Category Archives: Gene Medicine

Are deficits in attention limited to those with attention-deficit/hyperactivity disorder (ADHD) or is there a spectrum of attention function in the general population? The answer to this question has implications for psychiatric diagnoses and perhaps for society, broadly.

A new study published in the current issue of Biological Psychiatry, by researchers at Cardiff University School of Medicine and the University of Bristol, suggests that there is a spectrum of attention, hyperactivity/impulsiveness and language function in society, with varying degrees of these impairments associated with clusters of genes linked with the risk for ADHD.

Viewing these functions as dimensions or spectrums contrasts with a traditional view of ADHD as a disease category.

To answer this question, researchers led by senior author Dr. Anita Thapar used genetic data from patients with ADHD as well as data from the Avon Longitudinal Study of Parents and Children (ALSPAC). The ALSPAC is based in England and is a large, ongoing study of parents and children followed since birth in the early '90s.

They created polygenic risk scores -- a 'composite' score of genetic effects that forms an index of genetic risk -- of ADHD for 8,229 ALSPAC participants.

They found that polygenic risk for ADHD was positively associated with higher levels of traits of hyperactivity/impulsiveness and attention at ages 7 and 10 in the general population. It was also negatively associated with pragmatic language abilities, e.g., the ability to appropriately use language in social settings.

"Our research finds that a set of genetic risks identified from UK patients with a clinical diagnosis of childhood ADHD also predicted higher levels of developmental difficulties in children from a UK population cohort, the ALSPAC," said Thapar.

First author Joanna Martin added, "Our results provide support at a genetic level for the suggestion that ADHD diagnosis represents the extreme of a spectrum of difficulties. The results are also important as they suggest that the same sets of genetic risks contribute to different aspects of child development which are characteristic features of neurodevelopmental disorders such as ADHD and autism spectrum disorder."

"It may be the case that at some point polygenic risk scores may, in conjunction with other clinical information, help to identify children who will struggle in school and other demanding contexts due to attention difficulties," said Dr. John Krystal, Editor of Biological Psychiatry. "The objective of this type of early identification would be to provide children who are at risk for difficulties with support so that problems at school may be prevented."

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Gene variants implicated in ADHD identify attention, language

PHILADELPHIA A new form ofgene therapyfor boys with X-linked severe combined immunodeficiency syndrome (SCID-X1), a life-threatening condition also known as bubble boy disease, appears to be both effective and safe, according to an international clinical trial with sites inBoston, Cincinnati, Los Angeles, London, and Paris.

Early data published in theNew England Journal of Medicinesuggests that the therapy may avoid the late-developing leukemiaseen in a quarter of SCID-X1 patients in previous gene-therapy trials in Europe that took place more than a decade ago. Left untreated, boys with SCID-X1 usually die of infection before their first birthday.

The lab of coauthorFrederic Bushman, PhD, professor of Microbiology, from thePerelman School of Medicine at the University of Pennsylvania, carried out the deep DNA sequencing on patient specimens to track and verify distributions of integration sites of the vector.The vector used in the new trial was engineered to remove molecular signals implicated in cancers in the first trial.

Eight of nine boys recruited to date to the present trial are alive between 12 and 38 months after treatment, with no SCID-X1-associated infections. The gene therapy alone generated functioning immune systems in seven of eight boys. Genetic studies showed that the new viral vector did not lead to vector insertions near known cancer-causing genes, raising cautious hopes about the vector's long-term safety.

We showed that fewer cells accumulated with integration sites near cancer genes in the second trial, suggesting that the adverse properties had indeed been engineered out, explains Bushman So far there are no clinical adverse events in the present trial -- the integration site data has suggested improved safety.

The modified vector created for the current trial is a self-inactivating gammaretrovirus, designed to deliver its payload effectively while minimizing the chance of inadvertently turning on oncogenes that could lead to leukemia.

The core question of the trial was whether the new self-inactivating viral vector could safely and successfully shuttle a gene called theIL-2 receptor gamma(IL2RG) subunit into the patients' hematopoietic stem cells. In boys born with SCID-X1, mutations render theIL2RGgene inactive, robbing the children of the ability to produce a functional immune system.

For more information, see theDana-Farber/Boston Children's Cancer and Blood Disorders Centersnews release.

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Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of theRaymond and Ruth Perelman School of Medicine at the University of Pennsylvania(founded in 1765 as the nation's first medical school) and theUniversity of Pennsylvania Health System, which together form a $4.3 billion enterprise.

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New Gene Therapy for "Bubble Boy" Disease Appears to be Safe, Effective

PUBLIC RELEASE DATE:

14-Oct-2014

Contact: Matt Solovey msolovey@hmc.psu.edu 717-531-8606 Penn State @penn_state

Slow-healing or non-healing bone fractures in otherwise healthy people may be caused by gene variants that are common in the population, according to Penn State College of Medicine researchers.

"We found associations between certain gene polymorphisms and delayed fracture healing in a sample of patients," said J. Spence Reid, professor of orthopaedics and rehabilitation. "Our study was preliminary but it demonstrated the feasibility of a larger one, which we're now working to set up."

The identification of gene variants that delay fracture healing could lead to screening tests for patients with broken bones. Those patients deemed likely to experience slow healing could be given more aggressive treatment when they first reach the hospital, potentially avoiding months of debilitation.

The researchers reported their results in the Journal of Bone and Joint Surgery.

Of the eight million bone fractures in the U.S. every year, about 10 percent fail to heal normally. Smoking, diabetes, NSAID use, low vitamin D levels and old age are known risk factors, but in a significant subset of cases, unknown factors appear to be involved.

"Some fractures are slow-healing for no obvious reason, and we wondered if there is a genetic basis for those cases," said Reid.

He and his colleagues selected from their records 33 patients diagnosed with "atrophic nonunion" -- the failure of a fracture to knit together on its own within six months. As controls, they selected 29 patients whose fractures had healed normally.

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Common gene variants linked to delayed healing of bone fractures

PUBLIC RELEASE DATE:

15-Oct-2014

Contact: Rhiannon Bugno Biol.Psych@utsouthwestern.edu 214-648-0880 Elsevier @ElsevierConnect

Philadelphia, PA, October 15, 2014 Are deficits in attention limited to those with attention-deficit/hyperactivity disorder (ADHD) or is there a spectrum of attention function in the general population? The answer to this question has implications for psychiatric diagnoses and perhaps for society, broadly.

A new study published in the current issue of Biological Psychiatry, by researchers at Cardiff University School of Medicine and the University of Bristol, suggests that there is a spectrum of attention, hyperactivity/impulsiveness and language function in society, with varying degrees of these impairments associated with clusters of genes linked with the risk for ADHD.

Viewing these functions as dimensions or spectrums contrasts with a traditional view of ADHD as a disease category.

To answer this question, researchers led by senior author Dr. Anita Thapar used genetic data from patients with ADHD as well as data from the Avon Longitudinal Study of Parents and Children (ALSPAC). The ALSPAC is based in England and is a large, ongoing study of parents and children followed since birth in the early '90s.

They created polygenic risk scores a 'composite' score of genetic effects that forms an index of genetic risk of ADHD for 8,229 ALSPAC participants.

They found that polygenic risk for ADHD was positively associated with higher levels of traits of hyperactivity/impulsiveness and attention at ages 7 and 10 in the general population. It was also negatively associated with pragmatic language abilities, e.g., the ability to appropriately use language in social settings.

"Our research finds that a set of genetic risks identified from UK patients with a clinical diagnosis of childhood ADHD also predicted higher levels of developmental difficulties in children from a UK population cohort, the ALSPAC," said Thapar.

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Gene variants implicated ADHD identify attention and language deficits general population

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The mutations were familiar, but the patients conditions seemed baffling at first. A team lead by Rockefeller University researchers had linked variations in an immune gene to rare bacterial infections. Shortly afterward, Chinese scientists told them of three children in that country with mutated versions of the same gene. However, the Chinese children had no history of the severe bacterial infections. Instead, they had seizures and unusual calcium deposits deep in their brains.

This discrepancy led to the discovery of an immune protein with paradoxical roles: It both aids and tamps down aspects of an immune system response, according to research conducted in Jean-Laurent Casanovas St. Giles Laboratory of Human Genetics of Infectious Diseases at Rockefeller in collaboration with scientists in China and elsewhere. The teams report was published today (October 12) in Nature.

It has turned out that mutations in a single gene eliminate the immune protein ISG15, giving rise to two different problems: an inability to resolve harmful inflammation, which can lead to autoimmune disease, and susceptibility to infections caused by the tuberculosis bacterium and its cousins, Casanova says. By identifying the source of this genetic disorder, we have taken a first step toward finding treatments for those facing the autoimmune disease and severe TB-related infections it may produce.

When under attack, the immune system releases signaling proteins known as interferons, which further activate the bodys defenses. In previous research, Dusan Bogunovic, a former postdoc in the lab now an Assistant Professor at the Department of Microbiology at Icahn School of Medicine at Mount Sinai, linked a lack of ISG15 to an unusual vulnerability to infections by mycobacteria, a group of common bacteria that include the TB bug. He and colleagues found three children, one from Turkey, two from Iran, who became severely ill after receiving the anti-tuberculosis BCG vaccine. Normally, ISG15 protects against infection by mycobacteria by prompting the release of type 2 interferon, but all three children had two copies of a defective form of the ISG15 gene, and became infected by a TB-related component of the vaccine.

After this discovery, ISG15s story continued to unfold. Bogunovic and his colleagues reported this link, and then scientists in China reached out saying they had also seen loss-of-function mutations in three patients, all from a single family. But none of these three had had unexplained mycobacterial infections, such as those caused by the vaccine.

We asked, why were they patients? Bogunovic recalls. Our Chinese colleagues said these kids had seizures; in fact, one child had died from them. When we looked into their BCG vaccination history, we found these children, who were born at home in a remote village, never received their shots, so they never became sick. Next we looked back at our first set of patients. None of them had ever had seizures, but we performed brain scans that found abnormal calcium deposits in a deep part of the brain involved in controlling movement just like the deposits in brains of the Chinese children.

The researchers recognized the calcium deposits as a feature of a group of autoinflammatory diseases, including the neurodevelopmental disorder Aicardi-Goutieres syndrome. These are thought to occur when type 1 interferon, which normally helps fight viral infections, runs amok, triggering harmful and unnecessary inflammation, leading to disease. When Bogunovic and his colleagues then looked for evidence something similar was happening to the six patients, they found unusually high expression of genes stimulated by type 1 interferon.

Using cells from the patients, the researchers found that when they restored the ISG15 gene, the cells became able to resolve the inflammation. Further experiments performed in collaboration with Sandra Pellegrini at the Pasteur Institute in Paris, France, revealed the mechanics that linked a lack of ISG15 with an increase in type 1 interferon signaling: Under normal conditions, ISG15 prevents the degradation of another protein, USP18, which is responsible for turning down the dial on type 1 interferon. With no ISG15, and as a result, little USP18, interferon becomes too active.

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Single Gene Links Susceptibility to Rare Infections with Predisposition to Autoimmune Disease

By Steven Reinberg HealthDay Reporter

THURSDAY, Oct. 9, 2014 (HealthDay News) -- In a small study, Swedish researchers found that the impotence drug yohimbine might help people with type 2 diabetes who have a particular gene mutation that lowers their insulin production.

Among 50 men and women with type 2 diabetes partially caused by a mutation in a gene called alpha(2A)-AR, those treated with yohimbine showed improved insulin production and lower blood sugar levels, compared with those receiving a placebo.

"If a diabetic patient carries the risk mutation, he or she is more sensitive to stress hormones such as adrenaline," said lead researcher Dr. Anders Rosengren, head of the translational diabetes research group at Lund University Diabetes Center in Malmo.

About 40 percent of patients with type 2 diabetes carry this mutation. "It is not that patients are more stressed, but that adrenaline suppresses insulin secretion," he added.

Rosengren explained how the drug overcomes the effects of the mutation: "It is like driving a car with the brakes constantly on. If you add yohimbine, you release the brake and the car -- the insulin-producing cells -- can go at normal speed. The cells secrete adequate amounts of insulin in response to sugar."

Yohimbine isn't without side effects, however, Rosengren said. In the study, some patients experienced anxiety, stress and high blood pressure. His group is trying to find a way to reduce these side effects while preserving the benefits of the drug.

One expert also noted that targeting a single gene may not help many patients with diabetes.

Close to 300 genes play a role in diabetes, according to Dr. Joel Zonszein, director of the Clinical Diabetes Center at Montefiore Medical Center in New York City.

"Only a few have this mutation alone," Zonszein said. "In real life, we are not able to treat most patients with diabetes with a genetic therapy."

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Impotence Drug Might Counter Common Gene Mutation in Type 2 Diabetes: Study

By Amy Norton HealthDay Reporter

WEDNESDAY, Oct. 8, 2014 (HealthDay News) -- A new form of gene therapy may offer a safe and effective way to treat "bubble boy" disease -- a severe immune deficiency that is fatal unless treated in infancy.

Researchers have long known that gene therapy can cure the disease, known medically as severe combined immunodeficiency, or SCID. Over a decade ago, trials in Europe showed that gene therapy worked -- but five of the 20 children treated developed leukemia (a type of cancer) within two to five years, according to background information in the study.

In the new trial, reported in the Oct. 9 New England Journal of Medicine, researchers refined the gene therapy approach to hopefully negate the leukemia risk.

Eight of nine children who received the therapy are still alive one to three years later, the investigators report. And so far, none has developed leukemia.

It's too early to say the therapy carries no leukemia risk, cautioned researcher Dr. David Williams, a pediatric hematologist/oncologist at Dana-Farber Cancer Institute and Boston Children's Hospital.

"We'll continue to follow these children for 15 years," Williams said.

But based on the early results, he noted, the tweaked gene therapy appears as effective at generating a functional immune system as the earlier form of treatment.

SCID refers to a group of rare genetic disorders that all but eliminate the immune system, according to the Immune Deficiency Foundation (IDF). That leaves children at high risk of severe infections.

In the United States, 40 to 100 babies are born with SCID each year, according to the National Institutes of Health. Early detection is becoming more common because a screening test recently became available. So far, 24 states and the District of Columbia have adopted the test, according to the IDF.

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Gene Therapy Shows Potential for 'Bubble Boy' Disease

TIME Health Genetics Gene-Therapy Trial Shows Promise Fighting Bubble Boy Syndrome The immune system-related disease affects about 1 in 100,000 babies each year

A new gene-therapy treatment is showing promise in treating a rare and severe congenital condition that involves extreme immune-system deficiencies.

Bubble boy syndrome, an X-linked condition, takes its name from a famous case in which an affected boy, vulnerable to infection, lived inside a plastic bubble that protected him from the worlds germs. Outside of such sterile environments, babies with the syndrome seldom live longer than a year, the Wall Street Journal reports.

The condition has for decades bested medical researchers, despite occasional bouts of optimism hope for one previous gene-therapy treatment was felled when some recipients developed leukemia.

Gene-therapy treatment works, essentially, by replacing unperforming genes with functional ones. Dysfunctional cells are removed from the childs immune system and exposed to a genetically engineered virus that can reprogram the cells to function properly, explains Reuters. Those cells are then reinserted back into the patient.

In the earlier treatment, the virus to which the cells were exposed apparently activated a part of their genetic code that leads to leukemia, Reuters says.

But initial results reported in the New England Journal of Medicine show that none of the nine babies from the U.S. and Europe who received the latest treatment are exhibiting any signs of cancer.

Of the nine infant participants in the research who were between 4 and 10 months old when they began receiving the therapy eight were still alive 16 to 43 months later, without living in a protective bubble. (The ninth child died four months after treatment began from an earlier infection he had been fighting.)

Out of the eight boys still living, the treatment upped blood T-cell levels, rebuilding the immune system, of seven. In the case of the eighth child, the treatment did not rebuild his immune system, but a successful stem-cell transplant has kept him in improved health, Reuters reports.

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Gene-Therapy Trial Shows Promise Fighting Bubble Boy Syndrome

PUBLIC RELEASE DATE:

8-Oct-2014

Contact: Hillary Hoffman hillary.hoffman@nih.gov 301-402-1663 NIH/National Institute of Allergy and Infectious Diseases @NIAIDNews

WHAT:

Researchers have found that gene therapy using a modified delivery system, or vector, can restore the immune systems of children with X-linked severe combined immunodeficiency (SCID-X1), a rare, life-threatening inherited condition that primarily affects boys. Previous efforts to treat SCID-X1 with gene therapy were initially successful, but approximately one-quarter of the children developed leukemia two to five years after treatment. Results from a study partially funded by the National Institute of Allergy and Infectious Diseases (NIAID), a component of the National Institutes of Health (NIH), suggest that the new vector is equally effective at restoring immunity and may be safer than previous approaches.

In SCID-X1, mutations in a specific gene prevent the development of infection-fighting T cells. The standard therapy for SCID is transplantation of blood-forming stem cells, but some patients lack a suitable donor. In gene therapy, doctors remove stem cells from the patient's bone marrow, use a vector to insert a corrected gene and then return the corrected cells to the patient. Scientists suspect that the vectors used in earlier studies may have activated genes that control cell growth, contributing to leukemia.

In the current study, nine boys with SCID-X1 underwent gene therapy using a vector engineered by the study researchers. Seven boys developed functional T cells at levels comparable to those seen in previous studies and have remained healthy for one to three years after treatment. Analyses of the children's T cells suggest that the new vector causes fewer genomic changes that could be linked to leukemia. Researchers will continue to monitor the boys for leukemia development. Of the two other boys, one died of a pre-existing viral infection shortly after receiving the therapy, and one failed to develop corrected T cells and was given a stem cell transplant from an unrelated donor.

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ARTICLE:

S Hacein-Bey-Abina, S-Y Pai et al. A modified y-retrovirus vector for X-linked severe combined immunodeficiency. New England Journal of Medicine DOI: 10.1056/NEJMoa1404588 (2014).

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Gene therapy shows promise for severe combined immunodeficiency

Oct 06, 2014 C. elegans, a one-millimeter-long worm that scientists have used as a model organism since the 1970s. Courtesy of the Curran Laboratory

Imagine being able to take a pill that lets you eat all of the ice cream, cookies, and cakes that you wanted without gaining any weight.

New research from USC suggests that dream may not be impossible. A team of scientists led by Sean Curran of the USC Davis School of Gerontology and the Keck School of Medicine of USC found a new way to suppress the obesity that accompanies a high-sugar diet, pinning it down to a key gene that pharmaceutical companies have already developed drugs to target.

So far, Curran's work has been solely on the worm Caenorhabditis elegans and human cells in a petri dish but the genetic pathway he studied is found in almost all animals from yeast to humans. Next, he plans to test his findings in mice.

Curran's research is outlined in a study that will be published on Oct. 6 by Nature Communications.

Building on previous work with C. elegans, Curran and his colleagues found that certain genetic mutants those with a hyperactive SKN-1 gene could be fed incredibly high-sugar diets without gaining any weight, while regular C. elegans ballooned on the same diet.

"The high-sugar diet that the bacteria ate was the equivalent of a human eating the Western diet," Curran said, referring to the diet favored by the Western world, characterized by high-fat and high-sugar foods, like burgers, fries and soda.

The SKN-1 gene also exists in humans, where it is called Nrf2, suggesting that the findings might translate, he said. The Nrf2 protein, a "transcription factor" that binds to a specific sequence of DNA to control the ability of cells to detox or repair damage when exposed to chemically reactive oxygen (a common threat to cells' well being), has been well studied in mammals.

Pharmaceutical companies have already worked to develop small-molecule drugs that target Nrf2, in hopes that it will produce more anti-oxidants and slow aging.

Though the promise of a pill to help control your body's response to food is enticing, it is not without risk, Curran said. Increased Nrf2 function has been linked to aggressive cancers.

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Gene discovery prevents weight gain with a high-sugar diet