Categories: In Translation

Masitinib Phase 3 Clinical Trial Update

clock January 15, 2015

It was recently announced via press release from AB Science that their drug masitinib will continue to be trialed in ALS.  Currently, more than 200 people are enrolled in the trial, which is taking place in a single center in Spain. The announcement comes as a result of the trial’s Data and Safety Monitoring Board recommendation for the continuation of the study.  This is not uncommon.  It is one of the jobs of this board to review data continuously throughout the trial and to make a recommendation for its continuation or cancellation based on that data. This announcement should not be interpreted as any indication that masitinib is effecting ALS disease progression in either a positive or negative way. It should only be considered a sign that the Board believes that the trial should continue.

What is Masitinib?

Masitinib aims to slow progression of ALS by reducing inflammation. A kinase inhibitor, masitinib blocks mast cell-mediated degranulation, the release of cytotoxic substances that might further damage the motor nerves. Marketed by AB Science under the name Kinavet, masitinib is currently being used to treat certain cancers in dogs.  It is important to note that masitinib is also in a large Phase 2b/3 clinical trial for Multiple Sclerosis.

What preclinical evidence is there for Masitinib?

There have been preclinical experiments on masitinib reported, however ALSTDI has not sought to independently reproduce those findings. There were some challenges with the preclinical reports, including that at least one of the studies was done in female mice alone.  The full data sets on these preclinical experiments haven’t been published, so it is challenging to comment fully on them.

Helpful Links 

FMI about Masitinib: http://www.als.net/ALS-Research/128/ALS-Topics/

FMI about the Clinical Trial: http://www.als.net/ALS-Research/174/ClinicalTrials/

Click Here to Read the Press Release from AB Science

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Categories: In Translation

Weighing in on the high fat diet in ALS

clock March 28, 2014

 

Fuel up Calorie rich diets including a high fat and a ketogenic diet may help people fight a growing number of diseases. But only a high calorie high carbohydrate diet (30% fat; 54% carbohydrate; 17% protein) appears to be safe and well tolerated by people with ALS - at least in later stages of disease according to a new study led by Massachusetts General Hospital neurologist Anne-Marie Wills MD MPH. Image: Purplemattfish, Flickr.

Eating right helps keep us healthy. But for people with ALS, this can be difficult to do. 

About 2 out of 3 people with ALS by some estimates burn calories too quickly. And, according to University of Kentucky’s Ed Kasarskis MD PhD, most of them do not eat enough food to meet their recommended daily allowance.

A growing number of clinicians suspect that a high calorie diet implemented early in their disease may help people with ALS meet their increased energy needs.  And, extend their survival.

Maintaining or slightly exceeding their recommended calorie intake may extend life for people with ALS.

People with ALS who are slightly overweight (BMI: 30 – 35 m/kg2) appear to progress more slowly according to a retrospective analysis led by Massachusetts General Hospital neurologist Anne-Marie Wills MD MPH.  And, people with ALS that lose no more than 5% of their body weight at diagnosis live about 9 months longer according to studies led by nutrition specialist Jean-Claude Desport MD and neuroepidemiologist Phillipe Couratier MD PhD of Université de Limoges.

What’s more, people with ALS who do not eat enough appear to die more quickly from the disease.

But how to increase calorie intake remains an open question. Many people with ALS have trouble swallowing (dysphagia). And, lose weight rapidly due to muscle atrophy and disuse.

Certain high calorie supplements appear to be safe and well tolerated by people with ALS according to studies led by Universitätsklinikum Ulm's Albert Ludolph MD. And, appear to stabilize body weight within 3 months.

At Massachusetts General Hospital in Boston, Anne-Marie Wills MD MPH weighs in on nutrition for people with ALS.  And, key challenges implementing such nutritional changes into general practice.

 

 

What is a calorie-rich diet? Massachusetts General Hospital neurologist Anne-Marie Wills MD MPH explains. Image: Brian Talbot, Flickr.

Patient Resources

High Fat/High Calorie Trial in Amyotrophic Lateral Sclerosis (Completed)  ALS TDI  |  Website

Safety and Tolerability of Ketogenic Diet in Amyotrophic Lateral Sclerosis (Terminated)  ALS TDI  |  Website

Quantitative Measurement of Nutritional Substrate Utilization in Patients with Amyotrophic Lateral Sclerosis  Contact  |  ALS TDI  |  Website

References

Wills, A.M. et al. (2014) Hypercaloric enteral nutrition in patients with ALS: a randomised, double-blind, placebo-controlled phase 2 trial.  Lancet doi: 10.1016/S0140-6736(14)60222-1. Abstract  |  Full Text  (Subscription Required)

Dorst, J., Cypionka, J. and Ludolph, A.C. (2013)  High-caloric food supplements in the treatment of amyotrophic lateral sclerosis: A prospective interventional study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 14(7-8), 533-536.  Abstract  |  Full Text  (Subscription Required)

Paganoni, S., Deng, J., Jaffa, M., Cudkowicz, M.E. and Wills, A.M. (2011) Body mass index, not dyslipidemia, is an independent predictor of survival in amyotrophic lateral sclerosis. Muscle and Nerve 44(1), 20-24.  Abstract |  Full Text (Subscription Required)

Marin, B., Desport, J.C., Kajeu, P., Jesus, P., Nicolaud, B., Nicol, M., Preux, P.M. and Couratier, P. (2011) Alteration of nutritional status at diagnosis is a prognostic factor for survival of amyotrophic lateral sclerosis patients.  Journal of Neurology, Neurosurgery and Psychiatry 82(6), 628-634.  Abstract  |  Full Text  (Subscription Required)

Bouteloup, C., Desport, J.C., Clavelou, P., Guy, N., Derumeaux-Burel, H., Ferrier, A. and Couratier P. (2009)  Hypermetabolism in ALS patients: an early and persistent phenomenon.  Journal of Neurology 256(8), 1236-1242.  Abstract  |  Full Text  (Subscription Required)

Desport, J.C., Torny, F., Lacoste, M., Preux, P.M. and Couratier, P. (1999) Hypermetabolism in ALS: correlation with clinical and paraclinical parameters.  Neurodegenerative Diseases 2(3-4), 202-207.  Abstract  |  Full Text (Subscription Required)

Desport, J.C., Preux, P.M., Truong, T.C., Vallat, J.M., Sautereau, D. and Couratier, P. (1999) Nutritional status is a prognostic factor for survival in ALS patients.  Neurology 53(5), 1059-1063.  Abstract  |  Full Text (Subscription Required)

Kasarskis, E.J., Berryman, S., Vanderleest, J.G., Schneider, A.R. and McClain, C.J. (1996)  Nutritional status of patients with amyotrophic lateral sclerosis: relation to the proximity of death. American Journal of Clinical Nutrition 63(1), 130-137.  Abstract  |  Full Text

Further Reading

Al-Chalabi, A. (2014) High-calorie diets in ALS. Lancet doi:10.1016/S0140-6736(14)60270-1.  Abstract   (Subscription Required)

Paganoni, S. and Wills, A.M. (2013) High-fat and ketogenic diets in amyotrophic lateral sclerosis.  Journal of Child Neurology 23(8), 989-992.  Abstract  |  Full Text  (Subscription Required)

Dupuis, L., Pradat, P.F., Ludolph, A.C. and Loeffler, J.P. (2011)  Energy metabolism in ALS. (2011) Lancet Neurology 10(1), 75-82.  Abstract  |  Full text  (Subscription Required)

 

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Categories: Featured , In Translation

Breaking the ultrasound barrier in ALS

clock August 26, 2013

neuromuscular ultrasound NMUS ALS MND

 

Sounding out NMJs A growing number of neurologists are looking to ultrasound  in hopes to deduce the integrity of muscle-nerve connections. Image: Georgia Institute of Technology.

More than 30 potential ALS medicines are being tested in the clinic.  But many people do not have access to them – waiting instead for a definitive diagnosis of disease.

A growing group of neurologists hopes to change that by turning to electrophysiological methods including electromyography (EMG) to check for subclinical signs of ALS. 

The strategy, based on “Awaji criteria”, helps clinicians solidify the diagnosis of ALS by checking the muscles for twitches (fasciculations) – an early sign of the disease. The technique by some estimates might increase the number of people eligible for clinical trials by 25%.

But checking muscles by EMG can hurt.  And, the test can sometimes miss key signs of disease.

Some clinicians suspect that ultrasound can enable them to peer into the muscles of people with suspected ALS. And, confirm whether their patients have the disease. 

The non-invasive technique, known as neuromuscular ultrasound (NMUS), might identify key signs of ALS in the muscles and motor nerves.  And, check if the muscles contract properly - without the pain of EMG.

A clinical trial at Duke University School of Medicine is now ongoing.

"We are trying to see how the two compare - to see how good ultrasound might be diagnostically," says principal investigator Lisa Hobson-Webb MD.

Pumping up ALS diagnosis

Wake Forest University School of Medicine neurologist Francis Walker MD turned to NMUS in the 1980s in hopes to better diagnose neuromuscular disease. The technique, he reasoned, could enable clinicians to evaluate larger areas of muscles for signs of atrophy and weakness.  And, check their function.

EMG electromyography ALS MND

 

Spacing the needles Clinicians hope to reduce the number of muscles that need to be tested by electromyography (EMG) by checking first via NMUS for key signs of disease. Image: Joe Stevens, Gruenrekorder.

Reporting in 1990, he found that NMUS appeared to outperform EMG in identifying fasciculations in people with diseases neuromuscular in nature – including 2 people with ALS. 

The technique according to more recent studies led by Chiba University Hospital neurologist Satoshi Kuwabara MD appears to detect twitches in 98% of people with ALS – 10% more than EMG.

What’s more, NMUS appears to enable clinicians to diagnose more people suspected to have the disease.  Nearly 80% of people were diagnosed with either probable or definite ALS  – twice the number identified via El Escorial criteria using conventional methods. And, 5% more via Awaji criteria using EMG.

The results suggest that NMUS may enable more people to be diagnosed – enabling them to participate in clinical trials of medicines earlier in their course of disease.

Getting the nerve

With the advent of higher resolution ultrasound machines, clinicians began to examine the peripheral nerves of people with ALS for additional signs of the disease.

Some signs of atrophy could be detected in a key motor nerve in people with ALS according to a 2011 study led by Wake Forest’s Michael Cartwright MD. But a key sensory nerve remained unaffected. A nerve untouched by the disease.

The results suggested that tell tale changes in the size of the motor nerves alone might help identify people with ALS.

And, according to Michael Cartwright MD, also help rule out key disorders often confused with the disease. Motor nerves typically become bigger in people with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). In people with ALS, the motor nerves slightly shrink.

Now, Duke University School of Medicine clinicians are putting NMUS to the test to determine whether the technique can be used to identify people with ALS - strongly suspected to have the disease. Muscles in the arms, legs and tongue will be checked for signs of atrophy and weakness (increased fibrosis). And, the nerves in the arms and legs will be checked for signs of axonal damage (reduced size).

All participants will be examined by NMUS on a periodic basis for one year to determine if these signs can also be used to monitor the disease.

“I think the bigger promise in ultrasound is in clinical trials. I think it could really help in clinical trial design,” says Duke University School of Medicine’s Lisa Hobson-Webb MD.

A clinical trial is ongoing. The study is in collaboration with neurologist Rick Bedlack MD, Director of the Duke ALS Clinic.  50 people with suspected ALS are expected to participate.

A brighter future

neuromuscular ultrasound NMUS DMD

 

And the muscles echoed Clinicians look at muscles by NMUS for signs of fibrosis (bright speckles) – a key contributor of muscle weakness. Here, ultrasounds of leg muscles of a healthy person (A) and a person with Duchenne muscular dystrophy are shown. Image: Sigrid Pillen MD, UMC St Radboud Medical Centre, The Netherlands. Courtesy of PAGE Press.

UMC St Radboud University Nijmegen Medical Centre neurophysiologist Sigrid Pillen MD PhD turned to NMUS in the early 2000s to help identify young people with neuromuscular disease.  Her strategy, which involved looking for changes in muscle architecture, appeared to help identify children with key neuromuscular disorders including Spinal Muscular Atrophy and Friedrich’s Ataxia.  And, distinguish them from those with other muscle or nerve diseases (myopathies or neuropathies) at about 90% accuracy.

UMC St Radboud neurologists suspected that these same techniques could be used to improve the diagnosis of ALS.  Reporting in 2008, the clinicians found that NMUS appears to identify key signs of muscle atrophy and weakness (increased fibrosis). And, spot twitches in most people with ALS - confirming observations by Wake Forest University School of Medicine's Francis Walker MD.

In 2012, the team proposed a new strategy to increase the certainty of diagnosis of ALS.  The plan: identify fasciculations in at least four muscles.  And, increased fibrosis (muscle echogenicity) in two muscles.  The technique appears to identify people with ALS at about 96% accuracy.   And, rule out ALS, 84%.

Now, a growing number of neurophysiologists are using combined methods to identify people with ALS.  The strategy reduces the number of muscles that need to be checked using electrophysiological methods – including EMG.  EMG however is still needed according to Wake Forest School of Medicine's Michael Cartwright MD to determine whether the condition is primarily a nerve disease.

“We use ultrasound to increase the certainty of diagnosis.  And, exclude other disorders,” explains Wake Forest School of Medicine’s Michael Cartwright MD.

diaphragm pacing DPS ALS MND

 

Setting the pace? In future, clinicians hope to use NMUS to evaluate the diaphragm in people with ALS – reducing the testing needed to determine whether the NeuRx DPS might be of benefit to them. 

But whether NMUS alone can be used to increase the certainty of ALS diagnosis remains an open question according to Hannover Medical School's Reinhard Dengler MD.

NMUS may be able to distinguish people with ALS from other outwardly similar disorders including hereditary spastic paraparesis (HSP) according to a study led by UMC St Radboud's Jurgen Schelhaas MD.  But other conditions including Kennedy’s disease and multifocal motor neuropathy (MMN) remain untested.  Key disorders often confused with the disease.

And, the tests need to be standardized according to Duke University School of Medicine's Lisa Hobson-Webb MD. Sonographers can spot changes in the size of muscles.  But estimating the degree of fibrosis (muscle echogenicity) is trickier.  The measures can differ from person to person. And, machine to machine.

Multi-center trials are needed to rigorously evaluate NMUS in the ALS clinic. And, to develop standardized guidelines to implement NMUS in general practice.

Clinicians nevertheless remain confident that the technology holds great benefit for people with ALS.

"Ultrasound could be an excellent tool to reduce invasive testing," says Duke University School of Medicine's Lisa Hobson-Webb MD, "and increase the power of clinical trials."

***

To learn more about how clinicians currently diagnose the disease, check out What is ALS?  To find out about other non-invasive strategies being developed to diagnose ALS, check out TMS, a headstart for PALS? and MRI, Make that a Double

Patient Resources

Neuromuscular ultrasound in ALS   Contact | ALS TDI | Website

Video: What to expect during a Nerve conduction study and EMG Youtube

References

Cartwright, M.S., Walker, F.O., Griffin, L.P. and Caress, J.B. (2011) Peripheral nerve and muscle ultrasound in amyotrophic lateral sclerosis. Muscle & Nerve 44(3), 346-351. Abstract | Full text

Arts, I.M., Overeem, S., Pillen, S., Schelhaas, H.J. and Zwarts, M.J. (2011) Muscle ultrasonography to predict survival in amyotrophic lateral sclerosis.  Journal of Neurology, Neurosurgery and Psychiatry 82(5), 552-554. Abstract | Full text  (Subscription Required)

Arts, I.M., van Rooij, F.G.,  Overeem, S., Pillen, S., Janssen, H.M., Schelhaas, H.J. and Zwarts, M.J. (2008) Quantitative muscle ultrasonography in amyotrophic lateral sclerosis.  Ultrasound in Medicine and Biology 34(3), 354-361. Abstract | Full text  (Subscription Required)

Further Reading

Padua, L. and Hobson-Webb, L.D (2013)  Ultrasound as the first choice for peripheral nerve imaging? Neurology 80(18), 1626-1627.  Abstract | Full text  (Subscription Required)

Hobson-Webb, L.D. (2013)  Neuromuscular ultrasound in polyneuropathies and motor neuron disease. Muscle & Nerve 47(6), 790-804.  Abstract | Full text  (Subscription Required)

Mayans, D., Cartwright, M.S. and Walker, F.O. (2012) Neuromuscular ultrasonography: quantifying muscle and nerve measurements. Physical Medicine and Rehabilitation Clinics of North America 23(1), 133-148.  Abstract | Full text

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Categories: In Translation , Postcards

TMS: a headstart for PALS?

clock June 19, 2013

NeuRX DPS diaphragm pacing ALS

 

A headstart program? Corticomotor hyperexcitability testing may help clinicans diagnose ALS earlier and develop more effective treatments for the disease.  Learn more by tuning into our Postcard from Sydney.

More than 20 potential treatments for ALS are being tested in the clinic.  But for many people with ALS, the medicines developed may be too little too late.  More than 70% of motor neurons by some estimates are lost in people with ALS one year after the first signs of muscle weakness – the time the disease often takes to be diagnosed.

A growing number of researchers are developing tools to identify people with ALS more quickly in hopes to more effectively treat their disease.  One of these techniques, called threshold tracking transcranial magnetic stimulation (TMS), enables clinicians to measure increased levels of activity of key motor neurons in the brain and spinal cord. The changes, known as corticomotor hyperexcitability, may be an early step in ALS.

The test, developed by Neuroscience Research Australia’s Steve Vucic PhD and Matthew Kiernan MBBS, PhD, DSc, FRACP, may also help clinicians identify people that will likely develop familial ALS - months before the first signs of disease.

Brainstorming ALS

In 1992, Vancouver General Hospital’s Andrew Eisen MD proposed that the overactivity of motor neurons in the brain and spinal cord could lead to ALS by contributing to their destruction.

To put Eisen’s theory to the test, Neuroscience Research Australia’s Steve Vucic PhD and Matthew Kiernan MBBS, PhD, DSc, FRACP, turned to TMS.  The technique enables researchers to measure the activity of key motor neurons by stimulating the motor cortex, the motion-enabling regions of the brain. 

 

Fire when ready  In TMS, a series of magnetic pulses is used to stimulate key circuits of the brain in order to evaluate them. The technique is currently being developed to diagnose and monitor a number of conditions including stroke. Video: Oliver Ende.

The researchers found that increased activity could be detected early in people with ALS – including C9ORF72, the most common form of the disease.  What’s more, these changes according to a small study appeared months before the clinical onset of familial ALS – at least in SOD1-linked disease. 

The results suggest that cortical hyperexcitability could be a general feature of ALS.  And, these changes could be an early sign of disease.

Furthermore, TMS appears to distinguish ALS from other outwardly similar disorders – suggesting that this technique may help diagnose people with the disease.  No significant increases in activity could be detected in people with key neuromuscular disorders often confused with ALS including multifocal motor neuropathy (MMN), spinal muscular atrophy (SMA) and Kennedy’s disease.

Now, the Neuroscience Research Australia team is working hard to bring TMS to the ALS clinic.  The test could be in ALS clinics as early as next summer.

***

To learn more about emerging tools to diagnose ALS, read Imaging ALS.  To find out about potential early treatments of ALS that may reduce hyperexcitability, check out Channeling ALS?

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Categories: In Translation

Q&A: Martin Turner, Imaging ALS

clock November 20, 2012

Martin Turner neurologist ALS MRI FLAIR fractional anistropy

Imaging ALS. Neurologist Martin Turner MA PhD FRCP is developing MRI methods to diagnose and monitor ALS. Image: Courtesy of Martin Turner MA PhD FRCP.

ALS is typically diagnosed within 12 to 14 months. But people with ALS do not have that kind of time to waste. Riluzole extends survival only 3 to 6 months. And, a growing number of clinical trials restrict participation to 24 months after the first symptoms appear - leaving people with ALS few opportunities to access potentially beneficial medicines to treat their disease.

Some neurologists suspect, however, that this diagnostic delay might be cut in half by scanning the brain by MRI and looking for tell-tale signs of ALS. Combined structural and functional MRI methods according to recent studies can help distinguish ALS patients – at least from healthy people. And, MRS-based measures of certain neuronal metabolites might help identify people with inherited forms of ALS before they exhibit the first signs of the disease.

What’s more, these techniques might help clinicians to more accurately diagnose people with ALS enabling better management of their disease. Certain structural MRI-based methods might help distinguish people with C9ORF72-linked ALS. Functional MRI measures might indicate certain cognitive challenges. And, certain structural MRI measures might help identify people with a rapidly progressing form of the disease.

ALS Today's Michelle Pflumm PhD talked to University of Oxford neurologist and neuroimaging specialist Martin Turner MA PhD FRCP at the 2012 American Neurological Association meeting to learn more about MRI and its potential for people with ALS going forward.

Can MRI be implemented today to help diagnose ALS?

We have got lots of ways to separate patients from healthy people.  But that’s not the question we’re asking in the clinic. We can see they’re not healthy.  What we want to know is whether they’ve got ALS or perhaps something else.  That’s the real question.

 

Map quest. Researchers are charting the highways in the brain of people with ALS by diffusion tensor imaging in hopes to identify differences that could be used to diagnose the disease. Video: Eleftherios Garyfallidis and Ian Nimmo-Smith BA MSc PhD, University of Cambridge.

What needs to happen to introduce these methods into the clinic?

We have the candidates.  We now need to translate them by taking people early in their workup - perhaps when they are first referred to electromyography (EMG).  Some of them will have ALS and some of them won’t.  If we scan people then, we can get a sense of how much it adds.  EMG is probably our biggest competitor in terms of making a diagnosis. That’s our benchmark.

No study to date has successfully used these methods to monitor people with ALS over the course of the disease.  Why is it so challenging?

It is what I call the inconvenient truth of ALS.  When we are studying affected patients, what we are effectively seeing is an iceberg rising up out of the water. But what lies underneath, I suspect, is many years of accumulating pathology. It’s been building up for a long long time.   I don’t think we are going to see a great change.  It is hard to detect changes in an already damaged system.

You recently kickstarted studies with University of Miami’s Michael Benatar MBChB DPhil to look for changes in people at high risk for developing inherited forms of ALS.  Why?

I think they’re the group that we need to focus on now.  There might be signatures that are much more important in terms of capturing the essence of the disease.

I think it will be possible to identify changes [in them].  In Alzheimer’s disease, we can pick up all sorts of changes in the brain 20 to 30 yrs before the disease. The bigger challenge is translating those changes to the 90% without clear genetic risk.

ALS MRS whole brain prefALS

Chemical imbalance? Researchers hope to zero in on chemical changes in certain parts of the brain using magnetic resonance spectroscopy to identify people likely to develop inherited forms of ALS and monitor their disease. Image: Govind et al. (2012), PLOS One.

Do you think these studies will nonetheless help people with the sporadic form of ALS (no family history of the disease)?

I think there is definitely great potential benefit. The biomarker signature that we find in a gene carrier without symptoms maybe what we can focus in on and look at in a patient in an early stage. This would allow potential drugs to be started sooner.

Your most recent results, presented here at ANA 12, suggest that a routine type of MRI scan called FLAIR might also be helpful in identifying people with ALS – potentially enable more routine diagnosis of the disease.  Can you tell us about that?

We find that the FLAIR signal is certainly higher in the corticospinal tract of ALS patients and even higher in PLS patients. [The technique] might be helpful in providing objective evidence of upper motor neuron involvement, a cornerstone of ALS diagnosis.

People with PLS often have to wait 4 years before being formally diagnosed.  Do you think that this technique can help speed up this process too?

Absolutely, with the caveat that it is not common.  PLS is rare.  Its only 3% of all cases. But it is important to study because it may help us understand how to slow ALS down.

What needs to happen to put these methods into practice on clinical MRI scanners?

The results are hinting that there is a lot of information encoded in a very routine scan which you can unlock using mathematical tools; software that’s been developed for non-routine scans such as diffusion tensor imaging.  The next step is to take images from a clinical MRI scanner and see whether they give the same information.

What do you think needs to happen to encourage neurologists to adopt MRI methods in general ALS practice?

What we have to show is that they have unique value – that we can get someone in a trial sooner.  I think that is pretty likely that they can deliver on that.

***

To learn more about how neurologists hope to use MRI to diagnose and monitor people with ALS, read MRI, Make That A Double. To find out how neurologists hope to use MRS to identify people with inherited forms of the disease more quickly, check out NAA MaRkS The Spot

References

Menke, R.A., Abraham, I., Thiel, C.S., Fillippini, N., Knight, S., Talbot, K. and Turner, M.R. (2011) Fractional anisotropy in the posterior imb of the internal capsule and prognosis in amyotrophic lateral sclerosis. Archives of Neurology doi:10.1001/archneurol.2012.1122. Abstract | Full Text (Subscription Required)

Douaud, G., Filippini, N., Knight, S., Talbot, K., and Turner, M.R. (2011) Integration of structural and functional magnetic resonance imaging in amyotrophic lateral sclerosis. Brain 134, 3470-3479. Abstract | Full Text (Subscription Required)

Carew J.D., Nair G., Andersen P.M, Wuu J., Gronka S., Hu X., and Benatar, M (2011). Presymptomatic spinal cord neurometabolic findings in SOD1-positive people at risk for familial ALS. Neurology 77(14), 1370-1375.  Abstract | Full Text (Subscription Required)

Filippini, N., Douaud, G., Mackay, C.E., Knight, S., Talbot, K., and Turner, M.R. (2011). Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis. Neurology, 75(18), 1645-1652.  Abstract | Full Text (Subscription Required)

Further Reading

Benatar, M. and Wuu, J. (2012). Presymptomatic studies of ALS: Rationale, challenges and approach. Neurology Abstract |  Full Text (Subscription Required)

Bowser, R., Turner, M.R., and Shefner J. (2011). Biomarkers in amyotrophic lateral sclerosis: opportunities and limitations. Nature Reviews Neurology, doi: 10.1038/nrneurol.2011.151 Abstract | Full Text (Subscription Required)

Turner, M.R. (2011). Towards a neuroimaging biomarker for ALS. Lancet Neurology10(5), 400-403. Full Text (Subscription Required)

Patient Resources

The Oxford Study for Biomarkers in MND/ALS (BioMOx).  Contact Website

The Pre-Familial Amyotrophic Lateral Sclerosis (Pre-fALS) StudyContact Website

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Categories: In Translation

Breaking the code of silence in ALS

clock February 1, 2012

 

Epigenome at a glance.  Chemical tags called epigenetic marks help control which genes are turned on and off in our tissues. Video: University of Utah, Learn Genetics.

With the discovery of nearly 20 genes linked to ALS, researchers are unraveling this complex disease at increasing speed.  But, according to recent research, there is much more than a handful of genetic errors in people with ALS that contributes to the destruction of the motor nerves.

The epigenome – the chemical tags that mark which genes are turned on and off in our tissues – is emerging as a new player in neurodegenerative diseases including ALS.  Inherently flexible, the epigenome rapidly evolves to help people adapt to a crash diet, stress or simply a change in scene. But in people with ALS, studies suggest, these changes might actually fuel the progression of the disease.

Emerging drugs that restore or remove these so-called epigenetic marks may have the potential to treat ALS.  But figuring out how to safely reset these chemical switches in motor neurons using these medicines, according to experts, may be tricky.

AcE AcE Baby 

Critical genes are switched on or off in specific tissues in part by adjusting their accessibility to the intracellular decoding machines. Known as acetylation, chromatin packing proteins called histones get pushed aside, allowing these genes to be transcribed and proteins, produced. But in people with a growing number of neurological conditions including ALS, the levels of histone acetylation drops, contributing to neurodegeneration.

HDAC acetylation epigenetics ALS

 

HDACs Crash.  Histone deacetylases (green) remove acetyl groups (red) rendering the genes unreadable by the transcriptional machinery (dark blue). Image: National Cancer Institute.

Epigenetics first grabbed neuroscientists’ attention in 2001 when University of California Irvine scientists Leslie Thompson PhD and Larry Marsh PhD reported that the loss of histone acetylation in fruit flies contributed to Huntington’s disease. The team found that the fruit flies did not produce a critical histone acetyltransferase (HAT). But treatment with histone deacetylase enzymes (HDACs) blockers to boost acetylation levels stopped the disease in its tracks.

“These results really created enormous awareness,” explained New York Burke Rehabilitation Center neurologist  Raj Ratan  MD, “that small molecule [HDAC] inhibitors that had been developed for cancer might actually have benefit for neurodegenerative diseases.”

Subsequent preclinical studies found that several compounds that broadly block HDACs appeared to slow neurodegeneration.  But researchers still remain unsure why exactly these drugs might be therapeutically beneficial. 

Scientists speculate that HDAC inhibitors may switch on the production of substances that helps nerves withstand stresses associated with these diseases.  A multi-institutional team led by Raj Ratan, for example, found in 2003 that the HDAC inhibitor trichostatin A increased the levels of acetylated transcription factor Sp1 in neurons, boosting the production of proteins that help protect them from the flood of damaging reactive oxygen species (ROS). And in 2006 and 2008, researchers from the National Institutes of Health in Washington D.C. found that HDAC inhibitors sodium phenylbutyrate, trichostatin A and valproic acid encouraged astrocytes to produce so-called neurotrophins that protected cultured neurons from destruction.

Lost In Translation

trichostatin A in ALS

 

Trichostatin A.  Researchers from University of Southern California reported in 2011 that trichostatin A could reduce motor neuron loss and extend survival of mice experiencing symptoms similar to ALS. 

Researchers first began to suspect that epigenetic changes contributed to ALS in 2003 when scientists reported that levels of a critical histone deacetlyase in mice dropped 70% primarily in degenerating motor nerves.  Subsequent preclinical studies indicated that three broad spectrum histone deacetylase inhibitors – sodium phenylbutyrate, trichostatin A, and valproic acid  – might be useful in treating ALS because treatment delayed clinical onset and/or extended survival of mouse models.  But independent research teams at ALS TDI in Massachusetts were unable to reproduce these findings for any of these medicines.  And, a phase III clinical trial of 160 ALS patients in the Netherlands found that valproic acid at least at a dose typically prescribed for epilepsy, did not appear beneficial.

A critical limitation of today’s HDAC blockers according to some experts is these drugs may simply need to be administered at too high a dose to be effective.

An estimated 3-5% of genes in people are switched on by today’s histone deacetylase inhibitors such as trichostatin A according to experts.  Many of these genes protect the motor nerves from further deterioration.  But many others likely promote their destruction.

Researchers are now working hard to develop potential medicines that block specific “classes” of histone deacetylases in hopes to identify a drug that more specifically switches on neuroprotective agents to improve the safety and tolerability of these medicines.  These include Repligen’s Class I HDAC1, HDAC2, HDAC3 and HDAC8 inhibitor RG2833 which is being developed for the treatment of Friedrich’s ataxia and GlaxoSmithKline spinoff Tempero Pharmaceuticals’ Class IIa HDAC4, HDAC5, HDAC7 and HDAC9 inhibitors, for the treatment of chronic inflammatory diseases including potentially multiple sclerosis. 

Meanwhile, researchers elsewhere are going for the gold hoping to create potential medicines that selectively block specific HDAC enzymes to treat neurological diseases.  MIT neuroscientist Li-Hui Tsai PhD, for example, hopes to create potential medicines for Alzheimer’s disease by generating compounds that specifically block HDAC2 to treat memory loss.

”I think you are really seeing the HDAC inhibitor [field] blossom,” says Ratan.

The jury is still out however whether any of these more selective drugs being developed are therapeutically beneficial in ALS. 

Despicable ME 

DNMT3a DNA methyltransferase epigenetics ALS

 

All about ME.  Researchers discovered that the DNA methyltransferase Dnmt3A may trigger the deterioration of the motor nerves. Image: Structural Genomics Consortium, University of Toronto.

Johns Hopkins neuroscientist Lee Martin PhD however, suspected that there was much more than changes in histone acetylation that occur in people with ALS.  Critical genes could also be inactivated by methylation in motor neurons by DNA methyltransferases, triggering the destruction of the motor nerves. Enzymes therefore, that could also be targeted to treat the disease.

“Seeing that there was promise in histone modifications,” explained Martin, “maybe there could also be some promise in [targeting] DNA methylation.”

To determine whether increases in methylation could also lead to ALS, Martin’s team in the late 2000s measured the amounts of DNA methyltransferases in the brain and spinal cord of patients and healthy people. The researchers found  that the levels of the two of these enzymes, Dnmt1 and Dnmt3A were significantly higher in the CNS of people with ALS, suggesting that hypermethylation of certain genes could indeed be contributing to the disease.

“There was no data to say that DNA demethylation,” however, explained Martin, “could actually cause neurodegeneration.”

So, the Johns Hopkins researchers turned to model systems. In culture, the researchers found that increased levels of Dnmt3A triggered the degeneration of mouse spinal cord motor neurons. And in mice, treatment with the DNA methyltransferase blocker RG108 protected the motor nerves nearly 100% after sustaining injury.

“It is an exciting first step,“ says Ratan. “I think this study has really implicated DNA methyltransferases in neurodegeneration in a way that no one has come close to."

defects in mitochondria may contribute to ALS

Circuit breaker.  Power plants called mitochondria (above) may breakdown in motor neurons in people with ALS due to the hypermethylation of critical genes. Image: David Furness PhD, Wellcome Trust.

Intriguingly, the Johns Hopkins team found that one of these DNA methyltransferases, Dnmt3A, was present in the right place – the nerve terminals – to potentially trigger ALS.  And, these enzymes could be found in these distal regions in mitochondria - potentially resulting in power outages, synaptic dieback and ultimately, the muscles to become unplugged.

“If we could actually show that ALS starts in the mitochondrial genomes at the nerve terminal,” says Martin, “that would be a new way of thinking.”

Now, Martin’s team is working hard to track down the genes in people with ALS that are silenced. Identifying these hypermethylated genes can give researchers a better idea of what signals could target the motor nerves for destruction, facilitating the design of better strategies to protect them in people with ALS.

But there may be no need to wait that long.  Several pre-cancer or cancer drugs that target methyltransferases are being developed or are already in the clinic. Emerging medicines that could be evaluated for the ability to slow or stop ALS.

The jury is still out whether such methylation-reducing medicines could be safe and selective enough to be useful to treat a neurodegenerative disease such as ALS.  But compared to potential medicines that target the histone deacetylases, there are considerable advantages to developing such a strategy for ALS according to Martin.

“If the changes occur at the nerve terminals at the neuromuscular junctions,” explains Martin, “we don’t have to worry about [the drug] crossing the blood brain barrier. That could not only be a new target but a new way of thinking about treating the disease.”

References

Chestnut, B.A., Chang, Q., Price, A., Lesuisse, C., Wong, M. and Martin, L.J.  (2011). Epigenetic regulation of motor neuron cell death through DNA methylation.  Journal of Neuroscience 31(46), 16619-16636. Abstract Full Text  (Subscription Required)

Del Signore, S.J., Amante, D.J., Kim, J., Stack, E.C., Goodrich, S., Cormier, K., Smith, K., Cudkowicz, M.E. and Ferrante R.J. (2009) Combined riluzole and sodium phenylbutyrate therapy in transgenic amyotrophic lateral sclerosis mice.  Amyotrophic Lateral Sclerosis 10(2), 85-94. Abstract | Full Text  

Piepers, S.,et al.(2009) Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis. Annals of Neurology 66(2), 227-234. Abstract | Full Text  (Subscription Required)

Rouaux, C., Panteleeva, I., René, F., Gonzalez de Aguilar, J.L., Echaniz-Laguna, A., Dupuis, L., Menger, Y., Boutillier, A.L. and Loeffler, J.P. (2007) Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model.  Journal of Neuroscience 27(21), 5535-5545. Abstract | Full Text

Ryu H  et al. (2003) Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway. Proceedings of the National Academy of Sciences 100(7), 4281–4286. Abstract | Full Text

Ryu, H et al. (2005) Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice. Journal of Neurochemistry 93(5), 1087-1098. Abstract | Full Text  (Subscription Required)

Scott, S. et al. (2008) Design, power, and interpretation of studies in the standard murine model of ALS. Amyotrophic Lateral Sclerosis 9(1), 4-15.  Abstract | Full Text  (Subscription Required)

Steffan JS et al. (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413(6857), 739–743. Abstract | Full Text  (Subscription Required)

Sugai F, Yamamoto Y, Miyaguchi K, Zhou Z, Sumi H, Hamasaki T, Goto M, Sakoda S. (2004) Benefit of valproic acid in suppressing disease progression of ALS model mice. European Journal of Neuroscience 20(11), 3179-3183. Abstract | Full Text  (Subscription Required)

Van Lint, C., Emiliani, S. and Verdin E (1996). The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Expression 5(4–5), 245–253. Abstract | Full Text  (Not available online)

Wu X et al. (2008) Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. International Journal of Neuropsychopharmacology 11(8):1123–1134. Abstract | Full Text

Yoo Y.E. and Ko C.P. (2011)  Treatment with trichostatin A initiated after disease onset delays disease progression and increases survival in a mouse model of amyotrophic lateral sclerosis. Experimental Neurology 231(1), 147-159.  Abstract Full Text  (Subscription Required)

Further Reading 

Fischer, A., Sananbenesi, F., Mungenast, A. and Tsai, L.H.. (2010). Targeting the correct HDAC(s) to treat cognitive disorders.  Trends in Pharmacological Sciences 31(12), 605-617. Abstract Full Text

Sleiman, S.F., Basso, M., Mahishi, L., Kozikowski, A.P., Donohoe, M.E., Langley, B. and Ratan, R.R. (2009). Putting the 'HAT' back on survival signalling: the promises and challenges of HDAC inhibition in the treatment of neurological conditions.  Expert Opinion Investigational Drugs 18(5), 573-584. Abstract Full Text

Urdinguio, R.G., Sanchez-Mut, J.V. and Esteller, M (2009).  Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurology 8(11), 1056-1072. Abstract Full Text  (Subscription Required)

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Categories: In Translation

Operation Neuroprotection

clock October 28, 2011

 

Going the distance. Motor neurons (green) innervate into the muscles of the growing mouse forelimb. Courtesy of Jeremy Dasen, PhD, New York University School of Medicine.

More than 70% of motor neurons in the spinal cord degenerate in people with ALS just one year after being diagnosed with the disease. To turn the tide of motor decline, researchers are developing stem cell-based strategies to regenerate the deteriorated motor nerves.

But some ALS experts worry that such strategies may simply take too much time to be effective.  Motor neurons could take by some estimates years to extend and plug back into muscles. The same time many people with ALS battle and ultimately die of the disease.

Researchers at Johns Hopkins School of Medicine introduced in 2008 another option. Healthy astrocytes are created in the cervical spinal cord to protect remaining motor neurons in the diaphragm from degeneration. The strategy, currently being developed in mice, is thought to work in part by reducing levels of glutamate in the central nervous system which at high levels can kill motor nerves.

Reporting in 2008, the team found that such a strategy reduced motor decline and increased survival of mice with an ALS-like disease 11%.

“We thought that it would be clinically more feasible to introduce astrocytes when compared to motor neurons and re-establishing all those neuronal connections,” explains Johns Hopkins School of Medicine neurologist Nicholas Maragakis MD

Now, the Johns Hopkins team reports that such a strategy using human astrocyte precursors appears to generate astrocytes in the cervical spinal cord but does not offer neuroprotection in ALS mice.

The study is published this month in PLoS One.

Scientists implanted healthy human astrocyte precursors into the cervical spinal cord of mice with an ALS-like disease.  The team found these cells developed into astrocytes.  But the scientists observed no difference in life expectancy.

 

Transplantation post-op. Researchers transplanted healthy human astrocyte precursors (green) which subsequently differentiated into astrocytes (red) in the spinal cord of mice with an ALS-like disease. Here, a section of the spinal cord is shown at end-stage. Adapted from Lepore, A.C. et al. (2011) PLoS One, 6(10): e25968.

The reason, suspects Maragakis, is that these transplanted cells simply did not have enough time to develop into astrocytes and protect the motor nerves from deteriorating.  The team reported as few as 50% of cells developed into astrocytes in mice at the end-stage of disease.

“Human cells mature much more slowly,” explains Maragakis.  “I think it just might take longer to get that [neuroprotective] effect.”

The team is now taking a look at mice with a more slowing progression form of an ALS-like disease to determine whether or not these strategies given enough time could protect the motor nerves from degeneration.

Looking ahead, the team hopes to develop transplantation strategies using astrocytes generated from the patients themselves to eliminate the need for immunosuppressive medications.  But the researchers caution that astrocytes created using existing reprogramming technologies may not be exactly the same as native astrocytes.  And even more importantly, re-introducing cells from people with ALS may instead contribute to the disease.

“It may be that a patient getting back his or her own cells may not be a good thing,” says Maragakis, “particularly for those with genetic forms of the disease.”

Meanwhile, researchers from BrainStorm Cell Therapeutics in Israel are developing a different strategy to prevent further deterioration of the motor nerves.  Astrocyte-like cells derived from patients’ bone marrow are genetically modified to produce substances including glial cell-derived neurotrophic factor (GDNF) which protect the motor nerves.  Called NurOwn, this strategy is currently being evaluated in Israel in an open label phase I/II trial.  First results are expected in early 2013.

References

Lepore, A.C., O'Donnell, J., Kim, A.S., Williams, T., Tuteja, A., Rao, M.S., Kelley, L.L., Campanelli, J.T., and Maragakis N.J. (2011) Human Glial-Restricted Progenitor Transplantation into Cervical Spinal Cord of the SOD1 Mouse Model of ALS. PLOS One, 6(10), e25968.  Abstract Full Text

Lepore, A.C., Rauck, B., Dejea, C., Pardo, A.C., Rao, M.S., Rothstein, J.D., and Maragakis, N.J. (2008). Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nature Neuroscience, 11(11), 1294-1301.  Abstract Full Text

Further Reading

Maragakis N.J. (2010). Stem cells for the neurologist. Amyotrophic Lateral Sclerosis, 11(5), 417-423.  Abstract Full Text (Subscription Required)

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