Categories: In The Pipeline

A new player in the ALS Q

clock October 31, 2013

astrocyte als neuroinflammation neuroprotection stem cell

 

ALS Detox? Healthy astrocytes may help keep motor neurons alive in people with ALS by detoxifying the nervous system. Image: Andrew Swift for Duke University School of Medicine.

More than 50% of motor neurons are lost by some estimates in people with ALS before the first signs of disease. To turn the tide of destruction, clinicians hope to keep existing motor neurons healthy in their patients by increasing supplies of neuroprotective substances.  But whether these strategies are helpful to people with ALS remains hotly debated.

A growing number of neurologists suspect that the introduction of healthy astrocytes might provide ‘life support’  to existing motor neurons in people with ALS.  And, protect them from destruction.

The stem cell-based strategy, known as astrocyte replacement, involves the injection of astrocyte precursors directly into the spinal cord. The transplantation-based approach according to preclinical studies may work in part by reducing the build up of potentially toxic levels of glutamate in the brain and spinal cord.

One of these potential treatments, known as Q cells, is approaching the clinic. The strategy, developed by Johns Hopkins University School of Medicine’s Nicholas Maragakis MD, is emerging as one of a growing number of potential personalized medicines that may benefit people with certain forms of sporadic and inherited disease.

At the 2013 Northeast ALS Consortium Meeting, ALS Today talked to Nicholas Maragakis MD to learn more about astrocyte replacement and its potential for people with ALS going forward.

***

To learn more about astrocyte replacement strategies being developed for people with ALS, check out our report from the 2013 meeting of the International Society for Stem Cell Research (ISSCR), ALS Stem to Stern.

Further reading

Haidet-Phillips, A.M., Gross, S.K., Williams, T., Tuteja, A., Sherman, A., Ko, M., Jeong, Y.H., Wong, P.C. and Maragakis NJ (2013) Altered astrocytic expression of TDP-43 does not influence motor neuron survival.  Experimental Neurology doi: 10.1016/j.expneurol.2013.10.004.  Abstract |  Full Text  (Subscription Required)

Serio, A. et al. (2013) Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy.  Proceedings of the National Academy of Sciences 110(12): 4697-4702.   Abstract  |  Full Text

 

 

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Categories: Meeting Report

NEALS 2013: ALS, North by Northeast

clock October 23, 2013

Northeast ALS Consortium NEALS NEALS13

More than 30 potential ALS medicines are being tested in the clinic today.  Only Sanofi's Rilutek (riluzole), however, is FDA-approved to treat ALS.  And, extends life 2-3 months.

Researchers are working hard to develop a more effective treatment for ALS.  In 2013 alone, at least 10 new therapies entered the clinic.

Clinicians gathered at the 2013 annual meeting of the Northeast ALS (NEALS) Consortium to discuss the latest potential treatment strategies for ALS and the challenges implementing them going forward.

Neuralstem

 

Stemming the ALS tide?  Neuralstem aims to stem the loss of motor neurons in people with ALS by boosting levels of neuroprotective substances. The potential therapy requires anti-rejection medicines. Video: Lane Niles PhD, Sanford-Burnham Medical Research Institute.

A phase II clinical trial of Neuralstem’s potential stem cell therapy for ALS is “now on” according to Emory University’s Jonathan Glass MD

Sites include Emory University and University of Michigan.  15 people with ALS are expected to participate.

Neural stem cells, derived from a human embryo, will be surgically introduced into the cervical (diaphragm-moving) region of the spinal cord of people with ALS in hopes to protect motor neurons needed for breathing.  At least 200,000 neural stem cells will be injected in 10 places throughout the C3 – C5 region on one or both sides of the spinal cord.

“We think the cells don’t migrate far,” explains Glass.  “We think we can cover the whole pool of motor neurons with 10 injections.”

The study aims to determine the maximum number of stem cells that can be safely administered to potentially treat ALS.

Participants will also be checked on a regular basis to look for signs of reduced decline in functional abilities including breathing.

“We think the stem cells are getting in,” says Glass.  “The question is what they are doing.”

To learn more about stem cell therapies for people with ALS and the challenges toward bringing them into the clinic, check out ISSCR 2013: ALS, Stem to Stern.

NeuRX DPS

A phase II clinical trial of Synapse Biomedical’s NeuRx diaphragm pacing system (DPS) is now underway at the State University of New York School of Medicine.

The device, developed by Case Western School of Medicine’s Ray Onders MD, aims to help people with ALS keep breathing longer by electrically conditioning the respiratory muscles.

stem cell induced pluripotent iPS ALS Neuralstem Brainstorm Q Therapeutics Corestem

 

DPS testing made easier? Neuromuscular ultrasound may soon enable clinicians to identify people with ALS eligible to receive the NeuRX DPS - without the discomfort and pain often associated with EMG and NCS.

The clinical trial aims to determine whether the NeuRx DPS improves diaphragm function of people with the ALS.

The study is to take place at 18 sites throughout the US. 180 people with ALS with breathing difficulties (FVC: 45-50%) are expected to participate.

A key goal of the clinical trial according to California Pacific Medical Center’s Jonathan Katz MD is to identify key respiratory signs (parameters) that might help clinicians identify people with ALS most likely to benefit from the procedure.

The pre-operative testing is extensive according to Duke University School of Medicine’s Rick Bedlack MD PhD. And, these tests do not necessarily reflect the ability of the respiratory muscles to be conditioned according to Cedar Sinai Medical Center’s Bob Baloh MD PhD.  About one out of every five people with ALS wakes up in the recovery room without the device because their diaphragm cannot be stimulated according to preliminary results presented by his team at NEALS 2013.

What’s more, it remains unclear from these tests which people with ALS may benefit most from the device.

But this study is easier said than done according to Katz. The NeuRx DPS is approved by the FDA for humanitarian use.  And, people receiving the standard of care (non-invasive ventilation) know that they are not being treated by the device.

“We knew that this study wasn’t going to be perfect,” says Katz.

To learn more about the NeuRX DPS, check out Clearing the air on the DPS?

***

Gilenya

A phase IIA clinical trial of Novartis’ Gilenya is now underway at Massachusetts General Hospital and Houston Methodist Hospital in Texas.

fingolimod Gilenya ALS Treg Teff T cell infiltration

 

Regulating ALS? Immunomodulators including Gilenya aim to slow ALS by reducing inflammation. Image: National Institute of Allergy and Infectious Diseases.

The immunomodulator, currently used to treat multiple sclerosis, aims to slow progression of ALS by reducing infiltration of effector T cells, key instigators of inflammation – further damaging the motor nerves. 

Gilenya may also increase circulation of regulatory T cells, key watchdogs that might help keep inflammation in check in people with ALS – at least early in the disease.

The study, led by Massachusetts General Hospital's James Berry MD MPH, aims to determine the safety and tolerability of Gilenya.

The one month clinical trial is to take place at 4 sites throughout the US.  30 people with ALS are expected to participate.

People with ALS will be monitored during the first day of the study for signs of a brief drop in heart rate.  The potential treatable complication, known as bradycardia, according to Berry occurs in less than 0.5% of people first taking the medication.

“We need to be cautious about approaching this [strategy],” says Berry.

To learn more about Gilenya, check out our topics page.

Actemra

Elsewhere in the US, clinicians are gearing up to put Roche’s Actemra (tocilizumab)to the test in ALS.  The immunomodulator, currently used to treat rheumatoid arthritis, aims to slow progression by reducing production of pro-inflammatory substances that might further damage the motor nerves.

ALS MND potential therapies clinic

 

What's in the pipeline? Learn about therapies being developed for ALS in the clinic today by exploring our timeline.

The phase II clinical trial, announced at NEALS 2013 by MGH neurologist Merit Cudkowicz MD, is to be led by Barrow Neurological Institute’s Shafeeq Ladha MD and University of Kansas Medical Center’s Rick Barohn MD

The study aims to determine the safety and tolerability of Actemra in people with ALS.

This is important according to Duke University School of Medicine's Tso-Pang Yao PhD because IL-6 signaling, blocked by Actemra, may also be needed to repair and regenerate damaged muscles in people with ALS.

Sites include the Barrow Neurological Institute in Arizona, University of California Los Angeles and the University of Kansas. 80 people with ALS are expected to participate.

To learn more about Actemra, check out our topics page.

CellCept, Methylprednisolone, Prograf, Prednisone and Simulect

Meanwhile, clinicians at Emory University School of Medicine are taking another look at immunosuppressants as a potential treatment for the disease.

The anti-rejection drugs, which include Genentech’s CellCept (mycophenolate mofetil) and Astella’s Prograf (tacrolimus), are the same medicines prescribed to people with ALS participating in the ongoing clinical trial of Neuralstem’s potential stem cell therapy for ALS.

The approach stems from one participant, known as “patient 11”, who appears to benefit from the transplantation procedure. 

immunosuppressant CellCept mycophenolate mofetil ALS

 

Suppress ALS? Some clinicians suspect that one person with ALS may appear to benefit from Neuralstem's stem cell-based treatment strategy because of anti-rejection medicines.

This benefit, however, according to Emory University School of Medicine’s Christina Fournier MD, may instead be due to the anti-rejection medicines. The reason, according to Fournier, is that this improvement appears to occur too rapidly to be explained by a potential stem cell treatment.

“We have to study this patient,” says Duke University School of Medicine’s Rick Bedlack MD PhD.  “We have to figure out what in the world made him better."

A phase II clinical trial is to take place at Emory University School of Medicine, Massachusetts General Hospital and University of Massachusetts Medical Center. 30 people with ALS are expected to participate.

The multi-drug regimen includes intravenous injections of Novartis’ Simulect (basiliximab) and methylprednisolone during the first week. Decreasing doses of prednisone during the first month.  And, Genentech’s CellCept and Astellas’ Prograf for 6 months. 

“We might not understand how it works,” says Fournier. “So, we don’t want to change it.”

The study aims to identify another person with ALS that may also benefit from these medicines in hopes to determine why “patient 11” may benefit due to this treatment strategy.

These anti-rejection medicines, however, according to phase I results, are not tolerated by some people with ALS.

The phase II clinical trial is now ongoing.  Initial results are expected sometime in 2015.

To learn more about potential immunotherapies for people with ALS including immunomodulators and immunosuppressants being tested for the disease, tune into our podcast with ALS TDI’s Steve Perrin PhD.

Exercise

Certain forms of exercise appear to be safe for people with ALS according to initial observations from an ongoing clinical trial led by Johns Hopkins University School of Medicine’s Nicholas Maragakis MD

stationary bicycling exercise ALS

 

Exercise, does a body good? The Veterans Specific Activity Questionnaire (VASQ) may help clinicians create a safe exercise program for people with ALS according to results presented by Carolinas Medical Center physical therapist Mohammed Sanjak PhD PT MBA. Image: Northwest Guardian's Jim Bryant for Joint Base Lewis McCord, Washington.

The clinical trial is evaluating key forms of moderate aerobic and resistance exercise – stationary cycling and weightlifting - and comparing them to range of motion (ROM) exercises, the standard of care.

Sites include Carolinas Medical Center, Johns Hopkins University School of Medicine, Massachusetts General Hospital and Washington University School of Medicine.

The study aims to determine which forms of exercise are the most helpful for people with ALS.

All workouts are tailored to each person with ALS. No serious side effects were observed to date due to any of these exercise routines according to Johns Hopkins University School of Medicine’s Lora Clawson MSN CNRP.

To learn more about exercise and its potential benefits for people with ALS, check out Exercise: stretching the limits of ALS care.

Arimoclomol

Initial results from a phase II/III clinical trial of arimoclomol could be released as early as the fall of 2014 according to University of Miami’s Michael Benatar MBChB PhD

Arimoclomol, developed by CytrX, aims to slow progression of ALS by reducing levels of misfolded superoxide dismutase I (SOD1).  The buildup is a potential contributor of ALS – at least certain forms of familial disease.

***

To learn more about potential therapies being developed for ALS including elsewhere in the globe, check out our timeline ALS: In the pipeline 2013.

Patient Resources

A Dose Escalation and Safety Study of Human Spinal Cord Derived Neural Stem Cell Transplantation for the Treatment of ALS   Contact  |  Clinical TrialAbout Neuralstem

Note: Participants must live nearby either Emory University School of Medicine or University of Michigan.  The reason according to Emory's Jonathan Glass MD is to ensure participants can be seen quickly as possible if complications develop due to anti-rejection medicines.

Diaphragm Pacing System (DPS) In Participants With ALS   Contact  |  Clinical Trial  |  About the NeuRx DPS

Gilenya in ALS   Contact  |  Clinical Trial  |  About Gilenya

Immunosuppression in ALS  Contact  |  Clinical Trial

A Trial of Resistance and Endurance Exercise in ALS  Contact  |  Clinical Trial

A Phase II/III Randomized, Placebo-controlled Trial of Arimoclomol in SOD1 Positive FALS   Contact  |  Clinical Trial  |  About  Arimoclomol

Note: This study is ongoing, but not recruiting.

 

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Categories: Watchlist

US team puts NeuRX DPS through its paces

clock October 22, 2013

A phase II clinical trial of Synapse Biomedical’s NeuRx diaphragm pacing system (DPS) is now underway at the State University of New York School of Medicine.

The device, developed by Case Western School of Medicine’s Ray Onders MD, aims to help people with ALS keep breathing longer by electrically conditioning the respiratory muscles.

stem cell induced pluripotent iPS ALS Neuralstem Brainstorm Q Therapeutics Corestem

 

DPS testing made easier? Neuromuscular ultrasound may soon enable clinicians to identify people with ALS eligible to receive the NeuRX DPS - without the discomfort and pain often associated with EMG and NCS.

The clinical trial aims to determine whether the NeuRx DPS improves diaphragm function of people with the ALS.

The study is to take place at 18 sites throughout the US. 180 people with ALS with breathing difficulties (FVC: 45-50%) are expected to participate.

A key goal of the clinical trial according to California Pacific Medical Center’s Jonathan Katz MD is to identify key respiratory signs (parameters) that might help clinicians identify people with ALS most likely to benefit from the procedure.

The pre-operative testing is extensive according to Duke University School of Medicine’s Rick Bedlack MD PhD. And, these tests do not necessarily reflect the ability of the respiratory muscles to be conditioned according to Cedar Sinai Medical Center’s Bob Baloh MD PhD.  About one out of every five people with ALS wakes up in the recovery room without the device because their diaphragm cannot be stimulated according to preliminary results presented by his team at NEALS 2013.

What’s more, it remains unclear from these tests which people with ALS may benefit most from the device.

But this study is easier said than done according to Katz. The NeuRx DPS is approved by the FDA for humanitarian use.  And, people receiving the standard of care (non-invasive ventilation) know that they are not being treated by the device.

“We knew that this study wasn’t going to be perfect,” says Katz.

To learn more about the NeuRX DPS, check out Clearing the air on the DPS?

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Categories: Watchlist

Actemra for ALS?

clock October 22, 2013

Clinicians are gearing up to put Roche’s Actemra (tocilizumab) to the test in ALS according to MGH neurologist Merit Cudkowicz MD.  The immunomodulator, currently used to treat rheumatoid arthritis, aims to slow progression by reducing production of pro-inflammatory substances that might further damage the motor nerves.

ALS MND potential therapies clinic

 

What's in the pipeline? Learn about therapies being developed for ALS in the clinic today by exploring our timeline.

The phase II clinical trial, announced at the 2013 Northeast ALS Consortium meeting, is to be led by Barrow Neurological Institute’s Shafeeq Ladha MD and University of Kansas Medical Center’s Rick Barohn MD

The study aims to determine the safety and tolerability of Actemra in people with ALS.

This is important according to Duke University School of Medicine's Tso-Pang Yao PhD because IL-6 signaling, blocked by Actemra, may also be needed to repair and regenerate damaged muscles in people with ALS.

Sites include the Barrow Neurological Institute in Arizona, University of California Los Angeles and the University of Kansas. 80 people with ALS are expected to participate.

To learn more about Actemra, check out our topics page.

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Categories: Watchlist

Immunosuppressants revisited

clock October 22, 2013

Clinicians at Emory University School of Medicine are taking another look at immunosuppressants as a potential treatment for the disease.

The anti-rejection drugs, which include Genentech’s CellCept (mycophenolate mofetil) and Astella’s Prograf (tacrolimus), are the same medicines prescribed to people with ALS participating in the ongoing clinical trial of Neuralstem’s potential stem cell therapy for ALS.

The approach stems from one participant, known as “patient 11”, who appears to benefit from the transplantation procedure. 

immunosuppressant CellCept mycophenolate mofetil ALS

 

Suppress ALS? Some clinicians suspect that one person with ALS may appear to benefit from Neuralstem's stem cell-based treatment strategy because of anti-rejection medicines.

This benefit, however, according to Emory University School of Medicine’s Christina Fournier MD, may instead be due to the anti-rejection medicines. The reason, according to Fournier, is that this improvement appears to occur too rapidly to be explained by a potential stem cell treatment.

“We have to study this patient,” says Duke University School of Medicine’s Rick Bedlack MD PhD.  “We have to figure out what in the world made him better."

A phase II clinical trial is to take place at Emory University School of Medicine, Massachusetts General Hospital and University of Massachusetts Medical Center. 30 people with ALS are expected to participate.

The multi-drug regimen includes intravenous injections of Novartis’ Simulect (basiliximab) and methylprednisolone during the first week. Decreasing doses of prednisone during the first month.  And, Genentech’s CellCept and Astellas’ Prograf for 6 months. 

“We might not understand how it works,” says Fournier. “So, we don’t want to change it.”

The study aims to identify another person with ALS that may also benefit from these medicines in hopes to determine why “patient 11” may benefit due to this treatment strategy.

These anti-rejection medicines, however, according to phase I results, are not tolerated by some people with ALS.

The phase II clinical trial is now ongoing.  Initial results are expected sometime in 2015.

To learn more about potential immunotherapies for people with ALS including immunomodulators and immunosuppressants being tested for the disease, tune into our podcast with ALS TDI’s Steve Perrin PhD.

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Categories: Watchlist

Neuralstem phase II begins

clock October 22, 2013

 

Stemming the ALS tide?  Neuralstem aims to stem the loss of motor neurons in people with ALS by boosting levels of neuroprotective substances. The potential therapy requires anti-rejection medicines. Video: Lane Niles PhD, Sanford-Burnham Medical Research Institute.

A phase II clinical trial of Neuralstem’s potential stem cell therapy for ALS is “now on” according to Emory University’s Jonathan Glass MD

Sites include Emory University and University of Michigan.  15 people with ALS are expected to participate.

Neural stem cells, derived from a human embryo, will be surgically introduced into the cervical (diaphragm-moving) region of the spinal cord of people with ALS in hopes to protect motor neurons needed for breathing.  At least 200,000 neural stem cells will be injected in 10 places throughout the C3 – C5 region on one or both sides of the spinal cord.

“We think the cells don’t migrate far,” explains Glass.  “We think we can cover the whole pool of motor neurons with 10 injections.”

The study aims to determine the maximum number of stem cells that can be safely administered to potentially treat ALS.

Participants will also be checked on a regular basis to look for signs of reduced decline in functional abilities including breathing.

“We think the stem cells are getting in,” says Glass.  “The question is what they are doing.”

To learn more about stem cell therapies for people with ALS and the challenges toward bringing them into the clinic, check out ISSCR 2013: ALS, Stem to Stern.

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Categories: From The Bench

microManaging ALS

clock September 30, 2013

 

microRNAs decoded. microRNAs may promote the reinnervation of the motor nerves by blocking the expression or synthesis of key substances. Video: Nature Publishing Group.

Virginia Tech’s Greg Valdez PhD knew that miR-206 was in the right place at the right time to help plug motor nerves back into muscles. The short non-coding RNA, discovered in 1994 by the late Washington University School of Medicine neuroscientist John Merlie PhD, is at the motor endplate and its synthesis is turned up upon detachment of the connecting nerve.

“That’s what led us to jump on this bandwagon,” says Valdez, “to try and find out what this microRNA is doing at the neuromuscular junction.”

His advisor, Harvard University’s Joshua Sanes PhD, got a phone call from University of Texas Southwestern’s Eric Olson PhD. He told him about graduate student Andrew Williams' latest results:

A (G93A-SOD1mouse model of ALS without miR-206 appeared to progress much more quickly.  And, died more than 3 weeks earlier due to the disease.  

miR-206 might help stabilize neuromuscular junctions, keeping the motor nerves and muscles connected, thought Valdez.

He decided to take a closer look.  He peered at their muscles under the microscope. Upon the onset of disease, more than half of their motor neurons were unplugged - more than double than those with miR-206 in their muscles.

miR-206 appeared to help rebuild neuromuscular junctions in ALS mice.  And, protect them from the ravages of the disease.

Moving Target

In the earliest stages of ALS, most people feel their arms and legs gradually weaken. But their muscles keep moving – months after experiencing the first symptoms of disease.

The reason, according to a growing number of studies, is that many of the motor nerves reattach to muscles when they become unplugged.  This 'collateral reinnervation' is one of many changes that occur in people with ALS to help protect them early in the disease course.

HDAC4 miR206 ALS MND neuromuscular junction NMJ

 

Compensatory sparks. Motor nerves plug back into muscles early in the disease course- keeping people with ALS moving. Image: Brunteau et al. Brain (2013). Courtesy of Oxford University Press.

By tapping into these compensatory mechanisms, clinicians hope to create medicines that help keep their patients with ALS moving longer by keeping the motor nerves and muscles connected. 

But delivering miR-206 to people with ALS can be tricky to do.  miR-206 must be specifically targeted to the neuromuscular junctions in people with ALS.  And, must be packaged to protect the RNA from degrading en route.

Olson’s team is now working hard to figure out how miR-206 is turned up in people with ALS. The results might enable researchers to design treatments strategies that help keep people with ALS moving - by triggering miR-206 production before the muscles start to waste.

“We want this microRNA to come up as soon as there is any sign of neuromuscular destruction,” says Valdez.  “That is the ultimate goal.”

Meanwhile, a growing number of researchers are trying to understand how miR-206 helps the motor nerves plug back into muscles in hopes to identify new treatment strategies for the disease.

To do that, scientists are working hard to identify proteins regulated by miRNA-206 in muscles. One enzyme, histone deactetylase 4 (HDAC4), an instigator of muscle atrophy, is emerging as a key target in its crosshairs. 

HDAC4 production appears to be reduced by miR-206 in muscles according to results from Andrew Williams PhD, now at Columbia University. Introduction of miR-206 into cultured cells reduced enzyme levels about 60%. And, in mice lacking miR-206, levels of HDAC4 more than doubled in their muscles.

HDAC4 also appears to promote detachment of the motor nerves from muscles – at least in mice according to studies by Virginia Tech’s Greg Valdez PhD. Injured motor nerves appear to reattach more easily to muscles lacking HDAC4.  Upon injury, nearly a third more motor neurons reconnected as compared to those in normal mice.

muscle fibers ALS

 

Fast and furious. HDAC4 appears to build up in fast twitch muscle fibers before disease onset - leading to muscle atrophy. Image: David Gregory and Debbie Marshall, Wellcome Images.

What’s more, HDAC4 appears to be turned up in people with ALS according to studies led by Duke University School of Medicine’s Tso-Pang Yao PhD. And, this increase appears to occur in key muscles affected by ALS before the onset of disease - at least in mice. Increased HDAC4 appears to be detected only in fast skeletal muscles of a G93A-SOD1 mouse model of ALS.  The same muscles that ultimately fail in the disease.

The results suggest that miR-206 in part, helps motor neurons to reconnect in people with ALS early in the disease by lowering levels of HDAC4 in their muscles.

Reducing levels of HDAC4 might therefore be helpful in treating the disease.

*** 

Assistance Publique - Hôpitaux de Paris’ Pierre-François Pradat MD PhD suspected long ago that a lot could be learned from peering into the muscles of people with ALS. Key changes in muscles could contribute to ALS. And, exacerbate the disease.

These differences may enable clinicians to more accurately diagnose and monitor people with ALS.  And, inspire new treatment strategies for the disease.

“Atrophy and weakness may not be simply collateral damage,” explains Pradat.  “Crucial pathogenic events may occur in muscle fibers that could be reachable targets of future treatments.”

Pierre-François Pradat MD PhD got a call in 2000 from INSERM’s Jean-Philippe Loeffler PhD.  He told him about Luc Dupuis PhDs latest results

Nogo-A builds up in the muscles of a (G86R-SOD1) mouse model of ALS  before the onset of disease, said Loeffler.

Increased Nogo-A could prevent the motor nerves in people with ALS from being repaired and reconnected, Pradat thought. 

 

A go for anti-Nogo-A. Ozanezumab aims to help repair and reconnect injured motor axons by soaking up Nogo-A (red) in the surrounding debris. Learn more by tuning into our podcast with Pierre-François Pradat MD. Image(adapted): Uniklinik Bagrist, Switzerland.

Pierre-François Pradat MD PhD decided to look and see whether these same changes occurred in his patients with the disease.

He found that Nogo-A appeared to build up in the muscles of people with ALS.  And, its levels appeared to correlate with the progression rate of the disease.

What’s more, people with high levels of Nogo-A suspected to have ALS are more likely to develop the disease.  Nearly 90% of people who have detectable levels of Nogo-A in their weakening muscles develop tell tale signs of ALS including difficulties breathing, speaking and swallowing.  Whereas more than 90% of people who appear to be Nogo-A ‘negative’ did not develop the disease.

The results suggested that reducing Nogo-A in people with ALS may help enable the motor nerves to reattach to muscles.  And, slow progression of the disease. 

An international phase II clinical trial of GlaxoSmithKline’s ozanezumab, a Nogo-A antibody that reduces Nogo-A levels, is ongoing.  

"We hope that it could lead to a functional improvement and survival benefits in patients with ALS," says Pradat.

Now, Pierre-François Pradat MD PhD is using gene profiling to identify other changes in muscles in people with ALS in hopes to identify other potential strategies to treat and manage the disease.

His team reported in 2012 a fingerprint of 155 genes that appeared to reflect the degree of muscle decline in a small group of people with ALS. Expression profiles of 9 out of 155 genes could distinguish muscles that were seriously impaired.

One of the 9 genes was HDAC4.

The Sign of Four

ALS experts first looked to HDAC inhibitors in hopes to protect motor nerves in people with ALS. Researchers, however, have since discovered that these strategies could potentially provide more benefits - including help keep muscles healthy.

 

Tired muscle. HDAC4 turns off the expression of key genes by removing chemical marks (red) - leading to muscle atrophy. Image: National Cancer Institute.

HDAC4 promotes muscle atrophy – at least in mice. Increased levels of the enzyme induce muscle damage according to studies led by Duke University School of Medicine’s Tso-Pang Yao PhDWhereas muscles without HDAC4 appear to resist atrophy – even after the motor nerves detach from them according to studies led by University of Texas Southwestern’s Eric Olson PhD.

What's more, increased levels of HDAC4 can be detected in muscles of people with ALS according to studies led by Duke University’s Tso-Pang Yao PhD.

But HDAC4 blockers might do much more for people with ALS then reduce muscle atrophy according to recent studies led by Assistance Publique - Hôpitaux de Paris’ Gaëlle Bruneteau MD.  These strategies might help slow down the disease.

People who survived at least 5 years with ALS appeared to express at least one third less HDAC4 in their muscles than those that more rapidly declined.  And, appeared to be better at keeping the muscles and motor nerves connected.  Over half of the motor neurons appeared to plug back into the muscle fibers after becoming detached – more than double those in people with a more rapidly progressing form of the disease.

HDAC4 levels also appear to correlate with the rate of progression of the disease. 

The results suggest according to Assistance Publique - Hôpitaux de Paris’ Pierre-Francois Pradat MD PhD that the key to keeping people with ALS moving is not the number of normal muscle-motor nerve connections. But the ability of their muscles to plug back in upon becoming detached.

Blocking HDAC4 in people with ALS therefore might boost the reinnervation capacity of the motor nerves- slowing the disease.

”Inhibiting histone deacetylase 4 appears to be a very promising therapeutic strategy,” says Pradat.

Class IIa HDAC inhibitor HDACi HDAC4 ALS

 

HDAC4, on target? Tempero Pharmaceutical's Class IIa HDAC blocker (above) might be a first step toward developing HDAC4-targeted medicines. But whether this is the best approach to treat ALS remains an open question. Image: Courtesy of Nature Publishing Group.

Now, chemists across the globe are working hard to cook up HDAC4-targeted medicines in hopes to create treatments for a number of diseases including ALS. In 2013, the GlaxoSmithKline spinoff Tempero Pharmaceuticals unveiled its Class IIa HDAC blockers which target HDAC4, HDAC5, HDAC7 and HDAC9 – a key first step in developing HDAC4-specific treatment strategies. The compounds are now being developed to treat autoimmune diseases including multiple sclerosis.

Meanwhile, Duke University School of Medicine’s Tso-Pang Yao PhD is taking a different approach to develop HDAC4-specific medicines.  The potential therapies according to Yao might be helpful in treating many diseases neuromuscular in nature including ALS.

Whether targeting HDAC4 is the right strategy to treat ALS, however, remains an open question according to Virginia Tech's Greg Valdez PhD. HDAC4 plays a number of critical roles - including those outside skeletal muscles. The regulatory enzyme helps the heart keep up with demand by powering the remodeling of heart muscles. And, helps maintain vision by providing ‘life support’ to key nerves.

But according to Duke University School of Medicine’s Tso-Pang Yao PhD, these potential treatments may alleviate muscle weakness but leave other systems relatively unscathed. The reason according to Yao is that its enzymatic activity  does not appear likely to be needed – at least to regulate heart load.

“In principle, this offers a therapeutic window where targeting HDAC4 catalytic activity would suppress atrophy but with limited toxicity,” explains Yao.

Nevertheless, miR-206 regulates the production of a number of substances in muscles according to Virginia Tech Greg Valdez PhD. Other key proteins may need to be downregulated in people with ALS to help the motor nerves reattach.

Now, Valdez’s team is working hard to understand how miR-206 helps protect neuromuscular junctions in people with ALS. The regulatory switches he identifies might form the basis of new treatments of the disease.

In future, he hopes to develop strategies to deliver miR-206 directly to people with ALS.

“In a disease like this, you have to consider everything,” says Valdez.

 ***

To learn more about emerging treatment strategies that aim to keep the muscles and motor nerves connected, tune into out podcast A Go for anti-Nogo-A.  To find out more about HDAC-targeted treatment strategies amd their potential benefits for people with ALS, check out Emerging Potential of HDACIs in ALS.

References

Bruneteau, G. et al. (2013)  Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression. Brain 136, 2359-2368.  Abstract   |   Full Text  (Subscription Required)

Lobera, M. et al. (2013) Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group.  Nature Chemical Biology 9(5), 319-325.  Abstract | Full Text (Subscription Required)

Choi, M.C., Cohen, T.J, Barrientos, T., Wang, B., Li, M., Simmons, B.J., Yang, J.S., Cox, G.A., Zhao, Y. and Yao T.P. (2012) A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program. Molecular Cell 47(1), 122-132.  AbstractFull Text

Williams, A.H., Valdez, G., Moresi, V., Qi, X., McAnally, J., Elliott, J.L., Bassel-Duby, R., Sanes, J.R. and Olson, E.N. (2009) MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 326, 1549-1554. Abstract | Full Text (Subscription Required)

Cohen, T.J., Barrientos, T.,, Hartman, Z.C., Garvey, S.M., Cox, G.A., and Yao, T.P. (2009) The deacetylase HDAC4 controls myocyte enhancing factor-2-dependent structural gene expression in response to neural activity.  FASEB Journal 23(1), 99-106. Abstract  |  Full Text

Cohen, T.J., Waddell, D.S., Barrientos, T., Lu, Z., Feng, G., Cox, G.A., Bodine, S.C. and Yao, T.P. (2007) The histone deacetylase HDAC4 connects neural activity to muscle transcriptional reprogramming.  Journal of Biological Chemistry 282(46), 33752-33759.  Abstract  |  Full Text

Learn more about GSK's ozanezumab

Pradat, P.F. et al.  (2012) Muscle gene expression is a marker of amyotrophic lateral sclerosis severity. Neurodegenerative Diseases 9(1), 38-52. Abstract | Full Text (Subscription Required)

Pradat, P.F. et al. (2007) Muscle Nogo-A expression is a prognostic marker in lower motor neuron syndromes. Annals of Neurology62(1), 15-20.  Abstract | Full Text (Subscription Required)

Jokic, N., Gonzalez de Aguilar, J.L., Dimou, L., Lin, S., Fergani, A., Ruegg, M.A., Schwab, M.E., Dupuis, L. and Loeffler, J.P. (2006) The neurite outgrowth inhibitor Nogo-A promotes denervation in an amyotrophic lateral sclerosis model. EMBO Reports 7(11), 1162-1167. Abstract | Full Text

Jokic, N. et al. (2005) Nogo expression in muscle correlates with amyotrophic lateral sclerosis severity. Annals of Neurology 57(4), 553-556. Abstract | Full Text (Subscription Required)

Learn more about the neuromuscular junctions

Burden, S.J. (2011) SnapShot: Neuromuscular Junction.  Cell 144(5), 826-826.e1. Illustration (Subscription Required)

 

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Categories: In The Pipeline

What's in the ALS pipeline - 2013?

clock September 16, 2013

More than 30 potential ALS medicines have been tested in the clinic.  Only riluzole, however, is FDA-approved to treat ALS.  And, increases survival 2-3 months.

Researchers are working hard to develop a more effective treatment for ALS.  In 2012 and 2013 alone, more than 20 new strategies entered the clinic.

Ahead of the 2013 Northeast ALS (NEALS) Consortium meeting and the International Symposium on ALS/MND, ALS Today takes a second look at potential therapies for ALS being investigated in the clinic in this interactive timeline.  Click on the pipeline to learn more about medicines being developed for the disease.

motor neuron astrocyte als mnd

 

Toxic avenger? Astrocytes (green) are unable to soak up enough glutamate from diseased motor neurons (red) according to some studies, making them vulnerable to degeneration (glutamate- induced excitotoxicity). Image: Ludo Van Den Bosch PhD and Maarten Dewil MD PhD for the Proceedings of the National Academy of Sciences.

A long and winding road

In the 1980s, the first treatment of ALS emerged. Sanofi-Aventis’ riluzole, entering clinics in 1990, aims to help protect motor neurons by reducing glutamate buildup. The drug hit pharmacy shelves in 1995.

In 1993, scientists identified superoxide dismutase 1 (SOD1) as the first ALS-linked gene. And, began to develop treatment strategies to remove ‘free radicals’ in the brain and spinal cord. Mitsubishi Tanabe Pharma’s edavarone (Radicut), introduced in ALS clinics in 2001, aims to reduce the stress level of the motor neurons by lowering production of these toxic substances.

With the advent of the first mouse model of ALS, researchers discovered that the buildup of misfolded proteins may contribute to ALS. And, treatment strategies that aimed to sweep out aggregates out of motor nerves emerged. Chaperonin-targeted therapies including Cytrx’s arimoclomol aim to help proteins to properly fold.  And, ISIS’ SOD1RX aims to reduce their synthesis by sopping up the RNAs via antisense-steeped sponges.

By the late 1990s, ALS emerged as an energy crisis. And, clinicians began to look toward treatment strategies that could help keep the power on in the muscles and motor nerves. The metabolic supplement creatine, introduced in 2000, aims to boost energy production. And, putative mitochondrial-targeted therapies including Knopp’s dexpramipexole (licensed to Biogen Idec), Trophos’ olesoxime and Teva’s rasagiline (Azilect) hope to keep power production at full throttle by bolstering them.  

But specific targets of ALS remained elusive.  And,  many research teams turned to more general strategies in hopes to develop treatments for the disease. Repurposed HDAC-targeted medicines aim to keep motor neurons healthy by throwing key genetic switches – turning up production of neuroprotective substances.  And, stem cell strategies including Brainstorm’s NurOwn and Neuralstem’s NSI-266 hope to increase levels of these substances by delivering them directly to the nervous system. 

mitochondria dysfunction ALS

 

Power up? Mitochondrial-targeted medicines aim to slow progression of ALS by boosting power production in the motor nerves. Dexpramipexole and olesoxime however appeared to be ineffective in phase III trials. Image: Xiaowei Zhuang MD PhD, Harvard University.

In the mid 2000s, clinicians targeted the immune system in hopes to reduce neuroinflammation - slowing the progression of the disease. Anti-inflammatories including Sobi’s anakinra (Kineret) and Roche’s tocilizumab (Actemra) aim to soak up key substances that might damage the motor nerves in people with ALS. And more recently, immunomodulators including Novartis’ fingolimod (Gilenya) and Neuraltus’ NP001 may quiet down microglia by keeping out emerging instigators of inflammation including macrophages and certain T cells (Teffs).

Meanwhile, other research teams peered into the muscles of people with ALS in hopes to develop treatments for the disease. GlaxoSmithKline’s ozanezumab (anti-NogoA), entering clinics in 2009, aims to help keep the motor nerves connected. Cytokinetics’ tirasemtiv (CK-357) might help keep muscles moving by making the most of existing motor neuron-muscle connections.  And, Synapse Biomedical's NeuRx diaphragm pacing system, introduced in 2007, hopes to help keep people breathing by conditioning the respiratory muscles.

Many of these potential medicines are being tested in the clinic today.  Learn more about them by clicking on our interactive timeline.

Images:  Courtesy of Children's Hospital of Philadelphia, Montreal Neurological Institute, National Institute of Neurological Disorders and Stroke, Paul Derry, Rockefeller University Press, Wikimedia Commons.

Patient Resources

A Clinical Trial of Nuedexta in Subjects with ALS Contact   |   ALS TDI    |    Website

A Study of Creatine Monohydrate in Patients With ALS  Contact   |   ALS TDI    |    Website

A Phase 3 Study of MCI-186 for Treatment of ALS    ALS TDI    |    Website

A Phase II/III Randomized, Placebo-controlled Trial of Arimoclomol in SOD1 Positive FALS  Contact   |   ALS TDI    |    Website

A Study of Ozanezumab (GSK1223249) Versus Placebo in the Treatment of ALS   ALS TDI    |    Website

A Study of Safety, Tolerability & Efficacy of CK-2017357 in ALS   ALS TDI    |    Website

A Study of Rasagiline in Patients With ALS   Contact   |   ALS TDI    |    Website

SOD1 Inhibition by Pyrimethamine in Familial ALS    Contact  |   ALS TDI   |   Website

A Trial of Safety and Efficacy of Rasagiline in Patients With ALS   Contact   |   ALS TDI    |    Website

Safety and Tolerability of Anakinra in Combination With Riluzol in ALS  Contact   |   ALS TDI    |    Website

Autologous Cultured Mesenchymal Bone Marrow Stromal Cells Secreting Neurotrophic Factors (MSC-NTF), in Patients With ALS  Contact   |   ALS TDI    |    Website

A Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in ALS    ALS TDI    |    Website

Dose Escalation and Safety Study of Human Spinal Cord Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis    Contact   |   ALS TDI    |    Website

An Evaluation of masitinib in ALS   Contact   |   ALS TDI    |    Website

Mexiletine in Sporadic ALS   Contact   |   ALS TDI    |    Website

Mexiletine for the Treatment of Muscle Cramps in ALS Contact   |   ALS TDI    |    Website

Gilenya in Amyotrophic Lateral Sclerosis   Contact   |   ALS TDI    |    Website     

A Study to Explore the Safety and Tolerability of Acthar in Patients With ALS  Contact   |   ALS TDI    |    Website   

A GM604 Phase 2A Randomized Double-blind Placebo Controlled Pilot Trial in ALS  Contact   |   ALS TDI    |    Website   

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Categories: Watchlist

What's in the ALS pipeline -2013?

clock August 30, 2013

ALS MND potential therapies clinic

 

ALS Clinical Trials 101 Find out about therapies being developed for ALS in the clinic today by exploring our timeline.

More than 30 potential ALS medicines have been tested in the clinic. Only riluzole, however, is FDA-approved to treat ALS.And, increases survival 2-3 months.

Researchers are working hard to develop a more effective treatment for ALS.  In 2012 and 2013 alone, more than 20 new strategies entered the clinic.

Ahead of the 2013 Northeast ALS (NEALS) Consortium meeting and the International Symposium on ALS/MND, ALS Today takes a second look at potential therapies for ALS being investigated in the clinic in this interactive timeline.  Click on the pipeline to learn more about medicines being developed for the disease.

A long and winding road

In the 1980s, the first treatment of ALS emerged. Sanofi-Aventis’ riluzole, entering clinics in 1990, aims to help protect motor neurons by reducing glutamate buildup. The drug hit pharmacy shelves in 1995.

In 1993, scientists identified superoxide dismutase 1 (SOD1) as the first ALS-linked gene. And, began to develop treatment strategies to remove ‘free radicals’ in the brain and spinal cord. Mitsubishi Tanabe Pharma’s edavarone (Radicut), introduced in ALS clinics in 2001, aims to reduce the stress level of the motor neurons by lowering production of these toxic substances.

With the advent of the first mouse model of ALS, researchers discovered that the buildup of misfolded proteins may contribute to ALS. And, treatment strategies that aimed to sweep out aggregates out of motor nerves emerged. Chaperonin-targeted therapies including Cytrx’s arimoclomol aim to help proteins to properly fold.  And, ISIS’ SOD1RX aims to reduce their synthesis by sopping up the RNAs via antisense-steeped sponges.

mitochondria dysfunction ALS

 

Power up? Mitochondrial-targeted medicines aim to slow progression of ALS by boosting power production in the motor nerves. Dexpramipexole and olesoxime however appeared to be ineffective in phase III trials. Image: Xiaowei Zhuang MD PhD, Harvard University.

By the late 1990s, ALS emerged as an energy crisis. And, clinicians began to look toward treatment strategies that could help keep the power on in the muscles and motor nerves. The metabolic supplement creatine, introduced in 2000, aims to boost energy production. And, putative mitochondrial-targeted therapies including Knopp’s dexpramipexole (licensed to Biogen Idec), Trophos’ olesoxime and Teva’s rasagiline (Azilect) hope to keep power production at full throttle by bolstering them.  

But specific targets of ALS remained elusive.  And,  many research teams turned to more general strategies in hopes to develop treatments for the disease. Repurposed HDAC-targeted medicines aim to keep motor neurons healthy by throwing key genetic switches – turning up production of neuroprotective substances.  And, stem cell strategies including Brainstorm’s NurOwn and Neuralstem’s NSI-266 hope to increase levels of these substances by delivering them directly to the nervous system. 

In the mid 2000s, clinicians targeted the immune system in hopes to reduce neuroinflammation - slowing the progression of the disease. Anti-inflammatories including Sobi’s anakinra (Kineret) and Roche’s tocilizumab (Actemra) aim to soak up key substances that might damage the motor nerves in people with ALS. And more recently, immunomodulators including Novartis’ fingolimod (Gilenya) and Neuraltus’ NP001 may quiet down microglia by keeping out emerging instigators of inflammation including macrophages and certain T cells (Teffs).

Meanwhile, other research teams peered into the muscles of people with ALS in hopes to develop treatments for the disease. GlaxoSmithKline’s ozanezumab (anti-NogoA), entering clinics in 2009, aims to help keep the motor nerves connected. Cytokinetics’ tirasemtiv (CK-357) might help keep muscles moving by making the most of existing motor neuron-muscle connections.  And, Synapse Biomedical's NeuRx diaphragm pacing system, introduced in 2007, hopes to help keep people breathing by conditioning the respiratory muscles.

Many of these potential medicines are being tested in the clinic today.  Learn more about them by clicking on our interactive timeline.

Images:  Courtesy of Children's Hospital of Philadelphia, Montreal Neurological Institute, National Institute of Neurological Disorders and Stroke, Paul Derry, Rockefeller University Press, Wikimedia Commons.

Patient Resources

A Clinical Trial of Nuedexta in Subjects with ALS Contact   |   ALS TDI    |    Website

A Study of Creatine Monohydrate in Patients With ALS  Contact   |   ALS TDI    |    Website

A Phase 3 Study of MCI-186 for Treatment of ALS    ALS TDI    |    Website

A Phase II/III Randomized, Placebo-controlled Trial of Arimoclomol in SOD1 Positive FALS  Contact   |   ALS TDI    |    Website

A Study of Ozanezumab (GSK1223249) Versus Placebo in the Treatment of ALS   ALS TDI    |    Website

A Study of Safety, Tolerability & Efficacy of CK-2017357 in ALS   ALS TDI    |    Website

A Study of Rasagiline in Patients With ALS   Contact   |   ALS TDI    |    Website

SOD1 Inhibition by Pyrimethamine in Familial ALS    Contact  |   ALS TDI   |   Website

A Trial of Safety and Efficacy of Rasagiline in Patients With ALS   Contact   |   ALS TDI    |    Website

Safety and Tolerability of Anakinra in Combination With Riluzol in ALS  Contact   |   ALS TDI    |    Website

Autologous Cultured Mesenchymal Bone Marrow Stromal Cells Secreting Neurotrophic Factors (MSC-NTF), in Patients With ALS  Contact   |   ALS TDI    |    Website

A Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in ALS    ALS TDI    |    Website

Dose Escalation and Safety Study of Human Spinal Cord Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis    Contact   |   ALS TDI    |    Website

An Evaluation of masitinib in ALS   Contact   |   ALS TDI    |    Website

Mexiletine in Sporadic ALS   Contact   |   ALS TDI    |    Website

Mexiletine for the Treatment of Muscle Cramps in ALS Contact   |   ALS TDI    |    Website

Gilenya in Amyotrophic Lateral Sclerosis   Contact   |   ALS TDI    |    Website     

A Study to Explore the Safety and Tolerability of Acthar in Patients With ALS  Contact   |   ALS TDI    |    Website   

A GM604 Phase 2A Randomized Double-blind Placebo Controlled Pilot Trial in ALS  Contact   |   ALS TDI    |    Website   

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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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