The Whole C9 Yards Explore our 2014 timeline to learn more about emerging strategies to diagnose and treat C9 ALS.
Since the discovery of C9orf72 in 2012, the most common form of sporadic and familial ALS identified to date, potential underlying mechanisms are unraveling at a rapid pace. And, potential strategies to diagnose and treat this form of the disease are beginning to emerge.
In just the last two years alone, a genetic test for C9orf72 ALS (C9 ALS) entered the clinic.
A PET imaging technique, developed by Katholieke Universiteit Leuven’s Koen Van Laere MD PhD and Università di Torino’s Adriano Chiò MD, emerged – opening the door to predicting the outcome of people with C9 ALS. An MRI method, developed by Trinity College Dublin’s Peter Bede MD, which aims to help anticipate cognitive challenges, surfaced. And, a new map charting the spread of C9 ALS created by the research teams of Universitätsklinikum Ulm’s Heiko Braak MD and University of Pennsylvania’s John Trojanowski MD PhD may help clinicians in the future predict the course of their patients' disease.
In addition, the first genetic modifier of C9 ALS, TMEM 106B, was discovered – paving the way toward a genetic test for C9 ALS-FTD.
“This is one of the first modifiers that could really explain why some people get ALS and FTD,” says Mayo Clinic’s Rosa Rademakers PhD.
All about RNA?
A potential antisense therapy, which aims to reduce levels of possibly toxic repeat-rich C9 RNAs, is in the preclinical stage. And, an initiative to discover RNA-targeted small molecules led by Scripps Institute’s Matthew Disney PhD launched.
Don't repeat that Nearly 40% of inherited cases of ALS appear to be caused, at least in part, by expanded repeat sequences in the C9orf72 gene. Image: Courtesy of Nature Publishing Group.
Key questions remain. Expanded C9 RNAs appear to make motor neurons more vulnerable to ALS according to studies led by Jeff Rothstein MD PhD. But whether the reduction of these RNAs alone is sufficient to treat people with C9 ALS remains an open question.
Toxic proteins also may contribute to the destruction of motor neurons according to studies led by Ludwig Maximilians Universität München’s Christian Haass PhD and Mayo Clinic’s Len Petrucelli PhD. And, according to studies led by La Trobe University’s Julie Atkin PhD, the reduction of C9orf72 protein, may in part make the removal of misfolded proteins more difficult – further contributing to the disease.
What’s more, existing mouse models of the disease do not appear to exhibit key symptoms of ALS according to University of Massachusetts’ Bob Brown MD PhD– making the development of potential therapies challenging.
"It is important to keep striving for models that actually recaptiulate the pathology, because then you start to learn which pieces of the C9 puzzle actually lead to the disease," says ALS Therapy Development Institute's Fernando Vieira MD.
Testing the limits
The utility of genetic tests also remains limited.
People at high risk of developing C9 ALS can be detected by existing methods. But identifying people who will develop the disease remains tricky to do.
The reason, at least in part, is that C9 ALS appears to be one of a growing number of forms of ALS that may be oligogenic in nature. Multiple mutations in multiple genes may contribute to the onset and progression of the disease.
Standardized tests? Existing blood tests help identify people with C9 ALS by detecting expanded repeat-rich RNAs. But according to a study led by University of Umeå's Peter Andersen MD, nearly 8% of people may diagnosed incorrectly due to a lack of testing standards. Image: Courtesy of Nature Publishing Group.
An alteration in at least one other gene linked to ALS can be detected in people with C9 ALS - at least in some cases according to results from Marka Blitterswijk MD PhD, now at Mayo Clinic in Florida.
“It is probably the tip of the iceberg,” says University of Massachusetts’ Bob Brown MD PhD. “It is clear that we can find more than one variant in a person with ALS.”
What’s more, existing genetic tests only help identify people with C9 ALS. The size of the expanded RNA – at least in key cells isolated from the blood and the skin – do not appear to correlate with the progression rate of their disease.
“There is little we can do with repeat length to predict clinical outcome,” says Rosa Rademakers PhD.
To learn more about C9orf72 ALS, check out ALS Antisense and Sensibility. To find out more about emerging diagnostic strategies for the disease, check out C9 Comes Into Focus.
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van Blitterswijk, M. et al. (2014) TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. Acta Neuropathologica 127(3), 397-406. Abstract | Full Text (Subscription Required)
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