By Robert Bazell, Chief science and medical correspondent, NBC News

Should high school kids get a genetic test for the risk for Alzheimers disease before theyre allowed to play football? Two prominent scientists who study both Alzheimers and the traumatic brain injury suffered by some football players raise that ethically charged question in an editorial out Wednesday in the journal Science Translational Medicine.

We all carry a gene called APOE which comes in three forms.If we carry one copy of the form called E4, it triples our lifetime risk for Alzheimers. About 10 percent of the U.S. population falls in that category. If we have two copies of E4, the lifetime Alzheimers risk is 15 times greater.About 2 percent of us have that genetic makeup.

Although the connection between APOE E4 and Alzheimers risk has been known for years, few have suggested it as a screening tool because theres no known way to prevent the mind-robbing disease.But, now as scientists want to test drugs as early as possible as potential methods of preventing Alzheimers, APOE is getting more attention, as are brain scans and other techniques that might determine who is at risk.

At the same time, scientists have been finding that football players, boxers and soldiers suffering blast injuries are more likely to develop chronic traumatic encephalopathy (CTE), the form of dementia that can follow a brain injury --if they have one or two copies of the E4 version of APOE.

The U.S. government has launched a new website and is pouring millions of dollars into two large studies examining whether or not a drug can slow the progression of Alzheimer's among patients who are predisposed to the devastating disease. NBC's Robert Bazell reports.

Neurologist Dr. Sam Gandy of Mt. Sinai Medical Center in New York and Alzheimers researcher Dr. Steven DeKosky of the University of Virginia School of Medicine, Charlottesville, conducted a poll of 49 colleagues. By a 2 to 1 decision their fellow scientists said it is not yet appropriate to test high school students, and by a 3 to 1 ratio they opposed testing military recruits. But few of the scientists dismissed the ideas out of hand.

As the evidence of a connection mounts, testing may become more of an imperative.

There are obvious, enormous ethical difficulties. Telling a 14-year-old that he or she faces an increased lifetime risk of Alzheimers could lead to unknowable future strains on individuals and families, as well as a lifetime of difficulty in getting health and life insurance. But if scientists learn how to intervene to prevent the Alzheimers, or if the evidence of increased risk from sports or on the battlefield becomes overwhelming, the question may be asked more often.

Robert Bazell is NBC's chief science and medical correspondent. Follow himon Facebook and on Twitter: @RobertBazellNBC.

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Test teen football players for Alzheimer's gene?

Diane Cook's 65th birthday was a milestone for her, but not because of her age. That was the day she was diagnosed with Parkinson's disease.

"I was stunned," she said, adding that even though she had had symptoms for four years before being diagnosed, the news was still a surprise.

That day, she could not muster the courage to learn more about what was in store for her. But the next day she pored over the Internet to learn about the disease. She quickly discovered that it would continue to get worse, and that there was no cure.

Parkinson's disease, often associated with boxer Muhammad Ali and actor Michael J. Fox, affects 1 million Americans, according to the National Parkinson Foundation.

While the exact causes largely remain a mystery, doctors know that the condition arises from the degeneration of a specific area of the brain involved in movement. As a result, those with Parkinson's experience tremors, rigidity, slowness in moving, and difficulty with balancing and walking.

Parkinson's eventually leads to mood disorders and dementia. The complications associated with the condition are the 14th largest cause of death in the United States, according to the U.S. Centers for Disease Control and Prevention.

Not only is there no cure for Parkinson's, but many patients have no way of knowing how quickly their symptoms will progress.

"We all worry about how rapidly we'll lose our abilities," Cook said. "The uncertainty is very frustrating."

A new study from UCLA may help. Researchers have found two variants on a gene already known to be associated with Parkinson's that may be able to predict how quickly patients with the condition will deteriorate. The study found that patients with one particular variant were four times as likely to have rapid decline of motor function. Those patients having both of the variants studied were even more likely to see their disease progress more quickly.

The information is important, as patients who have more severe motor disease tend to die sooner.

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Gene Predicts Parkinson's Progression

SAN DIEGO, May 16, 2012 /PRNewswire/ -- Cardium Therapeutics (CXM) today announced a late-breaking poster presentation at the American Society of Gene & Cell Therapy (ASGCT) 15th Annual Meeting being held May 16-19, 2012 at the Pennsylvania Convention Center in Philadelphia, PA.

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The new research findings demonstrate that cardiac ischemia plays an important role in adenovector gene transfection (delivery) in mammalian hearts. Based on this understanding, using a standard balloon angioplasty catheter, researchers have developed and tested a new method to induce transient ischemia during a non-surgical interventional cardiac procedure, which when coupled with the infusion of nitroglycerin, boosts the delivery (cell transfection) of an adenovector gene construct into heart cells. The increase in adenovector-based gene transfection with the new technique is over two orders of magnitude (>100 fold).

Cardium's new method of adenovector delivery takes advantage of the findings that transient ischemia appears to alter the permeability barrier of the vascular endothelium and may expose the blood to the coxsackie-adenovirus receptor mediating adenovector uptake by the heart. Balloon angioplasty catheters have been used for many years to dilate blocked coronary arteries, sometimes with use of a stent, and these catheters have also been used safely by cardiologists in patients with coronary artery disease to study the effects of brief ischemia. Cardium's new technique inflates the balloon in non-narrowed areas, and only enough to briefly interrupt flow using inflation pressure that is less than that used for performing angioplasty.

Cardium's recently initiated Russian-based ASPIRE Phase 3 / registration clinical study uses transient ischemia techniques during non-surgical percutaneous catheterization with a standard angioplasty catheter together with the intracoronary infusion of nitroglycerin with the Generx [Ad5FGF-4] product candidate for the treatment of patients with myocardial ischemia and stable angina pectoris. These patients have atherosclerotic coronary artery disease, and the Company's Generx product candidate is intended to stimulate the growth of new or additional collateral blood vessels to bypass blockages.

These studies were conducted at Emory University School of Medicine, led by Jakob Vinten-Johnasen, PhD., and co-sponsored by a Small Business Innovative Research grant from the National Institutes of Health (Cardium Therapeutics) and the Carlyle Fraser Heart Center (Emory). At the conference Gabor M. Rubanyi, MD, PhD, Cardium's Chief Scientific Officer, will present the late-breaking poster entitled "Transient Ischemia is Necessary for Efficient Adenovector Gene Transfer in the Heart", on May 17, 2012 from 3:00 to 5:30 p.m. in Exhibit Hall A. The poster presentation can be viewed at http://www.cardiumthx.com/pdf/Generx-ASGCT-Poster-Presentation-May-2012.pdf.

In addition, Dr. Rubanyi will also make an oral presentation titled: "New Perspectives for Angiogenic Gene Therapy to Treat Myocardial Ischemia in Patients with Coronary Disease" to attendees at the ASGCT Meeting today, May 16. The presentation will provide a historical overview of the Generx clinical development program and how these new and important preclinical findings have been incorporated into the protocol for the 100-patient Generx ASPIRE Phase 3 registration study which was recently initiated in the Russian Federation for patients with myocardial ischemia and stable angina pectoris. The presentation is now available for viewing at http://www.cardiumthx.com/pdf/Generx-ASGCT-May-2012-Rubanyi.pdf.

About Generx and the ASPIRE Study

Generx (Ad5FGF-4) is a disease-modifying regenerative medicine biologic that is being developed to offer a one-time, non-surgical option for the treatment of myocardial ischemia in patients with stable angina due to coronary artery disease, who might otherwise require surgical and mechanical interventions, such as coronary artery by-pass surgery or balloon angioplasty and stents. Similar to surgical/mechanical revascularization approaches, the goal of Cardium's Generx product candidate is to improve blood flow to the heart muscle but to do so non-surgically, following a single administration from a standard balloon angioplasty catheter. The video "Cardium Generx Cardio-Chant" provides an overview Generx and can be viewed at http://www.youtube.com/watch?v=pjUndFhJkjM.

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Cardium Reports New Catheter-Based Methods Significantly Boost Cardiac Gene Delivery In Late-Breaking Presentation at ...

Public release date: 16-May-2012 [ | E-mail | Share ]

Contact: John Pastor jdpastor@ufl.edu 352-273-5815 University of Florida

Using gene transfer techniques pioneered by University of Florida faculty, Taiwanese doctors have restored some movement in four children bedridden with a rare, life-threatening neurological disease.

The first-in-humans achievement may also be helpful for more common diseases such as Parkinson's that involve nerve cell damage caused by lack of a crucial molecule in brain tissue. The results are reported today (May 16) in the journal Science Translational Medicine.

The children in the study, who ranged in age from 4 to 6, inherited a rare disease known as aromatic L-amino acid decarboxylase deficiency, or AADC. Patients with AADC are born without an enzyme that enables the brain to produce the neurotransmitter dopamine. They generally die in early childhood.

In a phase 1 clinical trial led by Paul Wuh-Liang Hwu, M.D., of the National Taiwan University Hospital, surgeons used a delivery vehicle called an adeno-associated virus type 2 vector to transport the AADC gene into localized areas of the brains of three girls and a boy.

Before therapy, the children showed practically no spontaneous movement and their upper eyelids continually drooped. After receiving the corrective gene, the children gradually gained some head movement. Sixteen months afterward, the children's weight had increased, one patient was able to stand and the other three were able to sit up without support.

The study shows gene therapy that targets AADC deficiency is well-tolerated and leads to improved motor development and function, according to co-authors Barry Byrne, M.D., Ph.D., director of UF's Powell Gene Therapy Center, and Richard O. Snyder, Ph.D., director of UF's Center of Excellence for Regenerative Health Biotechnology. Both are members of the UF Genetics Institute.

"The children in this study have the most severe form of inherited movement disorder known, and the only treatments so far have been supportive ones," said Byrne, a pediatric cardiologist and associate chairman of the department of pediatrics in the College of Medicine. "It is gratifying to see it is possible to do something to help them, other than providing feeding tubes and keeping them safe. This absolutely opens the door to the possibility of even earlier treatment of neurological diseases by direct gene transfer, and has implications for Parkinson's disease, ALS and even cognitive diseases such as dementia when caused by gene defects."

The Powell Gene Therapy Center provided expertise to the Taiwanese physicians on treating the patients and engineering the corrective gene that spurs production of the absent AADC enzyme. UF's Center of Excellence for Regenerative Health Biotechnology manufactured the vector, packaging genetic material it received from Taiwan into virus particles that were purified, characterized and tested for sterility and stability before being shipped to the clinic for use in patients.

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Children with rare, incurable brain disease improve after gene therapy

ScienceDaily (May 15, 2012) A novel mechanism for anxiety behaviors, including a previously unrecognized inhibitory brain signal, may inspire new strategies for treating psychiatric disorders, University of Chicago researchers report.

By testing the controversial role of a gene called Glo1 in anxiety, scientists uncovered a new inhibitory factor in the brain: the metabolic by-product methylglyoxal. The system offers a tantalizing new target for drugs designed to treat conditions such as anxiety disorder, epilepsy, and sleep disorders.

The study, published in the Journal of Clinical Investigation, found that animals with multiple copies of the Glo1 gene were more likely to exhibit anxiety-like behavior in laboratory tests. Further experiments showed that Glo1 increased anxiety-like behavior by lowering levels of methylglyoxal (MG). Conversely, inhibiting Glo1 or raising MG levels reduced anxiety behaviors.

"Animals transgenic for Glo1 had different levels of anxiety-like behavior, and more copies made them more anxious," said Abraham Palmer, PhD, assistant professor of human genetics at the University of Chicago Medicine and senior author of the study. "We showed that Glo1 was causally related to anxiety-like behavior, rather than merely correlated."

In 2005, a comparison of different mouse strains found a link between anxiety-like behaviors and Glo1, the gene encoding the metabolic enzyme glyoxylase 1. However, subsequent studies questioned the link, and the lack of an obvious connection between glyoxylase 1 and brain function or behavior made some scientists skeptical.

"When people discover a gene, they're always most comfortable when they discover something they already knew," Palmer said. "The alarming thing here was there was a discovery of something that nobody knew, and therefore it seemed less likely to actually be correct."

A 2009 study from Palmer's laboratory suggested that differences in Glo1 expression between mouse strains were due to copy number variants, where the segment of the genome containing the gene is repeated multiple times. To test this hypothesis, lead author Margaret Distler inserted two, eight or ten copies of the Glo1 gene into mouse lines. She then ran experiments such as the open field test, in which researchers measure how much time a mouse spends in the center of an arena versus along the walls, to detect changes in anxiety behavior.

The results confirmed a causative role for Glo1 copy number variants, as mice with more copies of the Glo1 gene exhibited higher anxiety-like behavior in their experiments.

"It's the first study to show that it's the copy number variant that has the potential to change Glo1 expression and behavior," said Distler, an MD/PhD student in the Pritzker School of Medicine's Medical Scientist Training Program. "Our study was a physiological representation of what it means to increase Glo1 expression for anxiety."

The researchers then set about answering the mystery of how Glo1 expression influences anxiety-like behaviors. The primary function of glyoxylase 1 is to metabolize and lower cellular levels of methylglyoxal, a waste product of glycolysis. Distler produced the opposite effect by injecting MG to artificially increase its levels in the brain, finding that raising MG levels quickly reduced anxiety symptoms in mice.

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Mystery gene reveals new mechanism for anxiety disorders

ScienceDaily (May 16, 2012) A well-known genetic risk factor for Alzheimer's disease triggers a cascade of signaling that ultimately results in leaky blood vessels in the brain, allowing toxic substances to pour into brain tissue in large amounts, scientists report May 16 in the journal Nature.

The results come from a team of scientists investigating why a gene called ApoE4 makes people more prone to developing Alzheimer's. People who carry two copies of the gene have roughly eight to 10 times the risk of getting Alzheimer's disease than people who do not.

A team of scientists from the University of Rochester, the University of Southern California, and other institutions found that ApoE4 works through cyclophilin A, a well-known bad actor in the cardiovascular system, causing inflammation in atherosclerosis and other conditions. The team found that cyclophilin A opens the gates to the brain assault seen in Alzheimer's.

"We are beginning to understand much more about how ApoE4 may be contributing to Alzheimer's disease," said Robert Bell, Ph.D., the post-doctoral associate at Rochester who is first author of the paper. "In the presence of ApoE4, increased cyclophilin A causes a breakdown of the cells lining the blood vessels in Alzheimer's disease in the same way it does in cardiovascular disease or abdominal aneurysm. This establishes a new vascular target to fight Alzheimer's disease."

The team found that ApoE4 makes it more likely that cyclophilin A will accumulate in large amounts in cells that help maintain the blood-brain barrier, a network of tightly bound cells that line the insides of blood vessels in the brain and carefully regulates what substances are allowed to enter and exit brain tissue.

ApoE4 creates a cascade of molecular signaling that weakens the barrier, causing blood vessels to become leaky. This makes it more likely that toxic substances will leak from the vessels into the brain, damaging cells like neurons and reducing blood flow dramatically by choking off blood vessels.

Doctors have long known that the changes in the brain seen in Alzheimer's patients -- the death of crucial brain cells called neurons -- begins happening years or even decades before symptoms appear. The steps described in Nature discuss events much earlier in the disease process.

The idea that vascular problems are at the heart of Alzheimer's disease is one championed for more than two decades by Berislav Zlokovic, M.D., Ph.D., the leader of the team and a neuroscientist formerly with the University of Rochester Medical Center and now at USC. For 20 years, Zlokovic has investigated how blood flow in the brain is affected in people with the disease, and how the blood-brain barrier allows nutrients to pass into the brain, and harmful substances to exit the brain.

At Rochester, Zlokovic struck up a collaboration with Bradford Berk, M.D., Ph.D.,a cardiologist and CEO of the Medical Center. For more than two decades Berk has studied cyclophilin A, showing how it promotes destructive forces in blood vessels and how it's central to the forces that contribute to cardiovascular diseases like atherosclerosis and heart attack.

"As a cardiologist, I've been interested in understanding the role of cyclophilin A in patients who suffer from cardiovascular illness," said Berk, a professor at the Aab Cardiovascular Research Institute. "Now our collaboration in Rochester has resulted in the discovery that it also has an important role in Alzheimer's disease. The finding reinforces the basic research enterprise -- you never know when knowledge gained in one area will turn out to be crucial in another."

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Alzheimer's gene causes brain's blood vessels to leak toxins and die

ScienceDaily (May 11, 2012) Regenerating sensory hair cells, which produce electrical signals in response to vibrations within the inner ear, could form the basis for treating age- or trauma-related hearing loss. One way to do this could be with gene therapy that drives new sensory hair cells to grow.

Researchers at Emory University School of Medicine have shown that introducing a gene called Atoh1 into the cochleae of young mice can induce the formation of extra sensory hair cells.

Their results show the potential of a gene therapy approach, but also demonstrate its current limitations. The extra hair cells produce electrical signals like normal hair cells and connect with neurons. However, after the mice are two weeks old, which is before puberty, inducing Atoh1 has little effect. This suggests that an analogous treatment in adult humans would also not be effective by itself.

The findings were published May 9 in the Journal of Neuroscience.

"We've shown that hair cell regeneration is possible in principle," says Ping Chen, PhD, associate professor of cell biology at Emory University School of Medicine. "In this paper, we have identified which cells are capable of becoming hair cells under the influence of Atoh1, and we show that there are strong age-dependent limitations on the effects of Atoh1 by itself."

The first author of the paper, Michael Kelly, now a postdoctoral fellow at the National Institute on Deafness and Other Communication Disorders, was a graduate student in Emory's Neuroscience program.

Kelly and his coworkers engineered mice to turn on the Atoh1 gene in the inner ear in response to the antibiotic doxycycline. Previous experimenters had used a virus to introduce Atoh1 into the cochleae of animals. This approach resembles gene therapy, but has the disadvantage of being slightly different each time, Chen says. In contrast, the mice have the Atoh1 gene turned on in specific cells along the lining of the inner ear, called the cochlear epithelium, but only when fed doxycycline.

Young mice given doxycycline for two days had extra sensory hair cells, in parts of the cochlea where developing hair cells usually appear, and also additional locations (see accompanying image).

The extra hair cells could generate electrical signals, although those signals weren't as strong as mature hair cells. Also, the extra hair cells appeared to attract neuronal fibers, which suggests that those signals could connect to the rest of the nervous system.

"They can generate electrical signals, but we don't know if they can really function in the context of hearing." Chen says. "For that to happen, the hair cells' signals need to be coordinated and integrated."

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Gene therapy for hearing loss: Potential and limitations

Public release date: 7-May-2012 [ | E-mail | Share ]

Contact: Glenna Picton picton@bcm.edu 713-798-4710 Baylor College of Medicine

HOUSTON -- (May 7, 2012) The deletion of part of a gene that plays a role in the synthesis of carnitine an amino acid derivative that helps the body use fat for energy may play a role in milder forms of autism, said a group of researchers led by those at Baylor College of Medicine (http://www.bcm.edu) and Texas Children's Hospital (http://www.texaschildrens.org).

"This is a novel inborn error of metabolism," said Dr. Arthur Beaudet (http://www.bcm.edu/genetics/index.cfm?pmid=10579), chair of molecular and human genetics at BCM and a physician at Texas Children's Hospital, and the senior author of the report that appears online in the Proceedings of the National Academy of Sciences (http://www.pnas.org). "How it is associated with the causes of autism is as yet unclear. However, it could point to a means of treatment or even prevention in some patients."

Beaudet and his international group of collaborators believe the gene deletion leads to an imbalance in carnitine in the body. Meat eaters receive about 75 percent of their carnitine from their diet. However, dietary carnitine levels are low in vegetarians and particularly in vegans. In most people, levels of carnitine are balanced by the body's ability to manufacture its own carnitine in the liver, kidney and brain, starting with a modified form of the amino acid lysine.

Carnitine deficiency has been identified when not enough is absorbed through the diet or because of medical treatments such as kidney dialysis. Genetic forms of carnitine deficiency also exist, which are caused when too much carnitine is excreted through the kidneys.

In this new inborn error, there is a deletion in the second exon the protein-coding portion of a gene of the TMLHE gene, which includes the genetic code for the first enzyme in the synthesis of carnitine (TMLHE stands for trimethyllysine epsilon which encodes the enzyme trimethyllysine dioxygenase).

Studies in the laboratory that identified the deletion were led by Dr. Patricia B.S. Celestino-Soper, as a graduate student in Beaudet's laboratory at BCM and by Dr. Sara Violante, a graduate student in the laboratory of Dr. Frdric M. Vaz of the Academic Medical Center in Amsterdam.

To determine the frequency of the gene deletion, Beaudet and his colleagues tested male autism patients who were the only people with the disorder in their families (simplex families) from the Simons Simplex Collection, the South Carolina Early Autism Project and Houston families. In collaboration with laboratories and researchers in Nashville, Los Angeles, Paris, New York, Toronto and Cambridge (United Kingdom), they tested affected male siblings in families with more than one male case of autism (multiplex families).

When they looked at the TMLHE genes in males affected by autism and compared them to normal controls, they found that the gene alteration is a fairly common one, occurring in as many as one in 366 males unaffected by autism. It was not significantly more common in males within families in which there is only one person with autism. However, it is nearly three times more common in families with two or more boys with autism.

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Defective carnitine metabolism may play role in autism

For a quarter of a century, gene therapy has been stymied, largely because the patient's immune system attacks the treatment as a suspected rogue - or because it actually does turn rogue.

Now, University of Pennsylvania researchers have convincingly shown that they can overcome these formidable obstacles. Cells that were genetically modified to fight HIV have persisted for up to 11 years - and counting - without bad side effects in 41 patients. In two other patients, the modified cells were safe but not as durable, according to the Penn study, published last week in Science Translational Medicine.

Although the gene therapies being tested showed hints that they could be effective against the AIDS virus, the studies looked at whether the approach was feasible and safe, not whether it worked. All of the patients were also taking standard HIV drugs, called antiretrovirals.

The study involved painstaking molecular analysis of blood samples taken annually from the patients, who participated in separate studies begun in 2000, 2002, and 2004.

"We were astonished that we could detect the modified cells for so long. It's a relatively small number of patients, but more than 500 years of patient data," said University of Pennsylvania pathologist Bruce Levine, a leader of the research. "But it's difficult to separate with certainty the effectiveness of this treatment from the antiretrovirals."

Gene therapy harnesses the insidious ability of viruses to slip their DNA into the cells they infect. By neutralizing a virus and then using it as a "vector" to insert DNA that is helpful rather than harmful, gene therapy can theoretically treat ailments ranging from arthritis to infections and cancer.

Levine, his Penn colleague Carl June, and their team have tested a variety of ways to outwit HIV with gene therapy. Their approach has focused on T cells, which are the big guns of the immune system but also the cells that HIV infects. The researchers took some of the patients' T cells and inserted a gene that makes them better at recognizing and killing HIV-infected cells. Then these super-T cells were multiplied using growth-stimulation technology and put back into the patient.

Over the years, many other research groups have tried using modified T cells, but the patient's immune system perceived them as invaders and wiped them out, sometimes within hours.

Another problem is finding precise ways to insert the modified virus and ensure that it will cause the desired genetic change. The chosen virus may put its genetic payload into a host's DNA in a way that triggers cancer. That happened in France when 3 of 10 children who underwent gene therapy and were cured of a severe combined immune deficiency disease - better known as the "Bubble Boy disease" - later developed leukemia.

The Penn analysis showed that its therapeutic gene entered varying spots in the DNA of the T cells, which then went on to divide and produce a new generation of cells. Yet annual monitoring of the patients "has not detected any suspected or documented" disorders that might be traced to the genetic manipulation.

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Penn researchers report a gene-therapy success

PALO ALTO, Calif.--(BUSINESS WIRE)--

CardioDx, Inc., a pioneer in the field of cardiovascular genomic diagnostics, today announced that data from two studies evaluating the effect of the Corus CAD gene expression test on clinician decision-making for patients with suspected obstructive coronary artery disease will be presented at two upcoming conferences.

On Wednesday, May 9, from 5:00 to 6:30 p.m. ET, John McPherson, M.D., director of the Cardiovascular Intensive Care Unit at Vanderbilt University Medical Center, in Nashville, Tenn., will present Improved Diagnostic Work-up of Patients Presenting to the Cardiologist with Symptoms of Suspected Obstructive Coronary Artery Disease: Results from the IMPACT (Investigation of a Molecular PersonalizedCoronary Gene Expression Test on Cardiology Practice Pattern) Trial at the Quality of Care and Outcomes Research (QCOR) 2012 Scientific Sessions, which will be held May 9-11, 2012, at the Omni Hotel at CNN Center in Atlanta, Ga.

The prospective IMPACT trial was designed to assess the effect of Corus CAD test scores on clinical decision-making on the assessment of stable patients referred to cardiologists for evaluation of chest pain and related symptoms suggestive of obstructive coronary artery disease. IMPACT enrolled 83 nondiabetic patients referred to Vanderbilt University Medical Center cardiologists. The cardiologists diagnostic strategies were evaluated before and after the Corus CAD score was known.

On Friday, May 11, from 11:30 a.m. to 1:00 p.m. ET, principal investigator Michael Conlin, M.D., of Johns Creek Primary Care, Suwanee, Ga., will present The Use of a Personalized Gene Expression Test to Improve Decision Making in the Evaluation of Patients with Suspected Coronary Artery Disease at the Society of General Internal Medicine (SGIM) 35th Annual Meeting taking place May 9-12, 2012 at the Walt Disney World Swan and Dolphin Resort in Orlando, Fla.

Dr. Conlins study evaluated the impact of the Corus CAD test in real-world clinical practice on 317 patients at four community-based primary care clinics in Arizona, Georgia, Louisiana and North Carolina. The objective of the study was to assess the role of low (15) and non-low (>15) Corus CAD test scores on patient referrals to cardiologists by primary care providers in stable nondiabetic patients with symptoms suggestive of coronary artery disease. Additionally, a secondary analysis was performed to evaluate the use of noninvasive and invasive cardiac testing in both low- and non-low-scoring Corus CAD patient groups.

About Corus CAD

With a simple blood draw, Corus CAD can help primary care clinicians and cardiologists exclude obstructive coronary artery disease as the cause of a stable non-diabetic patient's symptoms. It is the first sex-specific test for obstructive coronary artery disease, accounting for critical biological differences between men and women. The test is safe and does not expose patients to radiation risks or imaging agent intolerance.

The Corus CAD test measures the RNA levels of 23 genes. Because these blood RNA levels are altered when obstructive coronary artery disease is present, the Corus CAD score aids clinicians in assessing whether an individual patients symptoms may be due to obstructive coronary artery disease.

Corus CAD is commercially available through an innovative patient sample kit that includes everything needed for blood collection and express delivery to the companys CLIA-certified Palo Alto, Calif. laboratory. Test results are delivered promptly to the clinicians office. Corus CAD is currently available in the United States.

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CardioDx to Present Results from Two Studies Evaluating the Clinical Utility of a Gene Expression Test for Obstructive ...

02.05.2012 - (idw) Max-Delbrck-Centrum fr Molekulare Medizin (MDC) Berlin-Buch

People with good hearing also have a keen sense of touch; people with impaired hearing generally have an impaired sense of touch. Data supporting this hypothesis was presented by Dr. Henning Frenzel and Prof. Gary R. Lewin (Max Delbrck Center, MDC, Berlin). They showed that both senses have a common genetic basis. In patients with Usher syndrome, a hereditary form of deafness accompanied by impaired vision, they discovered a gene mutation that is also causative for the patients impaired touch sensitivity (PloS Biology doi:10.1371/journal.pbio.1001318)*. The examination was preceded by various studies, including twin studies. In total, they assessed sensory function in 518 volunteers. People with good hearing also have a keen sense of touch; people with impaired hearing generally have an impaired sense of touch. Extensive data supporting this hypothesis was presented by Dr. Henning Frenzel and Professor Gary R. Lewin of the Max Delbrck Center for Molecular Medicine (MDC) Berlin-Buch, Germany. The two researchers showed that both senses hearing and touch have a common genetic basis. In patients with Usher syndrome, a hereditary form of deafness accompanied by impaired vision, they discovered a gene mutation that is also causative for the patients impaired touch sensitivity. The examination was preceded by various studies, including studies with healthy identical and non-identical human twins (PloS Biology, doi:10.1371/journal.pbio.1001318)*. In total, the researchers assessed sensory function in 518 volunteers.

In all vertebrates, and consequently also in humans, hearing and touch represent two distinct sensory systems that both rely on the transformation of mechanical force into electrical signals. When we hear, sound waves trigger vibrations that stimulate the hair-like nerve endings in the cochlea in the inner ear. These then transform the mechanical stimuli into electrical signals, which are transmitted to the brain via the auditory nerve. When we touch something a similar process takes place: The mechanical stimulus - sliding the fingers over a rough or smooth surface, the perception of vibrations - is taken up via sensors in the skin, converted into an electrical stimulus and transmitted to the brain.

Twin study with 100 pairs of twins In recent years about 70 genes have been identified in humans, mutations in which trigger hearing loss or deafness. Surprisingly, no genes have been found that negatively influence the sense of touch, Professor Lewin said. To see whether the sense of touch also has a hereditary component, the researchers first studied 100 pairs of twins - 66 pairs of monozygotic twins and 34 dizygotic pairs of twins. Monozygotic twins are genetically completely identical; dizygotic twins are genetically identical to 50 percent. The tests showed that the touch sensitivity of the subjects was determined to more than 50 percent by genes. Furthermore, hearing and touch tests showed that there is a correlation between the sense of hearing and touch.

The researchers therefore suspected that genes that influence the sense of hearing may also have an influence on the sense of touch. In a next step, they recruited test subjects at a school in Berlin for students with hearing impairments. There they assessed the touch sensitivity in a cohort of 39 young people who suffered from severe congenital hearing impairment. The researchers compared these findings with the data from their twin study and discovered that not all of the young people with hearing loss had impaired tactile acuity. Strikingly, however, many of these young people did indeed have poor tactile acuity, Professor Lewin explained.

The researchers examined one cohort of patients in a special consultation at the Charit - Universittsmedizin Berlin for Usher patients from all over Germany. A second cohort was recruited at the university hospital La Fe in Valencia, Spain. The studies revealed that not all patients with Usher-syndrome have poor tactile acuity and touch sensitivity. The researchers showed that only patients with Usher syndrome who have a mutation in the gene USH2A have poor touch sensitivity. This mutation is also responsible for the impaired hearing of 19 patients. The 29 Usher-syndrome patients in whom the mutation could not be detected had a normal sense of touch. The researchers thus demonstrated that there is a common genetic basis for the sense of hearing and touch. They suspect that even more genes will be discovered in the future that influence both mechanosensory traits.

Women hear better than men and have a finer sense of touch The researchers discovered another interesting detail during their five-year study. When women complain that their men are not really listening to them, there is some truth in that, Professor Lewin said. The studies with a total of 518 individuals including 295 women have actually shown that women hear better and they also have a finer sense of touch than men; in short woman hear and feel more than men!

*A genetic basis for mechanosensory traits in humans Henning Frenzel1, Jrg Bohlender2, Katrin Pinsker2, Brbel Wohlleben2, Jens Tank3, Stefan G. Lechner1, Daniela Schiska2, Teresa Jaijo5, Franz Rueschendorf4, Kathrin Saar4, Jens Jordan3, Jos M. Milln5 and Manfred Gross2, Gary R. Lewin1,6

1Department of Neuroscience, Max Delbrck Center for Molecular Medicine, Robert-Rssle-Str. 10, Berlin-Buch D-13092 Germany, 2Department of Audiology and Phoniatrics, Charit, Universittsmedizin, Berlin, Augustenburger Platz 1, Berlin D-13353 Germany. 3Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover D-30625, Germany, 4Experimental genetics of cardiovascular disease, Max Delbrck Center for Molecular Medicine, Robert-Rssle-Str. 10, Berlin-Buch D-13092 Germany, 5Genetics Unit, Hospital Universitario La Fe, Avda. de Campanar, 21, 46009 and CIBERER, Valencia, Spain 6Author for Correspondence

Contact: Press Department Max Delbrck Center for Molecular Medicine (MDC) Berlin-Buch in the Helmholtz Association Robert-Rssle-Strae 10; 13125 Berlin; Germany Phone: +49 (0) 30 94 06 - 38 96 Fax: +49 (0) 30 94 06 - 38 33 e-mail: presse@mdc-berlin.de http://www.mdc-berlin.de/ jQuery(document).ready(function($) { $("fb_share").attr("share_url") = encodeURIComponent(window.location); }); Weitere Informationen: http://www.nature.com/neuro/journal/v15/n1/pdf/nn.2985.pdf

See the original post here:
Gene Mutation Leads to Impairment of Two Senses: Touch and Hearing

Todays post is a repost from October 2010. Ive got some major stuff cooking in the lab right now and I need all of my brain power for it. Enjoy the repost and I shall return!

Reader David sent me this paper the other day, and asked if I could blog about it. I said ok, maybe, and then I read

Gene therapy

oooooh

Sounds very cool, doesnt it? Sounds like the FUTURE! Wheres my JETPACK!!!?!?!

But of course gene therapy is kind of a buzzword. A lot of people throw it around, but it seems like a lot of people dont know what it really MEANS, and what it can be used for.

But it turns out, it can be used for quite a lot! And it may not be quite so far in the future. After all, theyre marketing jetpacks.

Alexander et al. Reversal of Depressed Behaviors in Mice by p11 Gene Therapy in the Nucleus Accumbens Science Translational Medicine, 2010.

So lets start with gene therapy and what it is, and then well go into why they used it in this particular paper. Gene therapy is based on the idea of inserting a gene into someones genome, either in the whole body or in specific parts, to change the gene expression of that cell or group of cells, and to use this technology to treat disease. In this case, what were talking about is viral-mediated gene expression. This is where we use a virus (for our own nefarious purposes mwah-ha-ha-ha!!), take out the nasty bits of the viral DNA, and load the virus with the gene you want to express. You then inject the virus into your area of interest (normally this is really site specific), and the virus, using its own virusy ways, will insert your gene of interest into your area of interest. The gene will get incorporated into the genome, and get expressed by your cells!

Read the original here:
Repost: Depressed mice, gene therapy, and p11

$19 million collaboration fuelling groundbreaking discoveries

TORONTO, May 7, 2012 /CNW/ - Lawrence Tanenbaum, O.C., along with his wife Judy Tanenbaum, today joined the Honourable Brad Duguid Minister of Economic Development and Innovation, renowned researcher Dr. Jim Kennedy and Dr. Catherine Zahn, President and CEO, CAMH, to announce a $19 million collaboration and open the Tanenbaum Centre for Pharmacogenetics at the Centre for Addiction and Mental Health (CAMH).

This centre, a collaboration between Larry Tanenbaum, the Ontario Government and CAMH, has been established to support the groundbreaking research in the DNA laboratory of Dr. Kennedy and the clinic of Dr. Daniel Mueller to accelerate the time it takes to get genetic information to physicians and patients across Ontario. The Centre will be part of the Campbell Family Mental Health Research Institute at CAMH's College Street location.

"Pharmacogenetics" is an aspect of personalized medicine research that aims to help doctors understand in advance which individuals carry a genetic risk for serious side-effects from specific drugs. Genetic testing will also be helpful in determining who is more likely to respond to a given medication and if dose adjustments need to be considered. Similar work is being done in cancer and pain management, but CAMH is one of the world leaders in psychiatric applications of this research.

"Mistakes in drug treatment can result in devastating, even tragic side-effects. Still, inaccurate predictions of treatment for depression happen in about 30 per cent of cases and 11 per cent of all mental health patients are at serious genetic risk of suffering from inappropriate dosages of medication. The size of the problem is staggering, but the research in gene science that Dr. Kennedy and his team are doing can - and will - change that," said Mr. Tanenbaum, Chairman and CEO of the Kilmer Group, Chair of the Board, Maple Leaf Sports and Entertainment, and Governor of the NHL, NBA and Major League Soccer.

"We are honoured to be part of this collaboration because it holds the promise that one day soon drugs will be adapted to each person's genetic make-up. The faster these discoveries can get out of the lab, the sooner more effective and safe therapies will become available - changing and saving lives."

"Ontario's ongoing commitment to world-class research is one reason the province is home to more than 500 top neuroscientists," said Minister of Economic Development and Innovation Brad Duguid. "Our support of the new Tanenbaum Centre for Pharmacogenetics promises to improve medical care and quality of life for psychiatric patients and their families, save our health care system millions of dollars, while creating good jobs."

Most recently, Dr. Kennedy's lab has identified a new genetic risk factor for serious weight gain, a side-effect for 40 per cent of schizophrenia patients who receive a commonly used group of anti-psychotic drugs. Understanding in advance which individuals carry this genetic risk would help doctors know when to prescribe different drugs.

Along with establishing the Centre, the investment will move this and other genetic tests into medical practice through "lab-on-a-chip" technology currently in development. Clinical delivery of these tests is already available for CAMH patients, and extension to GTA-area physicians is expected to begin in 2014. Furthermore, the biotechnology development initiative within this program will create an increasing number of knowledge-based jobs in Ontario as the core genetics research expands.

For Dr. Kennedy, this investment sets in motion the potential to revolutionize psychiatry by scaling up testing and fueling the drive to find new genetic tests: "If we could prevent serious side effects such as movement disorders, sleep disturbance and increased risk of cardiovascular disease, I truly believe more people in need would stay on their medication and derive the long-term benefits of better mental health, living longer more productive and fuller lives with their families."

Original post:
New Tanenbaum Centre for Pharmacogenetics to accelerate gene-based personalized medicine in psychiatry

Public release date: 2-May-2012 [ | E-mail | Share ]

Contact: Holly Auer holly.auer@uphs.upenn.edu 215-200-2313 University of Pennsylvania School of Medicine

PHILADELPHIA -- HIV patients treated with genetically modified T cells remain healthy up to 11 years after initial therapy, researchers from the Perelman School of Medicine at the University of Pennsylvania report in the new issue of Science Translational Medicine. The results provide a framework for the use of this type of gene therapy as a powerful weapon in the treatment of HIV, cancer, and a wide variety of other diseases.

"We have 43 patients and they are all healthy," says senior author Carl June, MD, a professor of Pathology and Laboratory Medicine at Penn Medicine. "And out of those, 41 patients show long term persistence of the modified T cells in their bodies."

Early gene therapy studies raised concern that gene transfer to cells via retroviruses might lead to leukemia in a substantial proportion of patients, due to mutations that may arise in genes when new DNA is inserted. The new long-term data, however, allay that concern in T cells, further buoying the hope generated by work June's team published in 2011 showing the eradication of tumors in patients with chronic lymphocytic leukemia using a similar strategy.

"If you have a safe way to modify cells in patients with HIV, you can potentially develop curative approaches," June says. "Patients now have to take medicine for their whole lives to keep their virus under control, but there are a number of gene therapy approaches that might be curative." A lifetime of anti-HIV drug therapy, by contrast, is expensive and can be accompanied by significant side effects.

They also note that the approach the Penn Medicine team studied may allow patients with cancers and other diseases to avoid the complications and mortality risks associated with more conventional treatments, since patients treated with the modified T cells did not require drugs to weaken their own immune systems in order for the modified cells to proliferate in their bodies after infusion, as is customary for cancer patients who receive stem cell transplants.

To demonstrate the long-term safety of genetically modified T cells, June and colleagues have followed HIV-positive patients who enrolled in three trials between 1998 and 2002. Each patient received one or more infusions of their own T cells that had been genetically modified in the laboratory using a retroviral vector. The vector encoded a chimeric antigen receptor that recognizes the HIV envelope protein and directs the modified T cell to kill any HIV-infected cells it encounters.

As is standard for any trial, the researchers carefully monitored patients for any serious adverse events immediately after infusion -- none of which were seen. Additionally, because of the earlier concerns about long-term side effects, the U.S. Food and Drug Administration also asked the team to follow the patients for up to 15 years to ensure that the modified T cells were not causing blood cancers or other late effects. Therefore, each patient underwent an exam and provided blood samples during each of the subsequent years.

Now, with more than 500 years of combined patient safety data, June and colleagues are confident that the retroviral vector system is safe for modifying T cells. By contrast, June notes, the earlier, worrying side effects were seen when viral vectors were used to modify blood stem cells. The new results show that the target cell for gene modification plays an important role in long-term safety for patients treated. "T cells appear to be a safe haven for gene modification," June says.

Read the original:
Genetically modified T cell therapy shown to be safe, lasting in decade-long study of HIV patients

Public release date: 1-May-2012 [ | E-mail | Share ]

Contact: Barbara Bachtler bachtler@mdc-berlin.de 49-309-406-3896 Helmholtz Association of German Research Centres

People with good hearing also have a keen sense of touch; people with impaired hearing generally have an impaired sense of touch. Extensive data supporting this hypothesis was presented by Dr. Henning Frenzel and Professor Gary R. Lewin of the Max Delbrck Center for Molecular Medicine (MDC) Berlin-Buch, Germany. The two researchers showed that both senses hearing and touch have a common genetic basis. In patients with Usher syndrome, a hereditary form of deafness accompanied by impaired vision, they discovered a gene mutation that is also causative for the patients' impaired touch sensitivity. The examination was preceded by various studies, including studies with healthy identical and non-identical human twins (PLoS Biology, doi:10.1371/journal.pbio.1001318)*. In total, the researchers assessed sensory function in 518 volunteers.

In all vertebrates, and consequently also in humans, hearing and touch represent two distinct sensory systems that both rely on the transformation of mechanical force into electrical signals. When we hear, sound waves trigger vibrations that stimulate the hair-like nerve endings in the cochlea in the inner ear. These then transform the mechanical stimuli into electrical signals, which are transmitted to the brain via the auditory nerve. When we touch something a similar process takes place: The mechanical stimulus - sliding the fingers over a rough or smooth surface, the perception of vibrations - is taken up via sensors in the skin, converted into an electrical stimulus and transmitted to the brain.

Twin study with 100 pairs of twins

In recent years about 70 genes have been identified in humans, mutations in which trigger hearing loss or deafness. "Surprisingly, no genes have been found that negatively influence the sense of touch," Professor Lewin said. To see whether the sense of touch also has a hereditary component, the researchers first studied 100 pairs of twins - 66 pairs of monozygotic twins and 34 dizygotic pairs of twins. Monozygotic twins are genetically completely identical; dizygotic twins are genetically identical to 50 percent. The tests showed that the touch sensitivity of the subjects was determined to more than 50 percent by genes. Furthermore, hearing and touch tests showed that there is a correlation between the sense of hearing and touch.

The researchers therefore suspected that genes that influence the sense of hearing may also have an influence on the sense of touch. In a next step, they recruited test subjects at a school in Berlin for students with hearing impairments. There they assessed the touch sensitivity in a cohort of 39 young people who suffered from severe congenital hearing impairment. The researchers compared these findings with the data from their twin study and discovered that not all of the young people with hearing loss had impaired tactile acuity. "Strikingly, however, many of these young people did indeed have poor tactile acuity," Professor Lewin explained.

The researchers decided it would take too much time to analyze which of the approximately 70 genes that adversely affect the sense of hearing may also negatively affect the sense of touch. Therefore, the researchers focused specifically on patients with the Usher syndrome, a hereditary form of hearing impairment, in which the patients progressively become blind. Usher syndrome patients have varying degrees of hearing impairment, and the disease is genetically very well studied. There are nine known Usher genes carrying mutations which cause the disease.

The researchers examined one cohort of patients in a special consultation at the Charit - Universittsmedizin Berlin for Usher patients from all over Germany. A second cohort was recruited at the university hospital La Fe in Valencia, Spain. The studies revealed that not all patients with Usher-syndrome have poor tactile acuity and touch sensitivity. The researchers showed that only patients with Usher syndrome who have a mutation in the gene USH2A have poor touch sensitivity. This mutation is also responsible for the impaired hearing of 19 patients. The 29 Usher-syndrome patients in whom the mutation could not be detected had a normal sense of touch. The researchers thus demonstrated that there is a common genetic basis for the sense of hearing and touch. They suspect that even more genes will be discovered in the future that influence both mechanosensory traits.

Women hear better than men and have a finer sense of touch

Excerpt from:
Gene mutation leads to impairment of 2 senses: Touch and hearing

PLoS Biology

HIV particles assemble at the surface of a white blood cell called a macrophage.

Millions of people around the world are living with HIV, thanks to drug regimens that suppress the virus. Now there's a new push to eliminate HIV from patients' bodies altogether. That would be a true cure.

We're not there yet. But a report in Science Translational Medicine is an encouraging signpost that scientists may be headed in the right direction.

Forty-three patients got immune cells designed to attack and kill cells infected with HIV. As long as 16 years later, these genetically engineered T cells are still circulating in their bloodstreams. And there's been no sign the gene therapy caused any cancers, or is likely to.

That may seem like a modest victory. After all, there's no evidence yet that the gene therapy did what it's supposed to eliminate the reservoir of HIV hiding in the patients' cells, waiting to emerge as soon as patients stop taking their antiviral drugs.

But to scientists in HIV and gene therapy research, it's a highly encouraging indicator. "We're not hitting a home run. This is a single," AIDS researcher Pablo Tebas of the University of Pennsylvania tells Shots.

"It looks like if you do this, it's going to be safe because we have not seen any toxicity in 16 years," he says. "And two, the genetically modified cells are still circulating. They perpetuate. Those are two important things this study is telling us."

Tebas is not an author of the study, but he works with the Penn researchers who did the work. They were unavailable for comment.

Previous attempts at this kind of gene therapy, called adoptive T cell transfer, have been plagued by cancers that can arise when the genes introduced into engineered cells insert themselves next to growth-promoting genes. In other cases the engineered cells have died out before they have a sustained positive effect.

Excerpt from:
A Step Forward For Gene Therapy To Treat HIV

By Robert Bazell, Chief science and medical correspondent, NBC News

One step closer to a cure for AIDS that is the implication of results out Wednesday from from several leading research centers.

It should be noted that many people involved in AIDS research, including several who carried out the latest research, avoid the c word. Their goal is to allow people infected with HIV to live without daily doses of the medications that usually keep the virus under control-- at a large financial cost --and a risk of side effects.

The latest work, published in Science Translational Medicine, details 43 HIV-infected volunteers who had experimental genes inserted into their disease-fighting white blood cells 11 years ago. All patients are doing fine. After more than a decade with this gene therapy, there are no side effects. In almost every one the inserted genes are still working properly.

While these experiments were never intended to treat or cure anything, they lay the groundwork for gene therapy that could have a substantial impact on HIV disease.

A cure for AIDS became an obvious goal as soon as the disease was discovered 30 years ago. But it became the dirty four letter word, as Jon Cohen of Science magazine put it, after some spectacular failures. Soon after the powerful cocktail of anti-AIDS drugs came on the market in 1996, some scientists speculated they could use the drugs to knock out all the infection in the body. But that idea crashed as repeated experiments showed that pockets of infected cells hid in various parts of the body, emerging quickly as soon as the drugs were withdrawn.

HIV has infected some 50 million people in the world and none has been cured -- except perhaps Timothy Ray Brown.

It was the case of Brown, also known as the Berlin patient, that energized the new search for a cure.Infected with HIV, Brown was dying not of that disease, but of leukemia. His only hope was a bone marrow transplant first killing, then replacing all the cells in his body that make blood cells with those from a donor. Browns doctor Gero Htter was not an AIDS specialist, but he knew that about 1 percent of people of European decent have a mutation in a receptor called CCR5 on certain white blood cells that make HIV infection very difficult.So the doctor sought a donor with that mutation.

The transplant took place in 2007. In 2010 Htter published his results. Not only had the transplant eliminated Browns leukemia, he no longer needed to take his HIV medications and the most sophisticated tests find no trace of HIV in his body.

A transplant with a serious risk of death, costing more than $250,000, will not be a treatment for a disease contained by medications.But the case raised the possibility that modifying the white blood cells with gene therapy might do the trick. Several experiments are underway in both animals and humans and more are planned.

More here:
AIDS gene therapy safe -- is it a "cure"?

Editor's Choice Main Category: Hearing / Deafness Also Included In: Genetics;Dermatology;Neurology / Neuroscience Article Date: 01 May 2012 - 15:00 PDT

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In individuals with Usher syndrome, the researchers identified a gene variation that is also responsible for the patients' impaired touch sensitivity. Usher syndrome is a genetic disorder characterized by deafness and gradual vision loss. In total the team evaluated sensory function in 518 volunteers.

The researchers note that both hearing and touch rely on the transformation of mechanical force into electrical signals. When we hear, sound waves travel down the ear canal and hit the eardrum causing it to vibrate. This vibration stimulates the hair-like nerve endings in the cochlea to fire off electrical signals to the brain via the auditory nerve. Likewise, when we touch, sensory receptors in the skin transform vibrations into electrical signals and transmit them to the brain.

In recent years, researchers have identified around 70 gene mutations in humans which trigger hearing loss or deafness.

Professor Lewin explains:

The researchers first examined 100 pairs of twins (66 pairs of identical twins and 34 non-identical twins) in order to determine whether the sense of touch also has a hereditary component. The tests showed that the touch sensitivity of the subjects was determined to more than 50% by genes. In addition, the team found an association between the sense of hearing and touch.

As a result, the team suspected that genes that influence the sense of hearing may also influence the sense of touch.

The researchers then enrolled 39 students in Berlin with congenital hearing impairment in order to evaluate touch sensitivity. The team compared these with results from their twin study and found that not all of the participants with impaired hearing had impaired tactile acuity.

View post:
Touch And Hearing Impaired By Gene Mutation

Public release date: 2-May-2012 [ | E-mail | Share ]

Contact: Dr. Robert M. Greene dr.bob.greene@gmail.com 502-852-3804 Society for Experimental Biology and Medicine

In the United States, a baby is born with a facial cleft every hour, of every day of the year! Such birth defects result from both gene mutations and environmental insults. PRDM16 is a transcription factor originally described as being aberrantly activated in specific types of leukemia's, and more recently as a master regulator of brown adipose tissue differentiation. In a study published in the April 2012 issue of Experimental Biology and Medicine, investigators have now shown that this transcription co-factor plays a critical role in development of the embryonic palate.

Mice lacking the gene for Prdm16 exhibit numerous defects including a complete cleft of the secondary palate and a shortened mandible. In a study led by Dr. Dennis Warner and his co-investigators at the University of Louisville Birth Defects Center chromatin immunoprecipitation followed by array analysis was utilized to identify genes regulated by Prdm16 in cells isolated from the secondary palate of mouse embryos.

This approach revealed the developmental processes regulated by this protein that are important for palate development.

"Identifying the cellular and molecular processes regulated by PRDM16 is an important step toward elucidating the underlying mechanisms important for normal embryonic development of the head and face", said Dr. Warner.

Over 100 genes, whose promoters were bound by PRDM16 were identified. These genes were found to be linked to such diverse processes as chromatin remodeling and muscle and bone development.

Dr. Michele Pisano, a co-investigator on this study added that: "little is known of the factors governing differentiation of embryonic palate mesenchymal cells into bone or muscle. Our study suggests that Prdm16 may be critical for these processes." Demonstration that loss of Prdm16 expression led to a significant decrease in the expression of osteopontin, a marker for bone formation, and an increase in the expression of Myf-4, a marker for muscle development, support Dr. Pisano's contention.

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine, said "This important study by Warner and colleagues demonstrates that the transcription co-factor Prdm16 plays an important role in the normal development of the embryonic palate. They further demonstrate genes essential to muscle and bone development which are regulated by Prdm16 in cells isolated from the secondary palate of mouse embryos. This study should be of great significance in our understanding of birth defects leading to facial clefts."

###

Excerpt from:
Prdm16: A novel gene important for craniofacial development

PHILADELPHIA HIV patients treated with genetically modified T cells remain healthy up to 11 years after initial therapy, researchers from the Perelman School of Medicine at the University of Pennsylvania report in the new issue of Science Translational Medicine. The results provide a framework for the use of this type of gene therapy as a powerful weapon in the treatment of HIV, cancer, and a wide variety of other diseases.

"We have 43 patients and they are all healthy," says senior author Carl June, MD, a professor of Pathology and Laboratory Medicine at Penn Medicine. "And out of those, 41 patients show long term persistence of the modified T cells in their bodies."

Early gene therapy studies raised concern that gene transfer to cells via retroviruses might lead to leukemia in a substantial proportion of patients, due to mutations that may arise in genes when new DNA is inserted. The new long-term data, however, allay that concern in T cells, further buoying the hope generated by work June's team published in 2011 showing the eradication of tumors in patients with chronic lymphocytic leukemia using a similar strategy.

"If you have a safe way to modify cells in patients with HIV, you can potentially develop curative approaches," June says. "Patients now have to take medicine for their whole lives to keep their virus under control, but there are a number of gene therapy approaches that might be curative." A lifetime of anti-HIV drug therapy, by contrast, is expensive and can be accompanied by significant side effects.

They also note that the approach the Penn Medicine team studied may allow patients with cancers and other diseases to avoid the complications and mortality risks associated with more conventional treatments, since patients treated with the modified T cells did not require drugs to weaken their own immune systems in order for the modified cells to proliferate in their bodies after infusion, as is customary for cancer patients who receive stem cell transplants.

To demonstrate the long-term safety of genetically modified T cells, June and colleagues have followed HIV-positive patients who enrolled in three trials between 1998 and 2002. Each patient received one or more infusions of their own T cells that had been genetically modified in the laboratory using a retroviral vector. The vector encoded a chimeric antigen receptor that recognizes the HIV envelope protein and directs the modified T cell to kill any HIV-infected cells it encounters.

As is standard for any trial, the researchers carefully monitored patients for any serious adverse events immediately after infusion -- none of which were seen. Additionally, because of the earlier concerns about long-term side effects, the U.S. Food and Drug Administration also asked the team to follow the patients for up to 15 years to ensure that the modified T cells were not causing blood cancers or other late effects. Therefore, each patient underwent an exam and provided blood samples during each of the subsequent years.

Now, with more than 500 years of combined patient safety data, June and colleagues are confident that the retroviral vector system is safe for modifying T cells. By contrast, June notes, the earlier, worrying side effects were seen when viral vectors were used to modify blood stem cells. The new results show that the target cell for gene modification plays an important role in long-term safety for patients treated. "T cells appear to be a safe haven for gene modification," June says.

The multi-year blood samples also show that the gene-modified T cell population persists in the patients' blood for more than a decade. In fact, models suggest that more than half of the T cells or their progeny are still alive 16 years after infusion, which means one treatment might be able to kill off HIV-infected cells for decades. The prolonged safety data means that it might be possible to test T cell-based gene therapy for the treatment of non-life threatening diseases, like arthritis.

"Until now, we've focused on cancer and HIV-infection, but these data provide a rationale for starting to focus on other disease types," June says. "What we have demonstrated in this study and recent studies is that gene transfer to T cells can endow these cells with enhanced and novel functions. We view this as a personalized medicine platform to target disease using a patient's own cells."

Read more here:
Genetically Modified T Cell Therapy Shown to be Safe, Lasting in Decade-Long Penn Medicine Study of HIV Patients