GENE RESPONSIBLE FOR TRAITS INVOLVED IN DIABETES DISCOVERED

A collaborative research team led by Medical College of Wisconsin (MCW) scientists has identified a new gene associated with fasting glucose and insulin levels in rats, mice and in humans. The findings are published in the September issue of Genetics.

Leah Solberg Woods, Ph.D., associate professor of pediatrics at MCW and a researcher in the Children's Hospital of Wisconsin Research Institute, led the study and is the corresponding author of the paper.

The authors of the paper identified a gene called Tpcn2 in which a variant was associated with fasting glucose levels in a rat model. Studies in Tpcn2 knockout mice also demonstrated the difference in fasting glucose levels as well as insulin response between the knockout animals and regular mice. Finally, Dr. Woods' team identified variants within Tpcn2 associated with fasting insulin in humans. Tpcn2 is a lysosomal calcium channel that likely plays a role in insulin signaling. Glucose tolerance, insulin resistance and beta cell dysfunction are key underlying causes of type 2 diabetes.

"Genome-wide association studies in humans have identified 60+ genes linked to type 2 diabetes; however, these genes explain only a small portion of heritability in diabetes studies. As we continue to identify genes and variants of interest, we will evaluate them in multiple models to understand the mechanism of disease," said Dr. Solberg Woods.

According to the American Diabetes Association, 29 million Americans have diabetes -- more than nine percent of the total population. It is the 7th leading cause of death, and experts estimate diabetes is an underreported cause of death because of the comorbidities and complications associated with the disease.

Gene Therapy Offers New Hope For Treatment Of Peripheral Neuropathy

ScienceDaily (June 1, 2007) (so not exactly new!)

— Researchers from the University of Pittsburgh School of Medicine report that they have successfully used gene therapy to block the pain response in an animal model of neuropathic pain, a type of chronic pain in people for which there are few effective treatments.



Neuropathic pain is the result of damage to nerve fibers caused by injuries or diseases, such as diabetes and cancer. These damaged nerve fibers continue to send signals to pain centers in the brain even after the surrounding tissue has healed. Unfortunately, neuropathic pain often responds poorly to standard pain treatments and occasionally may get worse instead of better over time. For some people, it leads to serious, long-term disability and dependence on pain medications that have a variety of unwanted side effects, including addiction.

The Pitt research team, led by Joseph Glorioso, III, Ph.D., chair of the department of biochemistry and molecular genetics, University of Pittsburgh School of Medicine, used a genetically engineered herpes simplex virus (HSV) to deliver the gene for part of the human glycine receptor (GlyR), a receptor found primarily on the surface of nerve cells in the spinal cord and the lower brain but not in the nerves in the limbs, to the paws of rats. A group of control rats received only the HSV vector without the inserted gene.

After the delivery of the therapeutic gene or empty vector (for the control group), the researchers injected the same paws of each rat with formalin, an irritant known to simulate the symptoms of a peripheral neuropathic pain at the site of injection. Following formalin injection, the rats were then given an injection of glycine to activate the GlyR receptor.

Both control and GlyR-HSV-infected rats showed a typical pain response to formalin. However, the application of glycine eliminated the pain response in GlyR-HSV infected animals, while it had no effect on animals infected with vector only. This alleviation of the pain response in GlyR-HSV-treated mice was reversed by the subsequent addition of low concentrations of strychnine, a strong GlyR-specific inhibitor, or antagonist.

According to Dr. Glorioso, these findings suggest that HSV-directed expression of GlyR in peripheral neurons and subsequent selective activation by glycine has the potential to be used therapeutically not only for neuropathic pain management but a variety of pain syndromes.

"The inability to effectively manage neuropathic pain associated with injuries and illnesses is a growing national and international problem. Gene therapy offers a more targeted, less toxic approach for effectively managing this condition. It also is our hope that targeted transgene delivery of GlyR may have even broader implications for managing a number of chronic pain syndromes, including pain resulting from shingles, arthritis and cancer," explained Dr. Glorioso.

These findings are being presented at the 10th annual meeting of the American Society of Gene Therapy, being held May 30 to June 3 at the Washington State Convention & Trade Center, Seattle.

In addition to Dr. Glorioso, others involved in the study included Michael Cascio, Ph.D., James Goss, Ph.D., David Krisky, M.D., Ph.D., and Rahul Scrinivasin, M.D., Ph.D., all with the department of molecular genetics and biochemistry, University of Pittsburgh School of Medicine.

Progress In Gene Therapy For Neuropathic Pain

Today's post from mybestlife.com (see link below) talks about the advances in gene therapy in trying to combat neuropathic pain. Scientists have identified a part of the brain (amygdala) responsibile for emotional responses to pain and to put it simply, are hoping that by injecting it with a selected virus this will block seretonin receptors responsible for pain signals. This is in response to decades of treatments using various drugs which have had limited or virtually no success. Gene therapy may well be the future in this field and the researchers have been awarded a substantial 5 year grant to investigate the possibilities. The article may seem to be a little complex but it's important to at least have some idea of the direction research is going. As always, the future is a long way off in terms of effective and inexpensive treatment but they have to start somewhere!

Gene therapy at center of UTMB effort to eliminate neuropathic pain
16th September 2013

University of Texas Medical Branch at Galveston researchers have been awarded a five-year, $1.8 million grant by the National Institute of Neurological Disorders and Stroke to apply the techniques of gene therapy to the problem of neuropathic pain — that is, pain that arises from a malfunction in the nervous system.

Neuropathic pain is a daily reality for millions of Americans, manifesting itself in a variety of life-impairing ways. Someone suffering from neuropathic pain might feel intense discomfort in response to a light touch, for example, or suddenly feel as though he or she were freezing in response to a small decrease in temperature. Caused by either accidental or disease-induced nerve damage, this kind of pain has proven very difficult to treat.

“Patients in neuropathic pain are willing to do almost anything to get relief,” said Dr. Volker Neugebauer, the co-principal investigator on the grant. “They’re in torment, often in really desperate situations.”

To make matters worse, long-term neuropathic pain often causes depression, acting through emotional mechanisms in the brain meant to underscore the importance of pain signals. Depression further increases the perception of pain, creating a vicious cycle of increasing pain and depression. And while conventional pain medicines can block the pain signal, they are usually successful for only a limited time only; eventually the pain returns when the nervous system compensates for the blockade.

Neugebauer and his UTMB colleague and co-principal investigator Thomas Green believe that a better anti-neuropathic pain strategy is to target higher brain regions and prevent the abnormal generation of persistent emotions. They focus on the amygdala, a structure best known for its role in emotional responses, including anxiety and depression and — in Neugebauer’s previous work — for its connection to pain regulation. Neugebauer and Green hypothesize that stopping abnormal activity in the amygdala by a particular type of receptor for the neurotransmitter serotonin will enable the successful treatment of neuropathic pain.

Although increased serotonin activity in the brain is generally thought of as a good thing — it’s the mechanism used by many antidepressant drugs — activation of the serotonin 2C receptor in the amygdala can cause problems, according to Neugebauer. “In neuropathic pain we see that this receptor is activated on cells that regulate output from the amygdala to brain areas where responses to potentially harmful situations are generated,” Neugebauer said. “This activity should be turned off when such response is no longer needed or useful, but these serotonin 2C receptors continue to drive amygdala output, creating a chronic pain state.”

In experiments with laboratory rats in which neuropathic pain behavior has been induced by nerve damage, Neugebauer and Green plan to investigate the possibility of “re-normalizing” the amygdala by injecting it with specially designed viruses containing genetic material that blocks cells’ generation of serotonin 2C receptors.

“The viruses that we’re using are adeno-associated viruses, very common vectors that about 80 percent of the people in our society have been exposed to,” Green said. “We’ve modified them so that they can’t replicate, and inserted a gene that instructs the amygdala cells to make small pieces of RNA that interfere with the production of serotonin 2C receptors.”

According to Green, who has been working with similar gene-therapy techniques for more than 10 years, the viral injections produce permanent effects in the brain and no off-target effects. The researchers plan to test the rats’ response to the treatment with a variety of behavioral experiments that will examine both its effect on chronic pain behavior and behaviors associated with depression.

In addition to the behavioral investigation, the project will include electrophysiological studies of amygdala activity, in an effort to further define the “circuitry” of this key pain and emotion center. It will also examine the inconsistent results achieved when chronic pain is treated with selective serotonin reuptake inhibitor antidepressants, attempting to determine whether serotonin 2C receptor activity might be responsible.

“SSRIs increase serotonin, and most of the serotonin receptors produce good effects,” Neugebauer said. “But increasing serotonin also means you’re hitting the 2C receptor as well, perhaps mediating undesirable effects. We want to take that out and then see if increasing serotonin produces consistently good effects.”

For more information
The University of Texas Medical Branch
http://www.utmb.edu/

http://www.mybestlife.com/health/News-2013-Sep/20130916-neuropathic-pain-study.htm

NEW GENE DISCOVERED THAT STOPS SPREAD OF CANCER

Scientists at the Salk Institute have identified a gene responsible for stopping the movement of cancer from the lungs to other parts of the body, indicating a new way to fight one of the world's deadliest cancers.

By identifying the cause of this metastasis -- which often happens quickly in lung cancer and results in a bleak survival rate -- Salk scientists are able to explain why some tumors are more prone to spreading than others. The newly discovered pathway, detailed today in Molecular Cell, may also help researchers understand and treat the spread of melanoma and cervical cancers.

"Lung cancer, even when it's discovered early, is often able to metastasize almost immediately and take hold throughout the body," says Reuben J. Shaw, Salk professor of molecular and cell biology and a Howard Hughes Medical Institute early career scientist. "The reason behind why some tumors do that and others don't has not been very well understood. Now, through this work, we are beginning to understand why some subsets of lung cancer are so invasive."

Lung cancer, which also affects nonsmokers, is the leading cause of cancer-related deaths in the country (estimated to be nearly 160,000 this year). The United States spends more than $12 billion on lung cancer treatments, according to the National Cancer Institute. Nevertheless, the survival rate for lung cancer is dismal: 80 percent of patients die within five years of diagnosis largely due to the disease's aggressive tendency to spread throughout the body.

To become mobile, cancer cells override cellular machinery that typically keeps cells rooted within their respective locations. Deviously, cancer can switch on and off molecular anchors protruding from the cell membrane (called focal adhesion complexes), preparing the cell for migration. This allows cancer cells to begin the processes to traverse the body through the bloodstream and take up residence in new organs.

In addition to different cancers being able to manipulate these anchors, it was also known that about a fifth of lung cancer cases are missing an anti-cancer gene called LKB1 (also known as STK11). Cancers missing LKB1 are often aggressive, rapidly spreading through the body. However, no one knew how LKB1 and focal adhesions were connected.

Now, the Salk team has found the connection and a new target for therapy: a little-known gene called DIXDC1. The researchers discovered that DIXDC1 receives instructions from LKB1 to go to focal adhesions and change their size and number.

When DIXDC1 is "turned on," half a dozen or so focal adhesions grow large and sticky, anchoring cells to their spot. When DIXDC1 is blocked or inactivated, focal adhesions become small and numerous, resulting in hundreds of small "hands" that pull the cell forward in response to extracellular cues. That increased tendency to be mobile aids in the escape from, for example, the lungs and allows tumor cells to survive travel through the bloodstream and dock at organs throughout the body.

"The communication between LKB1 and DIXDC1 is responsible for a 'stay-put' signal in cells," says first author and Ph.D. graduate student Jonathan Goodwin. "DIXDC1, which no one knew much about, turns out to be inhibited in cancer and metastasis."

Tumors, Shaw and collaborators found in the new research, have two ways to turn off this "stay-put" signal. One is by inhibiting DIXDC1 directly. The other way is by deleting LKB1, which then never sends the signal to DIXDC1 to move to the focal adhesions to anchor the cell. Given this, the scientists wondered if reactivating DIXDC1 could halt a cancer's metastasis. The team took metastatic cells, which had low levels of DIXDC1, and overexpressed the gene. The addition of DIXDC1 did indeed blunt the ability of these cells to be metastatic in vitro and in vivo.

"It was very, very surprising that this gene would be so powerful," says Goodwin. "At the start of this study, we had no idea DIXDC1 would be involved in metastasis. There are dozens of proteins that LKB1 affects; for a single one to control so much of this phenotype was not expected."

Right now, there is no specific treatment for cancers harboring LKB1 or DIXDC1 alterations, but those with a deletion of either gene would likely see results from cancer drugs that target the focal adhesions, says Shaw.

"The good news is that this finding predicts that patients missing either gene should be sensitive to new therapies targeting focal adhesion enzymes, which are currently being tested in early-stage clinical trials," says Shaw, who is also a member of the Moores Cancer Center and an adjunct professor at the University of California, San Diego.

"By identifying this unexpected connection between DIXDC1 and LKB1 in certain tumors, we have expanded the potential patient population that may be good candidates for these therapies," adds Goodwin.

GENE LINKED TO INCREASED DENTRITIC SPINES AUTISM FINDINGS

Scientists at the UNC School of Medicine have discovered that knocking out the gene NrCAM leads to an increase of dendritic spines on excitatory pyramidal cells in the brains of mammals. Other studies have confirmed that the overabundance of dendritic spines on this type of brain cell allows for too many synaptic connections to form between neurons – a phenomenon strongly linked to autism.

The finding, published in The Journal of Neuroscience, adds evidence that NrCAM is a major player in neurological disorders. Previous UNC studies showed that knocking out the NrCAM gene caused mice to exhibit the same sorts of social behaviors associated with autism in humans.

“There are many genes involved in autism, but we’re now finding out exactly which ones and how they’re involved,” said Patricia Maness, PhD, professor of biochemistry and biophysics and senior author of the Journal of Neuroscience paper. “Knowing that NrCAM has this effect on dendrites allows us to test potential drugs, not only to observe a change in behaviors linked to autism but to see if we can improve dendritic spine abnormalities, which may underlie autism.

Maness’s finding comes on the heels of a report from Columbia University researchers who found an overabundance of the protein MTOR in mice bred to develop a rare form of autism. By using a drug to limit MTOR in mice, the Columbia researchers were able to decrease the number of dendritic spines and thus prune the overabundance of synaptic connections during adolescence. As a result, the social behaviors associated with autism were decreased. However, the drug used to limit MTOR can cause serious side effects, and it is located inside cells, making it a potentially difficult protein to target.

It is too early to tell if NrCAM and MTOR are linked, but Maness is now studying if the decreased amount of the NrCAM protein could trigger activation of MTOR. If so, then NrCAM, which is an accessible membrane-bound protein, might be a preferred therapeutic target for certain autism-related conditions.

In their study, Maness and her colleagues found that the NrCAM protein forms a complex with two other molecules to create a receptor on the membrane of excitatory pyramidal neurons. Maness’s team found that this receptor allows dendritic spines to retract, allowing for proper neuron pruning during maturation of the cortex. As a result, excitatory and inhibitory synapses between neurons develop in a balanced ratio necessary for brain circuits to function properly.

Maness, a member of the UNC Neuroscience Center and the Carolina Institute for Developmental Disabilities, also said that there are likely many other proteins downstream of NrCAM that depend on the protein to maintain the proper amount of dendritic spines. Decreasing NrCAM could allow for an increase in the levels of some of these proteins, thus kick starting the creation of dendritic spines.

“Basic science in autism is converging in really exciting ways,” Maness said. “Too many spines and too many excitatory connections that are not pruned between early childhood and adolescence could be one of the chief problems underlying autism. Our goal is to understand the molecular mechanisms involved in pruning and find promising targets for therapeutic agents.”

MOTHERS SOOTHING PRESENCE MAKES PAIN GO AWAY CHANGES GENE ACTIVITY IN INFANTS BRAIN

A mother's "TLC" not only can help soothe pain in infants, but it may also impact early brain development by altering gene activity in a part of the brain involved in emotions, according to new study from NYU Langone Medical Center.

By carefully analyzing what genes were active in infant rat brains when the mother was present or not present, the NYU researchers found that several hundred genes were more, or less, active in rat infants experiencing pain than in those that were not. With their mothers present, however, fewer than 100 genes were similarly expressed.

According to senior study investigator and neurobiologist Regina Sullivan, PhD, who is scheduled to present her team's findings at the Society for Neuroscience annual meeting in Washington, D.C., on Nov. 18, the research is believed to be the first to show the short-term effects of maternal caregiving in a distressed infant pup's brain. The study was also designed to support her research into the long-term consequences of differences in how mammals, including humans, are nurtured from birth.

"Our study shows that a mother comforting her infant in pain does not just elicit a behavioral response, but also the comforting itself modifies -- for better or worse -- critical neural circuitry during early brain development," says Sullivan, a professor at the NYU School of Medicine and its affiliated Nathan S. Kline Institute for Psychiatric Research.

For the study, researchers performed genetic analyses on tissue from the almond-sized amygdala region of the infant rat pups' brains that is responsible for processing emotions, such as fear and pleasure.

Sullivan, whose earlier research showed how the mother's presence controlled electrical signaling in the infant pup's brain, says her latest findings shed insight on the complexity of treating pain in newborns.

"Nobody wants to see an infant suffer, in rats or any other species," says Sullivan. "But if opiate drugs are too dangerous to use in human infants because of their addictive properties, then the challenge remains for researchers to find alternative environmental stimuli, including maternal presence, coddling, or other cues, such as a mother's scent, that could relieve the pain."

Sullivan cautions, however, that the long-term consequences of these genetic modifications must also be compared to the short-term benefits for tying pain stimuli during infancy to such a powerful symbol of safety and security as the infant's mother.

"The more we learn about nurturing the infant brain during infancy, the better prepared we are to deal long-term with treating problems that arise from pain, and physical and mental abuse experienced during infancy," says Sullivan.

New Gene Therapy Relieves Neuropathic Pain Vid

Today's post from emaxhealth.com (see link below) looks at a new finding in the field of genetic therapies. Gene therapy seems to be one of the growth areas as far as nerve damage treatment in the future is concerned and each new story seems to offer genuine hope for the future. This article concerns VM202, a non-viral gene therapy that contains human hepatocyte growth factor (HGF). This is a growth factor that keeps nerves healthy and able to function. In this latest research, patients have responded extremely well to just two treatments and have achieved long-lasting pain relief. It's a fascinating story which you don't need to fully understand to appreciate that this may be an exciting development for the future.

Gene therapy offers new hope for diabetic neuropathy
By Kathleen Blanchard G+ 2015-03-06

Diabetes can lead to nerve damage known as neuropathy that is painful, permanent, irreversible and progressive. The most common symptoms of peripheral neuropathy that occurs in the extremities is a feeling of numbness and tingling and sharp, stabbing pain, especially in the feet. Researchers at Northwestern University have uncovered a new way to help diabetics get relief from diabetic neuropathy.

Researchers for the study that included 84 patients found patients with diabetes who were given two low dose rounds of a non-viral gene therapy called VM202 reported pain relief for more than a year.

Rather than just treating symptoms of diabetic neuropathy, the gene therapy actually helps the body heal.

Diabetes nerve damage can make it difficult to sense injury, making it easy to injure fragile skin. A simple foot injury for some with diabetes can mean slower wound healing, greater risk of infection, risk for chronic foot ulcers, amputation, increased medical costs, and decreased quality of life.

The non-viral gene therapy helped patients experience sensation with just a light touch.

“Those who received the therapy reported more than a 50 percent reduction in their symptoms and virtually no side effects,” said Dr. Jack Kessler, lead author of the study. “Not only did it improve their pain, it also improved their ability to perceive a very, very light touch, " Kessler added in a press release.

How the therapy works

The researchers explain VM202 contains a gene known as human hepatocyte growth factor (HGF) that is responsible to keeping nerve fibers healthy and functioning.

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Dr. Senda Ajroud-Driss, an author of the study said the hope is that the therapy will stimulate new blood vessel growth and nerve regeneration to reduce pain and heal the body.

Medications used to treat diabetic neuropathy can be expensive. Some have side effects that are intolerable including dizziness and mood changes.

Injections to treat the condition were administered twice during a two-week period for the study. The gene therapy is administered into the back of the calf muscle and lower leg. The study group received either the therapy or a placebo for comparison.

The finding is published in the Annals of Clinical and Translational Neurology.



The researchers are planning a phase III study in the near future. “Our goal is to develop a treatment. If we can show with more patients that this is a very real phenomenon, then we can show we have not only improved the symptoms of the disease, namely the pain, but we have actually improved function." The study offers new hope for treating diabetic neuropathy that affects 2 to twenty-five percent of people diagnosed with diabetes. Gene therapy used in the research had no side effects and resulted in a 50 percent reduction of symptoms.

http://www.emaxhealth.com/1020/new-hope-treating-diabetic-neuropathy