Researchers target specific gene mutation causing ALS, dementia

Johns Hopkins scientists have developed new drugs that – at least in a laboratory dish – appear to halt the brain-destroying impact of a genetic mutation at work in some forms of two incurable diseases, amyotrophic lateral sclerosis (ALS) and dementia.

They made the finding by using neurons they created from induced pluripotent stem cells (iPS cells), which are derived from the skin of people with ALS who have a gene mutation that interferes with the process of making proteins needed for normal neuron function.

“Efforts to treat neurodegenerative diseases have the highest failure rate for all clinical trials,” says Jeffrey D. Rothstein, M.D., Ph.D., a professor of neurology and neuroscience at the Johns Hopkins University School of Medicine and leader of the research described online this week in the journal Neuron.

“But with this iPS technology, we think we can target an exact subset of patients with a specific mutation and succeed. It’s individualized brain therapy, just the sort of thing that has been done in cancer, but not yet in neurology.” Scientists in 2011 discovered that more than 40% of patients with an inherited form of ALS and at least 10% of patients with the non-inherited sporadic form have a mutation in the C9ORF72 gene.

The mutation also occurs very often in people with frontotemporal dementia, the second- most-common form of dementia after Alzheimer’s disease. The same research appeared to explain why some people develop both ALS and the dementia simultaneously and that, in some families, one sibling might develop ALS while another might develop dementia.

In the C9ORF72 gene of a normal person, there are up to 30 repeats of a series of six DNA letters (GGGGCC); but in people with the genetic glitch, the string can be repeated thousands of times. Rothstein, who is also director of the Johns Hopkins Brain Science Institute and the Robert Packard Center for ALS Research, used his large bank of iPS cell lines from ALS patients to identify several with the C9ORF72 mutation, then experimented with them to figure out the mechanism by which the “repeats” were causing the brain cell death characteristic of ALS.

In a series of experiments, Rothstein says, they discovered that in iPS neurons with the mutation, the process of using the DNA blueprint to make RNA and then produce protein is disrupted. Normally, RNA-binding proteins facilitate the production of RNA. Instead, in the iPS neurons with the C9ORF72 mutation, the RNA made from the repeating GGGGCC strings was bunching up, gumming up the works by acting like flypaper and grabbing hold of the extremely important RNA binding proteins, including one known as ADARB2, needed for the proper production of many other cellular RNAs. Overall, the C9ORF72 mutation made the cell produce abnormal amounts of many other normal RNAs and made the cells very sensitive to stress.

To counter this effect, the researchers developed a number of chemical compounds targeting the problem. This compound behaved like a coating that matches up to the GGGGCC repeats like velcro, keeping the flypaper-like repeats from attracting the bait, allowing the RNA-binding protein to properly do its job.

Rothstein says Isis Pharmaceuticals helped develop many of the studied compounds and, by working closely with the Johns Hopkins teams, could begin testing it in human ALS patients with the C9ORF72 mutation in the next several years.

In collaboration with the National Institutes of Health, plans are already underway to begin to identify a group of patients with the C9ORF72 mutation for future research.



Gene variants associated with immune system and autoimmune disease

Numerous studies have reported that certain diseases are inherited. But genetics also plays a role in immune response, affecting our ability to stave off disease, according to a team of international researchers.

The new findings, from the SardiNIA Study of Aging, supported in part by the US National Institute on Aging (NIA) at the National Institutes of Health, are published in the September 26, 2013 issue of Cell. The SardiNIA researchers found 89 independent gene variants on the genome associated with regulating production of immune system cells.

Five of these sites for the gene variants coincide with known genetic contributors to autoimmune diseases, and extend previous knowledge to identify the particular cell types that are affected by these genes. “We know that certain diseases run in families. From this study, we wanted to know the extent to which relative immune resistance or susceptibility to disease is inherited in families,” said David Schlessinger, Ph.D., chief of NIA’s Laboratory of Genetics.

“If your mother is rarely sick, for example, does that mean you don’t have to worry about the bug that’s going around? Is immunity in the genes? According to our findings, the answer is yes, at least in part.”

The study team, led by Francesco Cucca, M.D., director of the National Research Council’s Institute of Genetic and Biomedical Research in Italy, discovered that variants in particular genes had very significant effects on the levels of one or more particular types of immune system cells.

A number of these genes are also implicated in risk for various autoimmune diseases, including ulcerative colitis, multiple sclerosis, rheumatoid arthritis, and celiac disease. Understanding the genes affecting immune system cells and risk for autoimmune disease is the first step in developing therapies that are personalized according to an individual’s needs, although more research is needed to further characterize the role genetics plays in the complex dynamics of the immune system, the researchers pointed out. The human immune system is a complex network of cells, tissues, and organs working together to fight disease and keep us at optimal health and function.

Our first line of defence, the innate immune system, includes barriers, like skin and mucus as well as specific cells and molecules providing a prompt but nonspecific response to harmful germs – pathogens – preventing them from entering the body or eliminating them rapidly after infection. The second line of defence, the adaptive immune system, engages the body to produce, store, and transport cells and molecules providing more specific responses to combat pathogens.

The immune system has evolved to reject pathogens and even some cancers, but high levels of immune function can also make the body prone to autoimmune disease. Autoimmune diseases occur when the body uses the immune system against itself, attacking normal, healthy cells. The number of adaptive immune system cells available to attack a pathogen or, in the case of autoimmune disease, attack healthy cells, is what appears to be regulated by genetics.

The SardiNIA research team tested the heritability of this immune response using a genome-wide association study, looking at approximately 8.2 million variants in blood samples taken from 1,629 Sardinians. Small, single-letter variations in genes naturally occur throughout the DNA code and are generally without effect on any specific trait.

However, in some instances, scientists find that a particular variant is more common among people with a trait or disease. In the analyses, researchers identified 89 independent variants and 53 sites associated with immune cell characteristics. Most of these associations were previously undiscovered. Some had been identified before in other studies, but without firm statistical significance.

The researchers compared their findings with data in public repositories, and in some cases, found that these genes had already been associated with autoimmune disease. This finding is the most recent of several discoveries made by the SardiNIA study itself and in conjunction with other groups in international consortia. Previous findings identified gene associations with height, fasting blood sugar, cholesterol and other fats in the blood, beta-thalassemia (a blood disorder), and uric acid levels, which can contribute to gout and risk of heart and kidney disease.

One of the unique features of the investigation is its study population – the Sardinians. “The lineage of most Sardinians goes back approximately 20,000 years, to the Mediterranean island’s original settler population – and an ideal group for this type of research,” said Cucca. “We have learned that in case after case, findings in Sardinia have been applicable world-wide.”



 

                                   
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