CF gene therapy via common cold virus?

Cystic fibrosis is a nasty inherited chronic illness.  It affects the lungs and digestive system of about 30,000 children and adults in the United States and an estimated 70,000 people worldwide.

CF is the most common lethal genetic disease in the Caucasian population, affecting one in 3300 births. Other ethnic populations are affected less frequently, ranging from one in 10,000 – 15,000 births in Hispanic and African-American populations, to one in 30,000 Asian births.

The underlying cause is a mutation in the ion channel gene CFTR (cystic fibrosis transmembrane conductance regulator).  This gene is responsible for controlling salt and water transport across the cells lining the lung, pancreas, and other organs.

When this gene is abnormal, secretions in these organs become dehydrated and sticky, and eventually clog airways and may block other organs (pancreas, intestines, male reproductive tract, bile ducts) as well.

Not too many decades ago, few children lived to attend elementary school. Today, with advances in research and treatment,  the median age of survival for children diagnosed with CF  is more than 37  years. Many with the disease can now expect to live beyond their 30s and 40s.

Scientists have worked for 20 years to perfect gene therapy for the treatment of cystic fibrosis.  In recent research, UNC scientists have found what may be the most efficient way to deliver a corrected gene to lung cells collected from cystic fibrosis patients. They also showed that it may take this high level of efficiency for cystic fibrosis (CF) patients to see any benefit from gene therapy.

Using parainfluenza virus, one of the viruses that causes common colds, the UNC scientists found that delivery of a corrected version of the CFTR  gene to 25 percent of cells grown in a tissue culture model that resembles the lining of the human airways was sufficient to restore normal function back to the tissue.

“This is the first demonstration in which we’ve been able to execute delivery in an efficient manner,” says Ray Pickles, Ph.D., associate professor of microbiology and immunology at the UNC Cystic Fibrosis Research and Treatment Center. “When you consider that in past gene therapy studies, the targeting efficiency has been somewhere around 0.1 percent of cells, you can see this is a giant leap forward.”

“We discovered that if you take a virus that has evolved to infect the human airways, and you engineer a normal CFTR gene into it, you can use this virus to correct all of the hallmark CF features in the model system that we used,” Pickles said. For instance, the experiment improved the cells’ ability to hydrate and transport mucus secretions.

The next step is to work to ensure the safety of the delivery system. “We haven’t generated a vector that we can go out and give to patients now,” Pickles says, “but these studies continue to convince us that a gene replacement therapy for CF patients will some day be available in the future.”

Les Lang

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Brain blood vessels love exercise

Here’s some new evidence that aerobic activity may keep the brain young.

A UNC School of Medicine study slated to appear July 9 in the American Journal of Neuroradiology, suggests that physically active elderly people have healthier cerebral blood vessels.

This is the first study to compare brain images of elderly subjects who exercise with those who don’t.

Researchers led by Elizabeth Bullitt, M.D., Van L. Weatherspoon Distinguished Professor of neurosurgery, used non-invasive magnetic resonance (MR) angiography to examine the number and shape of blood vessels in the brains of physically active elderly people, 7 men and 7 women, ages 60 to 80.

The study subjects were equally divided into 2 groups. The high activity group reported participating in an aerobic activity for a minimum of 180 minutes per week for the past 10 consecutive years, and the low activity group told investigators they had no history of regular exercise and currently spent less than 90 minutes a week in any physical activity. (The researchers did not know into which group participants were placed.)

Aerobically active subjects exhibited more small-diameter vessels with less tortuosity, or twisting, than the less active group, exhibiting a vessel pattern similar to younger adults.

Cerebral blood vessels, active elderly group

The authors, who were sponsored in part by the National Institutes of Health’s National Institute of Biomedical Imaging and Bioengineering, identified significant differences in the left and right middle cerebral artery regions confirmed by more than one statistical analysis.

The brain’s blood vessels naturally narrow and become more tortuous with advancing age, but the study showed the cerebrovascular patterns of active patients appeared “younger” than those of relatively inactive subjects. The brains of these less active patients had increased tortuosity produced by vessel elongation and wider expansion curves.

Cerebral blood vessels, inactive group

Bullitt says the pilot study lays the foundation for future research to determine whether aerobic activity improves anatomy, if older patients with “younger” brains are more likely to engage in physical activity, and whether elderly adults who begin a program of aerobic activity can reverse the cerebrovascular, anatomic and functional changes associated with advancing age.

Portions of this paper were presented in December 2008 at the Radiological Society of North America annual meeting in Chicago.

Les Lang

Xist not essential for X-inactivation

Science writer Marla Vacek Broadfoot reports this story for us:

Because females carry two copies of the X chromosome to males’ one X and one Y.  they harbor a potentially toxic double dose of the over 1000 genes that reside on the X chromosome.

To compensate for this imbalance, mammals such as mice and humans shut down one entire X-chromosome through a phenomenon known as X-inactivation. For almost two decades, researchers have believed that one particular gene, called Xist, provides the molecular trigger of X-inactivation.

Now, a new UNC study appearing online Wednesday July 1^st in the journal Nature disputes the current dogma by showing that this process can occur even in the absence of this gene. 

“Our study contradicts what is written in the textbooks,” said senior study author Terry Magnuson, Ph.D., Sarah Graham Kenan Professor and chair of genetics, director of the Carolina Center for Genome Sciences and a member of the UNC Lineberger Comprehensive Cancer Center. “Everybody thought that Xist triggers X-inactivation, but now we have to rethink how this important process starts.”

Previous studies showed that the Xist gene was active or “turned on” early in the course of X-inactivation and that disruptions in the gene resulted in irregular X-inactivation, eventually leading to the accepted assumption that Xist was the trigger. But it wasn’t clear in the literature if this genetic phenomenon would initiate if Xist isn’t present, said lead study author Sundeep Kalantry, Ph.D., postdoctoral fellow in the UNC department of genetics.

Kalantry used three different molecular techniques to look at X-inactivation in the embryos of mice that were genetically engineered to contain a defective Xist gene on their future inactive X-chromosome. He discovered that the genes on this X-chromosome could be silenced regardless of whether they produced Xist. But while Xist was not absolutely required to start X-inactivation, without it genes along the X-chromosome eventually became active again. Thus, Xist appears to stabilize silencing of the X-chromosome over the long term.

Unlike most genes, the Xist gene doesn’t code for a protein. Rather, it acts at the level of RNA – a copy of the DNA genetic sequence – which serves to recruit protein complexes through a process known as epigenetics. These proteins then form a molecular scaffold along the inactive-X chromosome that can stably silence the genes contained within it. The UNC researchers are now actively investigating how this chromosomal remodeling begins in the first place.

“If we can figure out the mechanism that triggers X-inactivation, we can potentially apply this knowledge to diseases that have an epigenetic component,” Kalantry said. “So it can have implications not only in fundamentally understanding X-inactivation but also to gain insight into the increasing array of illnesses where the epigenetic machinery has gone awry – such as in prostate and breast cancers.”

Study outlines schizophrenia puzzle

Scientists have long recognized that schizophrenia can run in families and  that it also has a genetic component.  But one might find any number of studies that point to other explanations for the disease, including dysfunctional communication patterns within families,  child abuse, drug abuse, or, as in the 1960s,  the “anti-psychiatry” view of Thomas Szasz and others that saw schizophrenia as a “social construct. ”

However, only recently has science begun to pinpoint the exact spots in our genetic material that contribute to the illness.  Last year, the International Schizophrenia Consortium found that rare chromosomal structural variants elevate the risk of developing schizophrenia.

Now, a multi-national group of investigators, including a scientist at the University of North Carolina at Chapel Hill, has discovered that nearly a third of the genetic basis of schizophrenia may be attributed to the cumulative actions of thousands of common genetic variants.

The effects of each of these genetic changes, innocuous on its own, add up to a significant risk for developing both schizophrenia and bipolar disorder.

The finding, published online July 1, 2009, in the journal Nature, suggests that schizophrenia is much more complex than previously thought, and can arise not only from both rare genetic variants but also from a significant number of common ones.

“This is an enormous first for our field,” said co-author Patrick Sullivan, M.D., Ray M. Hayworth and Family Distinguished Professor of Psychiatry in the department of genetics at the UNC School of Medicine. “You could say that we now have the outline of the puzzle, and we just need to take all of these pieces that we have identified and see how they fit them together.”

In this study, Sullivan and other investigators in the Consortium used “genechip” technology to identify 30,000 genetic variants (single nucleotide polymorphisms or “SNPs”) that were more common in 3,000 individuals with schizophrenia than in 3,000 comparison subjects without schizophrenia.

This pattern was found in three separate samples of individuals with schizophrenia and two samples with bipolar disorder – indicating a previously unrecognized overlap between the two diseases. These risk variants were not present in patients with other non-psychiatric diseases, such as hypertension or diabetes.

The researchers are also investigating how genes and environment interact to cause the disease. One additional finding of their study was the identification of the human leukocyte antigen (HLA) locus as a possible risk factor. Because this region plays an important role in immune response to infection, it could suggest that exposure to an infectious agent increases risk of developing psychiatric disease.