Posts tagged frontotemporal degeneration
Articles and news from the latest research reports.
New Therapeutic Target Identified for ALS and Frontotemporal Degeneration
A team of scientists led by researchers from the University of California, San Diego School of Medicine and Ludwig Institute for Cancer Research have identified a novel therapeutic approach for the most frequent genetic cause of ALS, a disorder of the regions of the brain and spinal cord that control voluntary muscle movement, and frontotemporal degeneration, the second most frequent dementia.
Published ahead of print in last week’s online edition of the journal PNAS, the study establishes using segments of genetic material called antisense oligonucleotides – ASOs – to block the buildup and selectively degrade the toxic RNA that contributes to the most common form of ALS, without affecting the normal RNA produced from the same gene.
The new approach may also have the potential to treat frontotemporal degeneration or frontotemporal dementia (FTD), a brain disorder characterized by changes in behavior and personality, language and motor skills that also causes degeneration of regions of the brain.
In 2011, scientists found that a specific gene known as C9orf72 is the most common genetic cause of ALS. It is a very specific type of mutation which, instead of changing the protein, involves a large expansion, or repeated sequence of a set of nucleotides – the basic component of RNA.
A normal C9orf72 gene contains fewer than 30 of the nucleotide repeat unit, GGGGCC. The mutant gene may contain hundreds of repeats of this unit, which generate a repeat containing RNA that the researchers show aggregate into foci.
“Remarkably, we found two distinct sets of RNA foci, one containing RNAs transcribed in the sense direction and the other containing anti-sense RNAs,” said first author Clotilde Lagier-Tourenne, MD, PhD, UC San Diego Department of Neurosciences and Ludwig Institute for Cancer Research.
The researchers also discovered a signature of changes in expression of other genes that accompanies expression of the repeat-containing RNAs. Since they found that reducing the level of expression of the C9orf72 gene in a normal adult nervous system did not produce this signature of changes, the evidence demonstrated a toxicity of the repeat-containing RNAs that could be relieved by reducing the levels of those toxic RNAs.
“This led to our use of the ASOs to target the sense strand. We reduced the accumulation of expanded RNA foci and corrected the sense strand of the gene. Importantly, we showed that we could remove the toxic RNA without affecting the normal RNA that encodes the C9orf72 protein. This selective silencing of a toxic RNA is the holy grail of gene silencing approaches, and we showed we had accomplished it,” Lagier-Tourenne added.
Targeting the sense strand RNAs with a specific ASO did not, however, affect the antisense strand foci nor did it correct the signature of gene expression changes. “Doing that will require separate targeting of the antisense strand – or both - and has now become a critical question,“ Lagier-Tourenne said.
“This approach is exciting as it links two neurodegenerative diseases, ALS and FTD, to the field of expansion, which has gained broadened interest from investigators,” said co-principal investigator John Ravits, MD, UC San Diego Department of Neurosciences. “At the same time, our study also demonstrates the – to now – unrecognized role of anti-sense RNA and its potential as a therapeutic target.”
(Source: health.ucsd.edu)
Improved Detection of Frontotemporal Degeneration May Aid Clinical Trial Efforts
A series of studies demonstrate improved detection of the second most common form of dementia, providing diagnostic specificity that clears the way for refined clinical trials testing targeted treatments. The new research is being presented by experts from the Perelman School of Medicine at the University of Pennsylvania at the American Academy of Neurology’s 65th Annual Meeting in San Diego March 16-23, 2013.
Frontotemporal degeneration, the most common dementia in people under 60, can be hereditary or sporadic in nature and caused by one of two different mutated proteins (tau or TDP-43). The disease results in damage to the anterior temporal and/or frontal lobes of the brain. As the disease progresses, it becomes increasingly difficult for people to plan or organize activities, behave appropriately in social or work settings, interact with others, and care for oneself, resulting in increasing dependency.
In one study, the team confirmed that a novel multimodal imaging approach was more accurate (88 percent) than using either MRI (72 percent) or DTI (81 percent) alone to detect FTD versus Alzheimer’s disease. The two imaging techniques integrate measures of white matter and grey matter, providing a statistically powerful method for predicting underlying pathology in order to screen patients for clinical trials.
“We are moving forward on our biomarker work to optimize our ability to identify the specific cause of an individual’s difficulties during life, said senior author Murray Grossman, MD, EdD, professor of Neurology and director of the Penn FTLD Center. “We use a novel multi-modality approach involving behavioral, imaging and biofluid biomarker measures.”
In a second study, researchers found that a brief series of neuropsychological tests of memory, word generation and conceptual flexibility (needed for creative problem-solving) helped differentiate people with very mild behavioral variant FTD (bvFTD) and those with mild cognitive impairment (MCI). The combination of tests correctly classified 85.7 percent of bvFTD cases and 83.3 percent of MCI cases at early stages of disease.
“This is particularly important because treatment trials with disease-modifying agents are emerging, often based on animal studies, yet we still don’t have all the tools we need to identify who is most appropriate to participate in one of these trials. Moreover, we can use this information we ascertain to help determine who is responding to a treatment in a clinical trial.”
The third study being presented at the meeting showed that hereditary forms of FTD appear to have more rapid cognitive decline and differing tau profiles compared with sporadic forms of the disease. For clinical trials testing whether a drug can delay damage caused by tau, any known differences in the speed of disease progression could interfere with trial results.
(Image courtesy: University of Pennsylvania)