's Hospital of Philadelphia.

©2012 WebMD, LLC. All Rights Reserved.

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Gene Therapy Helps People With Inherited Blindness See

Gene Therapy For Inherited Blindness Succeeds In Patients' Other Eye

In 3 Adults, Repeat Dose Safely Improves Vision

Gene therapy for congenital blindness has taken another step forward, as researchers further improved vision in three adult patients previously treated in one eye. After receiving the same treatment in their other eye, the patients became better able to see in dim light, and two were able to navigate obstacles in low-light situations. No adverse effects occurred.

Neither the first treatment nor the readministered treatment triggered an immune reaction that cancelled the benefits of the inserted genes, as has occurred in human trials of gene therapy for other diseases. The current research targeted Leber congenital amaurosis (LCA), a retinal disease that progresses to total blindness by adulthood.

Scientists from the Perelman School of Medicine at the University of Pennsylvania and The Children’s Hospital of Philadelphia led the study, published Feb 8 in Science Translational Medicine.

“Patients have told us how their lives have changed since receiving gene therapy,” said study co-leader Jean Bennett, M.D., Ph.D., F.M. Kirby professor of Ophthalmology at Penn. “They are able to walk around at night, go shopping for groceries and recognize people’s faces—all things they couldn’t do before. At the same time, we were able to objectively measure improvements in light sensitivity, side vision and other visual functions.”

Other objective results came from brain signals seen in neuroimaging. When a dimly flickering checkerboard pattern flashed in front of a patient’s recently treated eye, an area in the brain responsible for vision lit up during functional magnetic resonance imaging (fMRI). “This finding is telling us that the brain is responding to the eye’s sensitivity to dim light,” said radiology researcher Manzar Ashtari, Ph.D., of The Children’s Hospital of Philadelphia, the study’s co-leader.

LCA is a group of hereditary retinal diseases in which a gene mutation impairs production of an enzyme essential to light receptors in the retina. The study team injected patients with a vector, a genetically engineered adeno-associated virus, which carried a normal version of a gene called RPE65 that is mutated in one form of LCA.

The researchers in the current study previously carried out a clinical trial of this gene therapy in 12 patients with LCA, four of them children aged 11 and younger when they were treated. Exercising caution, the researchers treated only one eye—the one with worse vision. This trial, reported in October of 2009, achieved sustained and notable results, with six subjects improving enough to no longer be classified as legally blind.

The Center for Cellular and Molecular Therapeutics (CCMT) at The Children’s Hospital of Philadelphia sponsored both the initial clinical trial and the current study, and manufactured the vector used to carry the corrective gene. Katherine A. High, M.D., a co-author of both studies, is the director of the CCMT, and a pioneering gene therapy researcher.

The research team’s experiments in animals had showed that readministering treatment in a second eye was safe and effective. While these results were encouraging, the researchers were concerned that readministering the vector in the untreated eye of the patients might stimulate an inflammatory response that could reduce the initial benefits in the untreated eye.

“Our concern was that the first treatment might cause a vaccine-like immune response that could prime the individual’s immune system to react against a repeat exposure,” said Bennett. Because the eye is “immune-privileged” —relatively isolated from the body’s immune system—such a response was considered less likely than in other parts of the body, but the idea needed to be tested in practice.

As in the first study, retina specialist Albert M. Maguire, M.D., a study co-author and professor of Opthalmology at Penn, injected the vector into the untreated eyes of the three subjects at The Children’s Hospital of Philadelphia. The patients had been treated one and a half to three years previously.

The researchers continued to follow the three patients for six months after readministration. They found the most significant improvements were in light sensitivity, such as the pupil’s response to light over a range of intensities. Two of the three subjects were able to navigate an obstacle course in dim light, as captured in videos that accompanied the published study.

There were no safety problems and no significant immune responses. There was even an unexpected benefit—the fMRI results showed improved brain responses not just in the newly injected eye, but in the first one as well, possibly because the eyes were better able to coordinate with each other in fixating on objects.

The researchers caution that follow-up studies must be done over a longer period and with additional subjects before they can definitively state that readministering gene therapy for retinal disease is safe in humans. However, said Bennett, the findings bode well for treating the second eye in the remaining patients from the first trial—including children, who may have better results because their retinas have not degenerated as much as those of the adults.

What’s more, Bennett added, the research holds promise for using a similar gene therapy approach for other retinal diseases. Ashtari said that fMRI may play a future role in helping to predict patients more likely to benefit from gene therapy for retinal disease.

Funding support for this study came from the CCMT, the Foundation Fighting Blindness, the National Institutes of Health (National Center for Research Resources grants UL1-RR-024134, IR21EY020662, and 1R01EY019014-01A2), Research to Prevent Blindness, Hope for Vision, the Paul and Evanina Mackall Foundation Trust at the Scheie Eye Institute, anonymous donors, the Italian Telethon Foundation, and the F.M. Kirby Foundation. Dr. High is an Investigator of the Howard Hughes Medical Institute, which also provided support.

Image 2 Credit: Jean Bennett, MD, PhD, Perelman School of Medicine, University of Pennsylvania; Manzar Ashtari, Ph.D., of The Children’s Hospital of Philadelphia, Science Translational Medicine.

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Gene Therapy For Inherited Blindness Succeeds In Patients' Other Eye

Regenerative Medicine: Current Concepts and Changing Trends – Video

26-01-2012 07:54 Air date: Wednesday, January 25, 2012, 3:00:00 PM Timedisplayed is Eastern Time, Washington DC Local Category: Wednesday Afternoon Lectures Description: Patients with diseased or injured organs may be treated with transplanted organs. There is a severe shortage of donor organs which is worsening yearly due to the aging population. Regenerative medicine and tissue engineering apply the principles of cell transplantation, material sciences, and bioengineering to construct biological substitutes that may restore and maintain normal function in diseased and injured tissues. Stem cells may offer a potentially limitless source of cells for tissue engineering applications and are opening new options for therapy. Recent advances that have occurred in regenerative medicine will be reviewed and applications of these new technologies that may offer novel therapies for patients with end-stage tissue and organ failure will be described. The NIH Wednesday Afternoon Lecture Series includes weekly scientific talks by some of the top researchers in the biomedical sciences worldwide. For more information, visit: The NIH Director's Wednesday Afternoon Lecture Series Author: Anthony Atala, MD, Wake Forest School of Medicine Runtime: 00:51:29 Permanent link: videocast.nih.gov

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Regenerative Medicine: Current Concepts and Changing Trends - Video

New advance in gene therapy for blindness

US scientists on Wednesday reported a new advance in using gene therapy to restore eyesight in people with a rare, inherited form of blindness.

The therapy, which had been previously tried in just one eye of 12 people, worked well when injected into the other eye of three of the patients, offering a sign that the treatment is safe, effective and will not be rejected by the body.

"Our concern was that the first treatment might cause a vaccine-like immune response that could prime the individual's immune system to react against a repeat exposure," said lead author Jean Bennett, professor of ophthalmology at the University of Pennsylvania.

Despite the risks, three adult patients from the initial study -- whose results were published in 2009 showing that some level of vision had been restored in all of them and six were no longer legally blind -- agreed to try the therapy in their untreated eye.

The trio were all better able to see in dim light afterward, and two were able to navigate obstacles in low-light situations. There were no reports of ill side-effects.

The study appears in the journal Science Translational Medicine.

"Patients have told us how their lives have changed since receiving gene therapy," said Bennett. "They are able to walk around at night, go shopping for groceries and recognize people's faces -- all things they couldn't do before."

The revolutionary treatment targets a disease of light-catching retinal cells called Leber's congenital amaurosis, or LCA.

Caused by flaws in any one of around 13 key genes, LCA triggers severe loss of vision and abnormal eye movements in early infancy, usually leading to total blindness in the twenties or thirties.

Bennett and colleagues tested a way of tackling the disease by inserting a corrective gene in a disabled cold virus.

The modified virus was injected into the eyeball, and infected the diseased cells -- in effect, acting like a Trojan horse to deliver the right DNA to the retina.

Twelve patients aged eight to 44 years were recruited in the small, experimental study, and were given the treatment in the eye that had the worst vision.

None of the patients recovered normal sight, but all of them had an at-least 100-fold increase in so-called pupillary light response, meaning the constriction of the pupil when exposed to light.

Six of the 12 recovered sufficient sight that meant they may no longer be classified as legally blind.

The best results were among four children aged eight, nine, 10 and 11.

Their first study was published by The Lancet in 2009.

Gene medicine is one of the most alluring areas of biotechnology, offering the theoretical promise of blocking or reversing inherited disease.

But this new frontier has also been hit by occasional setbacks, notably an unexpected or uncontrollable response from the immune system.

The pioneering treatment for LCA, though, has so far had no side effects and its benefits have remained unchanged years later, say the researchers.

More research is needed before the therapy can be confirmed safe, but the latest findings bode well for trying it in more of the initial subjects, particularly the youngest ones whose retinas have not degenerated as much as those of the adults.

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New advance in gene therapy for blindness

"Encouraging results in gene therapy for hereditary eye diseases" – Video

20-01-2012 04:13 http://www.telethon.it - Alberto Auricchio is a researcher at the Telethon Institutes of Genetics and Medicine (TIGEM) in Naples. Trained as a paediatrician, he then chose to become a researcher to study the mechanisms of genetic diseases, in particular those of the eyes and the metabolism. After spending a number of years as a researcher in the United States, he returned to Italy in 2002 and now coordinates a research group of about 15 people. He is also an associate professor of medical genetics at the Department of Paediatrics at the "Federico II" University in Naples and in 2007 was made a "Knight of the Republic" by President Giorgio Napolitano.

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"Encouraging results in gene therapy for hereditary eye diseases" - Video

Too Much Weed~Gene Burnett – Video

29-01-2012 01:33 More fun with lip-synching and hats. This is my fourth video like this so far. You can find the others in my "Hat Tricks" playlist. The song is called "Too Much Weed". It's a friendly look at figuring out when enough is enough. In my experience, no medicine works if you get the dose wrong. This song is from my album "Undiscovered~Part One" and, like all of my songs, it's available for downloading free or with a donation at http://www.GeneBurnett.com It's also available at iTunes and CD Baby and other e-retailers of music, where it might be faster and easier to find...but it'll cost you a buck. Created on January 28, 2012 using FlipShare.

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Clues to common birth defect found in gene expression data

ScienceDaily (Feb. 6, 2012) — Researchers at MassGeneral Hospital for Children (MGHfC), The Jackson Laboratory and other institutes have uncovered 27 new candidate genes for congenital diaphragmatic hernia (CDH), a common and often deadly birth defect.

Their sophisticated data-filtering strategy, which uses gene expression during normal development as a starting point, offers a new, efficient and potentially game-changing approach to gene discovery.

Babies born with CDH -- representing one in every 3,000 live births -- have a hole in the diaphragm that separates the abdominal cavity from the chest cavity, and may die due to poor growth of the lung.

Patricia K. Donahoe, M.D., director of the Pediatric Surgical Research Laboratories at MGHfC, explained, "That hole can be fixed surgically if CDH has been diagnosed in time. But even surgery does not rescue the infants' impaired lung development, which often leads to fatal respiratory complications." Patients who survive into adulthood "tend to have a lot of ongoing health issues," she noted.

Donahoe and her colleagues Meaghan Russell, Ph.D., and Mauro Longoni, M.D., and Jackson Laboratory Professor Carol J. Bult, Ph.D., a computational biologist, led the research, published in the Proceedings of the National Academy of Sciences. The team had two goals: to identify the genes and gene networks that cause the hole in the diaphragm in order to develop new diagnostics and preventive treatments, and to learn more about how healthy lungs form to boost lung development in post-operative infant patients.

Bult and her Jackson colleague Julie Wells, Ph.D., generated gene expression profiles -- snapshots of gene activity -- for embryonic mouse diaphragms at multiple stages of development. Using algorithms designed by the JAX-MGH team, they used these data to then predict genes likely to contribute to diaphragm defects.

Bult said, "We asked which genes in our developmental data sets work together in common pathways, and which of these pathways contain previously known CDH genes from human studies and mouse models?"

To build gene networks, the researchers used the Mouse Genome Informatics (MGI) data base resource based at The Jackson Laboratory. MGI, freely available to the research community, maintains the most comprehensive collection of mouse genetic and genomic information.

The researchers' filtering strategy identified 27 new candidate genes for CDH. When the investigators examined the diaphragms of knockout mice for one of these candidate genes -- pre-B cell leukemia transcription factor 1 or Pbx1 -- they found previously unreported diaphragmatic defects, confirming the prediction.

The next step in the project is to screen patients for mutations in Pbx1 using the collection of CDH patient data and DNA that MGHfC and Children's Hospital Boston have been accumulating for years in collaboration with hospitals from around the world.

The research reported in the paper opens the door "not only to further research to explore the effects of the other 26 CDH candidate genes," Bult said, "but to a disease gene identification and prioritization strategy for CDH, an approach that can be extended to other diseases and developmental anomalies."

MassGeneral Hospital for Children is the pediatric service of Massachusetts General Hospital (www.massgeneral.org), the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $750 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, reproductive biology, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.

The Jackson Laboratory is an independent, nonprofit biomedical research institution and National Cancer Institute-designated Cancer Center based in Bar Harbor, Maine, with a facility in Sacramento, Calif., a future institute in Farmington, Conn., and a total staff of about 1,400. Its mission is to discover the genetic basis for preventing, treating and curing human disease, and to enable research and education for the global biomedical community.

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Journal Reference:

Russell et al. Congenital diaphragmatic hernia candidate genes derived from embryonic transcriptomes. Proceedings of the National Academy of Sciences, 2012 DOI: 10.1073/pnas.1121621109

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Clues to common birth defect found in gene expression data

Electro-Medicine : Neurons function revealed – Video

23-11-2011 22:10 There's a new way to explore biologys secrets. With a flash of light, scientists from the US Department of Energys Lawrence Berkeley National Laboratory and the University of California, Berkeley zeroed in on the type of neural cell that controls swimming in larval zebrafish. Using innovative light-activated proteins and gene expression techniques, the scientists zapped several zebrafish with a pulse of light, and initiated a swimming action in a subset of fish that was traced back to the type of neuron that drives the side-to-side motion of their tail fins. The technique behind this needle-in-haystack search for the neural roots of a specific behavior could become a powerful way to learn how any biological system works. newscenter.lbl.gov This three-dimensional microscopy image reveals an output neuron of the optic tectum lighting up in response to visual information from the retina. The scientists used this state-of-the-art imaging technology to learn how neurons in the optic tectum take visual information and convert it into an output that drives action. More information: newscenter.lbl.gov Dendrite growth and synaptogenesis in larval zebrafish optic tectum

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Gene mutation discovery sparks hope for effective endometriosis screening

Published in the Feb. 3 early online issue of EMBO Molecular Medicine, the study explored an inherited mutation located in part of the KRAS gene, which leads to abnormal endometrial growth and endometrial risk. In endometriosis, uterine tissue grows in other parts of the body, such as the abdominal cavity, ovaries, vagina, and cervix. The condition is often hereditary and is found in 5%-15% of women of reproductive age, affecting over 70 million women worldwide.

Although the disorder has been studied for many years, its exact cause and how it develops remained unclear. It was previously shown that activating the KRAS gene caused mice to develop endometriosis. However, no mutations in this gene have been identified in women with endometriosis.

Led by senior author Hugh S. Taylor, M.D., professor and chief of the Division of Reproductive Endocrinology and Infertility in the Department of Obstetrics, Gynecology & Reproductive Sciences, the authors studied 132 women with endometriosis and evaluated them for a newly identified mutation in the region of the KRAS gene responsible for regulation. This mutation was previously linked to an increased risk of lung and ovarian cancer by study co-author Joanne Weidhaas, M.D., assistant professor of therapeutic radiology.

"We found that 31% of the women with endometriosis in the study carried this mutation, compared to only 5.8% of the general population," said Taylor. "The presence of this mutation was also linked to higher KRAS protein levels and associated with an increased capacity for these cells to spread. It also may explain the higher risk of ovarian cancer in women who have had endometriosis."

The Yale team is the first to identify a cause of this common and previously little understood disease. "This mutation potentially represents a new therapeutic target for endometriosis as well as a basis of potential screening methods to determine who is at risk for developing endometriosis," said Taylor.

More information: EMBO Molecular Medicine, DOI:10.1002/emmm.201100200

Provided by Yale University (news : web)

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Gene mutation discovery sparks hope for effective endometriosis screening

Gene therapy, a totally Italian success – Video

16-01-2012 03:57 http://www.telethon.it - Gene therapy is the technique that allows the prevention and treatment of diseases thanks to DNA transfer. In the case of genetic diseases in which one gene is defective or absent, gene therapy basically consists in transferring a functioning version of the gene into a patient's organism so as to remedy the defect. The idea at the basis of gene therapy is a simple one, but implementing it means negotiating an obstacle course. The more delicate aspects include the safety of the procedure, the efficiency of the transfer and the immune system's reaction, which can result in the elimination of the genetically modified cells and annul the effects of the treatment. The first success in gene therapy was achieved in Italy in 2002, thanks to Telethon research, curing the first two children suffering from ADA-SCID and therefore born with no immune defences. Today there are 14 children who have been totally cured and Telethon is working on making gene therapy available for everyone. To this one must add the success achieved by researchers at the Telethon Institute of Genetics and Medicine (TIGEM) at Naples' Second University and at the Children's Hospital in Philadelphia, with the treatment of 12 patients suffering from Leber's congenital amaurosis, the disease of the retina that leads to blindness.

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Gene therapy, a totally Italian success - Video

'Goldilocks' gene used to find drug treatment that is 'just right' for TB patients

One of first examples of using personalised medicine for an infectious disease

By Lauren Paxman

Last updated at 3:28 PM on 3rd February 2012

Tuberculosis patients may soon receive treatments specially tailored to their DNA, an international research team from Oxford University, King's College London, Vietnam and the U.S. has revealed.

The idea of personalised medicine is already becoming familiar in the treatment of cancer. But this would be one of the first times where an individual's genetic profile can determine which drug will work best for them for an infectious disease.

The scientists found that people generate an immune response to tuberculosis that is 'too much', 'too little' or 'just right', according to what versions they have of the LTA4H gene.

Goldilocks effect: A scientists checks the results of a DNA test, as research reveals that people generate an immune response to tuberculosis according to what versions they have of the LTA4H gene (file photo)

This indicates that patients are likely to benefit from different drug treatments depending on their LTA4H gene profile.

Furthermore, the researchers show that steroids - used as part of the standard treatment for the most severe form of tuberculosis, TB meningitis - only benefit some patients.

The results of the study, part-funded by the Wellcome Trust, are published in the journal, Cell.

 

Tuberculosis is a major cause of death worldwide, with an estimated 9.4 million cases and 1.7 million deaths in 2009.

The disease is caused by Mycobacterium tuberculosis bacteria and differs according to where the infection takes hold.

Most TB affects the lungs, but around 40 per cent of cases involve disease elsewhere. In perhaps 1 per cent of cases, TB affects the brain. This form of the disease, TB meningitis, is the most serious. It is hard to diagnose and treat, and even with treatment it is often fatal.

The standard treatment for TB meningitis involves a range of antibiotics to try and kill the bacteria, and the steroid dexamethasone to dampen inflammation – the body's response to tuberculosis infection that can be almost as much of a problem.

An X-ray of a human chest showing pulmonary tuberculosis. Most TB affects the lungs, but around 40 per cent of cases involve disease elsewhere

The new study combines work on zebrafish at the University of Washington, to identify genes and biological pathways involved in the immune response to TB, with clinical research work in collaboration with Pham Ngoc Thach Hospital, the Hospital for Tropical Diseases and the Oxford University Clinical Research Unit in Vietnam.

The scientists identified a gene in zebrafish associated with susceptibility to tuberculosis, which controlled the balance of the inflammatory response.

Variations in the DNA code in this gene could alter different biological pathways, leading either to too much inflammation or too little. Both too much and too little inflammation were problems, allowing the tuberculosis bacteria to thrive and multiply.

The researchers showed that blocking the appropriate biological pathway with drugs could restore just the right level of inflammatory response.

The researchers based in Vietnam then went back to samples from a previous clinical trial in over 500 patients with TB meningitis. They showed changes at a single position in the human LTA4H gene were associated with treatment response.

'Depending on what versions of the LTA4H gene you have inherited, you could see an inflammatory response to tuberculosis that is "too much", "too little", or "just right"'

Only those having LTA4H genes that led to too much inflammation benefitted from the use of the steroid dexamethasone.

There is some suggestion that the steroid could have an adverse effect for those whose LTA4H genes already lead them to have a reduced inflammatory response, though the result is not statistically significant.

Dr Sarah Dunstan, Head of Human Genetics at Oxford University Vietnam, said: 'It's like a "Goldilocks" gene. Depending on what versions of the LTA4H gene you have inherited, you could see an inflammatory response to tuberculosis that is "too much", "too little", or "just right".'

She added: 'You are likely to benefit most from a treatment tailored to your own genes.'

Dr Guy Thwaites, of King's College London and who lead the clinical study in Vietnam on a Wellcome Trust Fellowship, says: 'This is a fundamental discovery. It is now possible to think about the use of simple but rapid genetic tests to determine how people will respond to tuberculosis infection and whether they would benefit from steroids.

'The findings could apply much more widely than just in TB meningitis, or other forms of tuberculosis,' adds Dr Thwaites.

'Since the inflammation pathways governed by the LTA4H gene are central to many infections, there could be implications for many diseases.

Professor Jeremy Farrar, who leads the Oxford University Clinical Research Unit in Vietnam, said: 'The idea that a patient's genes can determine what treatment they will benefit from is pretty novel outside of cancer.

'Nothing like this has been seen before in infectious disease.'

 

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'Goldilocks' gene used to find drug treatment that is 'just right' for TB patients

James Wilson, MD, Ph.D., on Gene Therapy as a Disruptive Technology – Video

20-01-2012 17:36 Dr. James Wilson is a professor in the department of pathology and laboratory medicine, and the director of the gene therapy program, at the University of Pennsylvania. He is also the editor of Human Gene Therapy, a peer-reviewed journal published by Mary Ann Liebert, Inc. During this interview with GEN, Dr. Wilson discusses his concept of a disruptive technology and explains why he believes gene therapy falls into this category. In addition to this SKYPE interview, Dr. Wilson further elaborated on his view of gene therapy as a disruptive technology in a column in the January 2012 issue of Human Gene Therapy which can be viewed here: online.liebertpub.com

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James Wilson, MD, Ph.D., on Gene Therapy as a Disruptive Technology - Video

'Goldilocks' gene could determine best treatment for tuberculosis patients

This is one of the first examples in infectious disease of where an individual's genetic profile can determine which drug will work best for them – the idea of personalised medicine that is gradually becoming familiar in cancer medicine.

The scientists found that people generate an immune response to tuberculosis that is 'too much', 'too little' or 'just right', according to what versions they have of the LTA4H gene.

The findings indicate that patients are likely to benefit from different drug treatments depending on their LTA4H gene profile.

Furthermore, the researchers show that steroids used as part of the standard treatment for the most severe form of tuberculosis, TB meningitis, only benefit some patients.

The results of the study, part-funded by the Wellcome Trust, are published in the journal Cell.

Tuberculosis is a major cause of death worldwide, with an estimated 9.4 million cases and 1.7 million deaths in 2009. The disease is caused by Mycobacterium tuberculosis bacteria and differs according to where the infection takes hold. Most TB affects the lungs, but around 40% of cases involve disease elsewhere. In perhaps 1% of cases, TB affects the brain. This form of the disease, TB meningitis, is the most serious. It is hard to diagnose and treat, and even with treatment it is often fatal.

The standard treatment for TB meningitis involves a range of antibiotics to try and kill the bacteria, and the steroid dexamethasone to dampen inflammation – the body's response to tuberculosis infection that can be almost as much of a problem.

The new study combines work in zebrafish at the University of Washington, Seattle to identify genes and biological pathways involved in the immune response to TB, with clinical research work in collaboration with Pham Ngoc Thach Hospital, the Hospital for Tropical Diseases and the Oxford University Clinical Research Unit in Vietnam.

The scientists identified a gene in zebrafish associated with susceptibility to tuberculosis, which controlled the balance of the inflammatory response. Variations in the DNA code in this gene could alter different biological pathways, leading either to too much inflammation or too little. Both too much and too little inflammation were problems, allowing the tuberculosis bacteria to thrive and multiply.

The researchers showed that blocking the appropriate biological pathway with drugs could restore just the right level of inflammatory response.

The researchers based in Vietnam then went back to samples from a previous clinical trial in over 500 patients with TB meningitis. They showed changes at a single position in the human LTA4H gene were associated with treatment response.

Only those having LTA4H genes that led to too much inflammation benefitted from the use of the steroid dexamethasone.

There is some suggestion that the steroid could have an adverse effect for those whose LTA4H genes already lead them to have a reduced inflammatory response, though the result is not statistically significant.

'It's like a "Goldilocks" gene. Depending on what versions of the LTA4H gene you have inherited, you could see an inflammatory response to tuberculosis that is "too much", "too little", or "just right",' explains Dr Sarah Dunstan Head of Human Genetics of Oxford University Vietnam. 'You are likely to benefit most from a treatment tailored to your own genes.'

Dr Guy Thwaites of King's College London and who lead the clinical study in Vietnam on a Wellcome Trust Fellowship says: 'This is a fundamental discovery. It is now possible to think about the use of simple but rapid genetic tests to determine how people will respond to tuberculosis infection and whether they would benefit from steroids.'

'The findings could apply much more widely than just in TB meningitis, or other forms of tuberculosis,' adds Dr Thwaites. 'Since the inflammation pathways governed by the LTA4H gene are central to many infections, there could be implications for many diseases.'

'This study highlights the power of really good clinical research supported through Wellcome Trust Fellowships and linked with some of the very best scientists in the world in Vietnam and the USA, which can bring immediate benefits to patients and also point the way to develop better, more targeted drugs to treat people with tuberculosis in the future,' says Professor Jeremy Farrar who leads the Oxford University Clinical Research Unit in Vietnam. 'The idea that a patient's genes can determine what treatment they will benefit from is pretty novel outside of cancer. Nothing like this has been seen before in infectious disease. Now we need to see if we can use this to help patients with this devastating disease'

More information: 'Host genotype-specific therapies can optimise the inflammatory response to mycobacterial infections', by David Tobin et al., Cell (2012).

Provided by King's College London (news : web)

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'Goldilocks' gene could determine best treatment for tuberculosis patients

Gene Mutation Linked to Inappropriate Lipid Buildup in Liver

Newswise — (SALT LAKE CITY)—A team of scientists from the University of Utah and the University of California at San Francisco has discovered that the mutation of a gene encoding a ketone body transporter triggers accumulation of fat and other lipids in the livers of zebrafish. This discovery, published in the Feb. 1, 2012, issue of Genes & Development, reveals that transport of ketone bodies out of the liver is a critical step in energy metabolism during fasting. It also provides a new approach for studying the development of fatty liver disease in humans.

Nonalcoholic fatty liver disease (NAFLD), or abnormally high accumulation of lipids in the liver, is the most common cause of chronic liver disease worldwide. Lipids are a broad group of molecules that include fats, triglycerides, and cholesterol. In some people, NAFLD causes no complications, but in others, excess fat in the liver can lead to inflammation or development of scar tissue, resulting in permanent liver damage or even liver failure. NAFLD may also increase the risk of heart disease in people who are overweight or obese.

The increasing prevalence of NAFLD in the United States is due, in large part, to the obesity epidemic. It is estimated that more than 6 million U.S. children already have fatty liver disease.

“Currently, there are a limited number of treatment options for decreasing excess fat in the liver and there are no methods for reversing damage to liver tissue due to NAFLD,” says Amnon Schlegel, M.D., Ph.D., investigator in the University of Utah Molecular Medicine program, assistant professor of internal medicine at the University of Utah School of Medicine, and senior author on the study. “By identifying and characterizing novel genes that regulate accumulation of lipids in the liver, we may be able to gain new insight into the physiological processes that lead to NAFLD.”

Previous research has shown that many of the proteins known to control lipid metabolism in humans are also present in zebrafish. Schlegel and his colleagues began by identifying a zebrafish mutant known as red moon (rmn), which developed abnormal lipid accumulation in liver cells, without evidence of associated liver inflammation or liver damage, when exposed to fasting conditions. Schlegel and his colleagues then used a molecular genetic technique called positional cloning to isolate the gene disrupted by the rmn mutation. They found that the rmn mutation inactivated slc16a6a, a gene thought to encode a protein required in the transport of nutrients during fasting.

“Until now, the activity of the Slc16a6a protein has not been functionally characterized in any organism,” says Schlegel, who’s also an adjunct assistant professor of biochemistry at the U medical school. “Our studies indicate that Slc16a6a is a protein involved in the transport of ?-hydroxybutyrate.”

?-hydroxybutyrate is a ketone body, a compound that is produced in the liver when blood glucose is low and fatty acids are broken down for energy. During periods of fasting, most body tissues can use fatty acids as an energy source, but the brain relies on ?-hydroxybutyrate and other ketone bodies for fuel. Schlegel and his colleagues discovered that, in rmn mutants deprived of nutrition, loss of Slc16a6a function disabled secretion of ketone bodies from liver cells and increased lipid accumulation in the liver. They also found that introducing the human form of the SLC16A6 protein into rmn mutant livers restored ketone body secretion.

“Our research has uncovered a previously unrecognized, but critical step, in the complicated physiology of fasting,” says Schlegel. “We still don’t know whether altered fasting liver metabolism influences the development of NAFLD, but knowing that Slc16a6a is required for secretion of ketone bodies from liver cells during fasting may have implications for our understanding and treatment of other medical conditions where ketone bodies play a role. These conditions include uncontrolled type 1 diabetes, obesity, and childhood metabolic disorders caused by defects in fatty acid metabolism.”


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Gene Mutation Linked to Inappropriate Lipid Buildup in Liver