ScienceDaily (May 14, 2012) A new study consisting of inducing cells to express telomerase, the enzyme which -- metaphorically -- slows down the biological clock -- was successful. The research provides a "proof-of-principle" that this "feasible and safe" approach can effectively "improve health span."

A number of studies have shown that it is possible to lengthen the average life of individuals of many species, including mammals, by acting on specific genes. To date, however, this has meant altering the animals' genes permanently from the embryonic stage -- an approach impracticable in humans. Researchers at the Spanish National Cancer Research Centre (CNIO), led by its director Maria Blasco, have demonstrated that the mouse lifespan can be extended by the application in adult life of a single treatment acting directly on the animal's genes. And they have done so using gene therapy, a strategy never before employed to combat aging. The therapy has been found to be safe and effective in mice.

The results were recently published in the journal EMBO Molecular Medicine. The CNIO team, in collaboration with Eduard Ayuso and Fatima Bosch of the Centre of Animal Biotechnology and Gene Therapy at the Universitat Autonoma de Barcelona (UAB), treated adult (one-year-old) and aged (two-year-old) mice, with the gene therapy delivering a "rejuvenating" effect in both cases, according to the authors.

Mice treated at the age of one lived longer by 24% on average, and those treated at the age of two, by 13%. The therapy, furthermore, produced an appreciable improvement in the animals' health, delaying the onset of age-related diseases -- like osteoporosis and insulin resistance -- and achieving improved readings on aging indicators like neuromuscular coordination.

The gene therapy consisted of treating the animals with a DNA-modified virus, the viral genes having been replaced by those of the telomerase enzyme, with a key role in aging. Telomerase repairs the extreme ends or tips of chromosomes, known as telomeres, and in doing so slows the cell's and therefore the body's biological clock. When the animal is infected, the virus acts as a vehicle depositing the telomerase gene in the cells.

This study "shows that it is possible to develop a telomerase-based anti-aging gene therapy without increasing the incidence of cancer," the authors affirm. "Aged organisms accumulate damage in their DNA due to telomere shortening, [this study] finds that a gene therapy based on telomerase production can repair or delay this kind of damage," they add.

'Resetting' the biological clock

Telomeres are the caps that protect the end of chromosomes, but they cannot do so indefinitely: each time the cell divides the telomeres get shorter, until they are so short that they lose all functionality. The cell, as a result, stops dividing and ages or dies. Telomerase gets around this by preventing telomeres from shortening or even rebuilding them. What it does, in essence, is stop or reset the cell's biological clock.

But in most cells the telomerase gene is only active before birth; the cells of an adult organism, with few exceptions, have no telomerase. The exceptions in question are adult stem cells and cancer cells, which divide limitlessly and are therefore immortal -- in fact several studies have shown that telomerase expression is the key to the immortality of tumour cells.

It is precisely this risk of promoting tumour development that has set back the investigation of telomerase-based anti-aging therapies.

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First gene therapy successful against aging-associated decline: Mouse lifespan extended up to 24% with a single ...

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

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

Contact: Tom Rickey tom_rickey@urmc.rochester.edu 585-275-7954 University of Rochester Medical Center

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.

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Alzheimer's gene causes brain's blood vessels to leak, die

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.

(Photo: http://photos.prnewswire.com/prnh/20120516/LA07787)

(Logo: http://photos.prnewswire.com/prnh/20051018/CARDIUMLOGO)

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 ...

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

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 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