ALS Research Journal News - June 2012

This summary includes some of the most recent advances in ALS research.  If you would like certain news items featured, or have questions, please contact researchgrants@alsa-national.org.

Clinical Updates:

Single Dose of Muscle Activator CK-2017357 Is Safe and Effective for ALS

A single dose of a drug that helps muscles deliver more power with each contraction is safe and effective in ALS. The drug does not alter the course of the disease but may help patients retain function longer, if it can be shown to be safe and effective when administered for longer periods of time.

The drug, called CK-2017357, helps muscles release more calcium during contraction. Calcium is needed by muscle proteins to pull past each other, which is the basis for contraction. The drug is most effective in the mid-range of a muscle’s power, rather than at the upper end, when all available calcium is already being used. Most daily activities, such as reaching and grasping, use mid-range power, suggesting this treatment may benefit daily function.

In this trial, 67 ALS patients received single doses of placebo, low-dose drug, or high-dose drug, given in random order separated by one week. Improvements on the drug were seen with maximal voluntary ventilation, submaximal handgrip endurance, and the global impression of change, as reported by both patients and physicians. Dizziness and general fatigue were the most common adverse events.

“Further studies are underway to determine the repeat-dose safety and tolerability of CK-2017357 and to establish appropriate dosing regimens for future efficacy studies,” the authors state. “Only larger, longer randomized clinical trials will determine whether the signals seen with administration of CK-2017357 in the current study will translate into a meaningful improvement in the functional abilities of ALS patients.”

Shefner J, Cedarbaum JM, Cudkowicz ME, Maragakis N, Lee J, Jones D, Watson ML, Mahoney K, Chen M, Saikali K, Mao J, Russell AJ, Hansen RL, Malik F, Wolff AA. Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis 2012 May 16. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/22591195

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Stem Cell Transplantation Can Be Performed Safely in ALS

Human spinal cord-derived stem cells (HSSCs) can be safely injected into the spinal cord of ALS patients, according to a new proof-of-principle study in a small number of patients. The cells were derived from human fetuses, allowed to multiply in cell culture, and then purified before injection. Because this was a safety study only, the initial group of patients enrolled were those already unable to walk (and were therefore least likely to lose function due to adverse effects of the surgery or treatment). After the treatment proved safe in that group, patients who could still walk were eligible to enroll. A total of 12 patients received cell injections along with immunosuppressant drugs to prevent immune rejection. No serious adverse events were observed related to the cells themselves although the surgical procedure did cause a small number of adverse events. Over the course of follow-up, ranging from 6 to 18 months, there was no evidence that treatment caused an acceleration of disease progression. While one patient improved after surgery, the trial was not large enough to allow any conclusions to be drawn regarding the potential for beneficial effects. “Based on these positive results, we can now advance this trial by testing intraspinal injections into the cervical spinal cord with the goal of protecting motor neuron pools affecting respiratory function, which may prolong life for patients with ALS,” the authors concluded.

Glass JD, Boulis NM, Johe K, Rutkove SB, Federici T, Polak M, Kelly C, Feldman EL. Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients. Stem Cells. 2012 Jun; 30(6):1144-51. doi: 10.1002/stem.1079.
http://www.ncbi.nlm.nih.gov/pubmed/22415942

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Review: How Effective is Diaphragm Pacing in ALS?

In 2011, The United States Food and Drug Administration approved a diaphragm pacing system for use in ALS patients. This system implants electrodes into the diaphragm, the breathing muscle used to inflate the lungs. The electrodes are powered by an implanted stimulator and controlled by an external controller. The system approved in ALS is similar to one used in spinal cord injury. The goal of the treatment is to replace invasive positive pressure ventilation in patients who require ventilatory help. In this article, the authors review the literature on diaphragm pacing in ALS. There have been few trials, and none that were double-blind or randomized. In addition, the trials have been in select groups of patients, and the results may not therefore be generalizable to the larger ALS population. Also, the authors note, the progression of ALS and the atrophy of the diaphragm raise the question of the long-term safety of metal electrodes implanted in this muscle.

“Based on the data available,” they conclude, “the [diaphragm pacing] system seems reasonably safe short term in carefully selected ALS patients with strict inclusion/exclusion
criteria. We found no information on long-term safety….Due to the progressive nature
of ALS and progressive denervation atrophy, long-term safety data from [spinal cord injury] patients is not translatable to ALS.” Further studies of diaphragm pacing in ALS patients are currently being planned.

Scherer K, Bedlack RS. Diaphragm pacing in amyotrophic lateral sclerosis: A literature review. Muscle Nerve. 2012 Jul; 46(1):1-8
http://www.ncbi.nlm.nih.gov/pubmed/22692995
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Research Highlights

C9ORF72: Clinical and Neuroimaging Features Emerge

A group of new studies examines the spectrum of clinical symptoms and pathological changes caused by the C9ORF72 gene expansion. In the study of Boeve et al. of 53 gene-positive subjects, 16% were sporadic cases, meaning there was no apparent family history of ALS or FTD. The age of onset ranged from 33 to 72 years with survival ranging from one to 17 years. Within families with multiple generations affected, younger generations often had earlier onset than the parents (a phenomenon called anticipation). Anticipation was also found by Chio et al. in their study of 182 subjects with the mutation. Parkinsonism (slowed movements, tremor, and/or rigidity) is beginning to be recognized as a potential feature of C9-caused ALS-FTD and was seen in a third of patients in the Boeve study. Two other studies described changes in the brain seen with neuroimaging or microscopy. The pattern of brain atrophy seen in C9 FTD patients differed from that in patients with FTD due to other gene mutations, suggesting that “imaging has the potential to be useful to help differentiate C9ORF72 from these other groups at the single-subject level,” according to Whitwell et al.

Mahoney CJ, Beck J, Rohrer JD, Lashley T, Mok K, Shakespeare T, Yeatman T, Warrington EK, Schott JM, Fox NC, Rossor MN, Hardy J, Collinge J, Revesz T, Mead S, Warren JD. Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain. 2012 Mar; 135(Pt 3):736-50.
http://www.ncbi.nlm.nih.gov/pubmed/22366791

Whitwell JL, Weigand SD, Boeve BF, Senjem ML, Gunter JL, DeJesus-Hernandez M, Rutherford NJ, Baker M, Knopman DS, Wszolek ZK, Parisi JE, Dickson DW, Petersen RC, Rademakers R, Jack CR Jr, Josephs KA. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain. 2012 Mar; 135(Pt 3):794-806. PubMed PMID: 22366795; PubMed Central PMCID: PMC3286334.
http://www.ncbi.nlm.nih.gov/pubmed/22366795

Boeve BF, Boylan KB, Graff-Radford NR, DeJesus-Hernandez M, Knopman DS, Pedraza O, Vemuri P, Jones D, Lowe V, Murray ME, Dickson DW, Josephs KA, Rush BK, Machulda MM, Fields JA, Ferman TJ, Baker M, Rutherford NJ, Adamson J, Wszolek ZK, Adeli A, Savica R, Boot B, Kuntz KM, Gavrilova R, Reeves A, Whitwell J, Kantarci K, Jack CR Jr, Parisi JE, Lucas JA, Petersen RC, Rademakers R. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain. 2012 Mar;135(Pt 3):765-83. PubMed  PMID: 22366793; PubMed Central PMCID: PMC3286335.
http://www.ncbi.nlm.nih.gov/pubmed/22366793

Chiò A, Borghero G, Restagno G, Mora G, Drepper C, Traynor BJ, Sendtner M, Brunetti M, Ossola I, Calvo A, Pugliatti M, Sotgiu MA, Murru MR, Marrosu MG, Marrosu F, Marinou K, Mandrioli J, Sola P, Caponnetto C, Mancardi G, Mandich P, La Bella V, Spataro R, Conte A, Monsurrò MR, Tedeschi G, Pisano F, Bartolomei I, Salvi F, Lauria Pinter G, Simone I, Logroscino G, Gambardella A, Quattrone A, Lunetta C, Volanti P, Zollino M, Penco S, Battistini S; ITALSGEN consortium, Renton AE, Majounie E, Abramzon Y, Conforti FL, Giannini F, Corbo M, Sabatelli M. Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. Brain. 2012 Mar;135(Pt 3):784-93. PubMed PMID: 22366794; PubMed Central PMCID: PMC3286333.
http://www.ncbi.nlm.nih.gov/pubmed/22418734

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The C9ORF72 Gene May Cause Atypical Symptoms

The clinical features of ALS-FTD due to the C9ORF72 expansion may include symptoms associated with at least three other neurodegenerative diseases, broadening the clinical spectrum associated with the gene mutation. Of 280 patients with a diagnosis of a dementing illness and no previously identified genetic cause, including 73 with a diagnosis of frontotemporal dementia, 14 had expansions in the C9ORF72 gene. Three of these patients had clinical features beyond those of FTD or ALS, including dystonia (involuntary, uncontrolled movements and postures) autonomic dysfunction (urinary incontinence, profuse sweating), and/or speech difficulties, among other symptoms. All patients were tested for mutations in the ataxin-2 gene; none were found. “Our study widens the clinical spectrum of C9ORF72 related disease,” the authors conclude.

Lindquist S, Duno M, Batbayli M, Puschmann A, Braendgaard H, Mardosiene S, Svenstrup K, Pinborg L, Vestergaard K, Hjermind L, Stokholm J, Andersen B, Johannsen P, Nielsen J. Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease. Clin Genet. 2012 May 31; 9999(999A). doi: 10.1111/j.1399-0004.2012.01903.x. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/22650353

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Some ALS Cases Are Due to Multiple Genes

In some cases of ALS, more than one gene may be to blame, according to a new study. Researchers searched for mutations in known ALS genes in 111 patients with familial ALS and large numbers of sporadic ALS patients and unaffected controls. They found mutations in 48% of familial cases, 8% of sporadic cases, and 0.5% of controls. In five families, they found multiple mutations, more than would be expected by chance. The combinations detected included C9ORF72 plus TARDBP, FUS, or SOD1, and angiogenin mutations plus TARDBP or FUS. “This may have important implications for the interpretation of whole exome/genome experiments designed to identify new ALS-associated genes and for genetic counseling, especially of unaffected family members,” the authors said.

van Blitterswijk M, van Es MA, Hennekam EA, Dooijes D, van Rheenen W, Medic J, Bourque PR, Schelhaas HJ, van der Kooi AJ, de Visser M, de Bakker PI, Veldink JH, van den Berg LH. Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Hum Mol Genet. 2012 Jun 16. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/22645277
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Ubiquilin-2 Not Found in The Netherlands

The recently discovered ubiquilin-2 (UBQLN2) gene is a rare cause of ALS, carried on the X chromosome. Researchers in The Netherlands examined 92 families with ALS but found no mutations in the UBQLN2 gene, indicating that this gene is not widespread among all populations with ALS but more likely is found in some populations but not others.

van Doormaal PT, van Rheenen W, van Blitterswijk M, Schellevis RD, Schelhaas HJ, de Visser M, van der Kooi AJ, Veldink JH, van den Berg LH. UBQLN2 in familial amyotrophic lateral sclerosis in the Netherlands. Neurobiol Aging. 2012 Jun 5. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/22676852

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Reviews: Understanding How FUS and TDP-43 Mutations Cause ALS

Several new review articles survey the contributions of the FUS and TDP-43 gene mutations to ALS and outline the wide range of studies that inform the current state of knowledge about each gene’s role in both health and disease.

Both FUS and TDP-43 are RNA binding proteins and are normally found largely in the cell’s nucleus. Mutations that lead to ALS cause the protein to be mis-localized to the cytoplasm. Almost all mutations in each gene cause a dominantly inherited disease, meaning only one gene copy (rather than two) is needed. This suggests the mutant takes on some new, toxic role (gain of function) rather than simply being nonfunctional (loss of function). However, a loss of function is possible, if, as some researchers suspect, depletion of normal TDP-43 leaves the cell unable to carry out vital tasks.

Mutant proteins are found in the protein aggregates that occur in most forms of ALS, including sporadic disease, but not in most ALS cases caused by SOD1 mutations (I just read a Neurology article where they describe TDP43 mutations in a rare SOD1 mutant ALS patient). Why they occur in aggregates, and why SOD1 ALS differs in this regard, is unknown. A variety of animal models is being used to explore the basic biology of each protein, both normal and mutant forms. Hypotheses of disease mechanism include the possibility that mutant protein alters the production, editing, transport, and/or expression of multiple different messenger RNAs, the intermediary between genes and the proteins they encode.

The discovery of these two genes has strengthened the case that abnormalities in handling RNA may be central to development of ALS. That hypothesis has been strengthened by the more recent discovery of the C9ORF72 gene, which, when mutated, created large amounts of excess RNA, possibly leading to its accumulation.

One possible aspect of disease pathogenesis may be that mutant protein takes on an abnormal conformation (shape), which then induces other molecules of the same protein to do the same. Proteins that spread disease through this templating process are broadly termed “prion-like proteins.” There is increasing evidence that a prion-like process may be involved in a large number of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and possibly ALS.


1. King OD, Gitler AD, Shorter J. The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res. 2012 Jun 26; 1462:61-80.
http://www.ncbi.nlm.nih.gov/pubmed/22445064

2. Lanson NA Jr, Pandey UB. FUS-related proteinopathies: Lessons from animal models. Brain Res. 2012 Jun 26; 1462:44-60.
http://www.ncbi.nlm.nih.gov/pubmed/22342159

3. Tsao W, Jeong YH, Lin S, Ling J, Price DL, Chiang PM, Wong PC. Rodent models of TDP-43: Recent advances. Brain Res. 2012 Jun 26; 1462:26-39.
http://www.ncbi.nlm.nih.gov/pubmed/22608070

4. Xu Z. Does a loss of TDP-43 function cause neurodegeneration? Mol Neurodegener. 2012 Jun 14; 7(1):27.
http://www.ncbi.nlm.nih.gov/pubmed/22697423

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Axonal “Death Program” Can Be Interrupted, Protecting Injured Axons

Axons are the long extensions of neurons that link up to other neurons or to muscles. In neurons that are injured, axons degenerate in a characteristic way, called Wallerian degeneration. It had long been thought that this process was a passive one, not requiring genetic instructions from the neuron. Researchers have now shown that, on the contrary, Wallerian degeneration is an active process and can be blocked by disabling a protein called Sarm1. When the action of Sarm1 is blocked, axons severed from the rest of the cell remained intact for weeks after degeneration of severed axons in which Sarm1 was active.

The results from this study are potentially relevant to ALS since motor neuron axons begin to degenerate even while the cell bodies of those neurons remain alive. If it can be shown that blocking Sarm1 in models of ALS improves function or survival, it may represent a new avenue of treatment for the disease.

Osterloh JM, Yang J, Rooney TM, Fox AN, Adalbert R, Powell EH, Sheehan AE, Avery MA, Hackett R, Logan MA, Macdonald JM, Ziegenfuss JS, Milde S, Hou YJ, Nathan C, Ding A, Brown RH Jr, Conforti L, Coleman M, Tessier-Lavigne M, Züchner S, Freeman MR. dSarm/Sarm1 Is Required for Activation of an Injury-Induced Axon Death Pathway. Science. 2012 Jun 7. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/22678360