March 30, 2017 by Genevieve Rajewski Giving these pets another one-and-a-half to two years of life would be a major success, Dominik Faissler said. Better yet, wed be doing something for dogs that at the same time contributes to human medicine. Credit: iStock

A gene-silencing therapy under development for people with amyotrophic lateral sclerosis (ALS) is being tested at Tufts in dogs with degenerative myelopathy, a fatal paralytic disease that is similar to ALS.

"If you look at the clinical progression [of degenerative myelopathy], a dog will go from dragging a toe, to stumbling, to falling over when it turns quickly," said Dominik Faissler, the veterinary neurologist at Cummings School who is leading the study. As the disease progresses, a dog can no longer stand.

"What's so extraordinary is that the dog is a naturally occurring model of one form of the human disease," said Robert H. Brown Jr., a University of Massachusetts Medical School neurologist who is one of the world's foremost experts on ALS and other neurodegenerative diseases. He approached Cummings School about testing the therapy developed in his lab, with the goal of speeding up clinical trials in humans.

"In dogs, it turns out there's a mutation in the SOD1 gene, which normally makes an antioxidant protein that helps protect nerve cells from a variety of cellular stresses and injuries. When this gene gets mutated, it becomes toxic to nerves, killing off the motor neurons in dogs the same way that this genetic mutation does in some people with ALS," said Brown, the Leo P. and Theresa M. LaChance Chair in Medical Research and chair of neurology at UMass Medical School.

Canine degenerative myelopathy causes progressive paralysis in older dogs in a number of breeds, including German shepherds, boxers, corgis, Chesapeake retrievers, Rhodesian ridgebacks and Bernese mountain dogs, Faissler said. "There is likely a genetic defect that interferes with the survival of the spinal cord tissue and brain tissue," he said. As in humans with ALS, dogs with degenerative myelopathy eventually die when the respiratory system stops working, but often pets are euthanized before, because their quality of life is poor.

The dogs in the Tufts trial receive a single spinal fluid injection of an engineered adenovirusfrom a family of viruses that can infect the nervous system, but is best known for causing the common cold. The engineered virus was designed to breach the blood-brain barrier to deliver DNA particles that turn offor silencethe mutated gene.

"This barrier is normally a very good thing, because it keeps bacteria out of our nervous system," Brown said. "But we must get the treatment to the cells where it can actually take effect, and a virus knows how to wend its way through that iron curtain." The therapy has shown promising results in mice genetically engineered to have a condition similar to ALS, he said, and it also was safe when tested in normal monkeys.

Dogs in the Cummings School trial, which began in December 2016, are checked every three months and undergo tests, which are videotaped, to assess their neurological and motor function. Four dogs are currently in the pilot study. So far, the therapy appears safe in pets, but Faissler and Brown said it's too early to determine whether it will halt or reverse the disease. "Does it work? That's the question I wake up and go to bed with every day," Brown said.

"Giving these pets another one-and-a-half to two years of life would be a major success," Faissler said. "Better yet, we'd be doing something for dogs that at the same time contributes to human medicine."

A successful trial in dogs could be a prelude to a clinical trial in people, Brown said. Ionis Pharmaceuticals, a California biotech company, is already testing a different gene therapy for SOD1-related ALS and for a similar type of mutation in patients with Huntington's disease, which attacks nerve cells in the brain. Such treatments one day could be used for a number of neurodegenerative and neuromuscular diseases, Brown said, including Parkinson's, Alzheimer's and a host of diseases known as ataxias, characterized by the loss of control over bodily movements.

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Fighting canine ALS - Medical Xpress

March 30, 2017 by Julia Evangelou Strait Credit: Washington University School of Medicine

Natural genetic changes can put some people at high risk of certain conditions, such as breast cancer, Alzheimer's disease or high blood pressure. But in rare cases, genetic errors also can have the opposite effect, protecting individuals with these helpful genetic mistakes from developing common diseases.

A new study of such "beneficial" genetic mutations, led by Washington University School of Medicine in St. Louis, may provide guidance on the design of new therapies intended to reduce the risk of heart attacks.

The study is published March 29 in the Journal of the American College of Cardiology.

The researchers studied members of a family with rare mutations in a gene called ANGPTL3. The gene is known to play important roles in processing lipoproteins, molecules that package and transport fat and cholesterol through the bloodstream. Partial or complete loss of this gene was known to cause low cholesterol and triglyceride levels in the bloodstream. But whether it affects risk of heart attack was unclear.

Three of these family membersthose with a complete loss of this geneshowed extremely low blood cholesterol and no evidence of plaque in their coronary arteries. According to the study authors, it was noteworthy that one of these patients showed no evidence of atherosclerosis despite having high risk factors for it, including high blood pressure and a history of type 2 diabetes and tobacco use.

"The family members with complete loss of ANGPTL3 have extraordinarily low cholesterol," said first author Nathan O. Stitziel, MD, PhD, an assistant professor of medicine and of genetics. "The interesting thing about this family is the individuals with total loss of this gene had siblings with normal copies of the same gene. So we could compare people with differences in the function of this gene who are otherwise closely related genetically and share similar environments. It's an anecdotal study of one family, but we felt it might provide some insight into the effects of blocking ANGPTL3."

While the individuals with nonfunctional copies of the gene showed no coronary plaque, their siblings with working copies of the gene showed evidence of plaque in the coronary arteries, though it was not yet causing symptomsa situation that is common in the general population, according to Stitziel.

To study the gene beyond the experience of a single family, the scientists also analyzed data available from large population studies. In data from one study of about 20,000 patients, the researchers found those with a partial loss of this gene had, on average, 11 percent lower total cholesterol, 12 percent lower LDL cholesterol, and 17 percent lower triglycerides, measured in the blood, than individuals with full gene function.

Analysis of data from other large population studies showed a link between partial loss of the gene and a lower risk of coronary artery disease and an association between lower circulating levels of ANGPTL3 protein and a lower risk of heart attack.

Taken together, these findings provide support for efforts to develop drugs that inhibit ANGPTL3 in order to reduce the risk of coronary artery disease and heart attack. The same reasoning led to the development of a class of drugs known as PCSK9 inhibitors, which have recently been shown to be effective at reducing the risk of heart attack in a large clinical trial of more than 27,000 men and women.

Several years ago, researchers found natural beneficial mutations in the PCSK9 gene that lowered people's cholesterol levels and protected them from coronary artery disease, much as mutations in ANGPTL3 seem to do. Both PCSK9 and ANGPTL3 are important in the body's processing of cholesterol from the diet. Any drugs that inhibit them, then, work differently than commonly prescribed statins, which reduce cholesterol levels in the blood by blocking the body's internal cholesterol manufacturing.

While reducing cholesterol levels in the blood typically is thought to be good for the heart, Stitziel pointed out that there may be dangers to inhibiting the normal function of a gene. Not all genetic mutations that result in low cholesterol in the bloodstream are healthy. For example, there is one genetic disorder in which cholesterol levels in the blood are low because cholesterol gets stuck in the liver, resulting in fatty liver disease.

"We need a better understanding of how cholesterol is processed in individuals with complete loss of ANGPTL3 function before we can fully say what effect inhibiting ANGPTL3 is going to have," Stitziel said. "Studies of people with mutations that completely knock out a gene's function are important because they can provide insight into the potential effectsboth good and badof drugs inhibiting that gene's function."

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Genetic errors associated with heart health may guide drug development - Medical Xpress

Egyptian Eman Ahmed, 36, who is in Mumbai for weight-reduction surgery, could be the first and only person in the world with a rare gene defect that causes severe obesity. Agene study revealed that a mutation in the gene which instructs a protein involved in the regulation of body weight, was causing the weight gain.

The genetic study, conducted by Core Diagnostics, to analyse 91 kinds of genes, isolated with obesity related syndromes was analysed by physicians and metabolism experts in USA, UK and India. Dr Muffazal Lakdawala, Emans treating doctor and bariatric surgeon at Saifee Hospital said Emans case is a medical miracle since patients suffering from monogenic disorders dont usually cross adolescence. Leptin hormone comes from fat tissues and signals the brain about depleting fat stores. In Emans case, the defective docking station in the brain that leptin plugs into doesnt receive any signals. As a result, Emans brain has perceived that she is constantly starving and that led her to constantly feel hungry, eat food, store it as fat and conserve energy, said Dr Lakdawala.

While two major gene defects were diagnosed, the cause of Emans obesity is a mutation in the leptin receptor protein (LEPR) gene. The variant has been previously detected in one individual in research setting by Personalized Diabetes Medicine Program, University of Maryland School of Medicine, and has been classified as a variant of uncertain significance (VUS). However, in Emans case this has assumed pathologic consequences leading to her obesity. Eman is the only one in the world with this gene defect causing obesity, said doctors from the hospital.

Mutations in this gene have been associated with an autosomal recessive disorder causing obesity and pituitary dysfunction. Leptin receptor deficiency leads to a disorder which is associated with excessive hunger, massive weight gain, and reduced production of hormones that direct sexual development. There is currently no specific treatment for this condition. However, a drug called MC4R Agonist, only available with one pharmaceutical company in the US, might help Eman. The drug has been tested on three paediatric patients and Eman will be the only adult case if she undergoes treatment. The plan is to track her weight loss for six months and then take a call on changing the line of treatment once her condition stabilises, added Dr Lakdawala.

Doctors said the drugs may be able, at least partially, bypass the signaling block in the brain but its too early to say if there will be a successful outcome. So if she has access to these drugs and they are effective then we have a solution. If not, then she may need a more radical surgery which causes malabsorption (process in which intestine cant adequately absorb certain nutrients into the bloodstream, said a doctor.

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Rare genetic mutation made Egyptian Eman the heaviest, says study - Hindustan Times