Categories: From The Bench

Newron Announces Phase 2 Clinical Trial of sNN0029 (VEGF)

clock January 27, 2015

Earlier this month, Newron Pharmaceuticals announced that it would soon execute a Phase 2 clinical trial of its VEGF treatment known as sNN0029.  The announcement comes shortly after one of the lead investigators, Philip Van Damme, PhD, reported the results of the Phase 1 clinical trial during the International ALS/MND Research Symposium in Brussels held in December 2014. The Phase 2 clinical trial announced by Newron is not open for enrollment at the time of publication of this statement.  As soon as it is, we will update our clinical trial database which provides email updates upon subscription.

VEGF is thought to play a role in the health of motor neurons, and the company NeuroNova began a clinical trial of their VEGF compound sNN0029 to in 2008. Newron Pharmaceuticals acquired NeuroNova in December 2012. 

Earlier preclinical studies conducted in SOD1 rats with the compound, and others in SOD1 mice, where both quite small but produced modest improvements in survival overall. These results provided the company enoughinformation to launch their clinical research efforts. 

The Phase 1 clinical trial of sNN0029 included three different doses of the compound, as well a placebo arm.  This multi-arm clinical trial is now completed.  In total there were 19 PALS enrolled in the study, which included two different cohorts, one placebo control (N=10) and the other not (N=8).  In the placebo controlled cohort, four PALS received the high dose (2ug/day) and three received a lower dose (0.8 ug/day) and were compared to three additional PALS given a placebo.  The other cohort looked at a lower dose as well (0.2 ug/day) in 2 PALS, 2 at the middle dose and 4 at the high dose.  During his presentation in December, Van Damme was clear to the audience that the study was in no way powered to measure efficacy, but that the data suggested clearly that sNN0029 was safe and tolerated in all PALS in the trial.

It is interesting to note that 66% of the trial’s participants were male, and on average the onset age of enrolled PALS was 48 years old.  During the post-presentation discussion, audience members asked Van Damme if he thought that a higher dose of VEGF would be tolerable, which he responded he thought perhaps but that any follow up trial would likely use the doses informed on in the early trial.  The announcement from Newron recently reports that PALS enrolled in the Phase 2 clinical trial may receive does up to two times greater than those given in the earlier trial.

For More Information:

·         About sNN0029

·         Newron Press Release

       ·         Recap of Van Damme’s Presentation on sNN0029 during 2014 International ALS/MND Research Symposium

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Categories: From The Bench

ALS, The Extracellular Matrix Reloaded?

clock February 20, 2014

neuromuscular junction stability laminin MMP9 ALS MND David Goodsell Scripps

 

A disruption in the matrix? MMP-9 may contribute to the destruction of motor neurons in part by degrading laminins, ECM components that may be important in stabilizing neuromuscular junctions. Image: Originally published in ASBMB Today. David Goodsell: The master of mol art. Sergei Shukov, August 2011. ©The American Society for Biochemistry and Molecular Biology.

In 1995, the first drug for ALS, riluzole, hit pharmacy shelves. The drug extends survival about 3 – 6 months. But nearly twenty years later, riluzole remains the only drug approved to treat the disease.

The reason, in part, is that researchers remain unsure why motor neurons are selectively destroyed in ALS. And, therefore how to best protect them from the onslaught of the disease.

In hopes to overcome these challenges, Columbia University’s Christopher Henderson PhD turned to gene profiling in G93A SOD1 mice to identify proteins that may make motor neurons vulnerable to ALS by looking for substances strongly reduced or absent in cells unaffected by the disease.

Now, the Columbia University team reports that the enzyme matrix metalloproteinase 9 (MMP-9) may make motor neurons susceptible to ALS. And, trigger their destruction.

Motor neurons producing high levels of MMP-9 appear to be selectively destroyed by ALS. And, the removal of the enzyme delays the onset of paralysis and extends survival 25%.

“It may explain why fast motor neurons are vulnerable,” explains Henderson. “That’s something that is common to all forms of ALS.”

The results suggest that MMP-9 may be a key contributor to ALS. And, reducing the enzyme may be a potential strategy to slow the progression of the disease.

Life of MMPIs

Clinicians first looked to MMPIs in the 1980s in hopes to stop cancer in its tracks.  But over the years, matrix metalloproteinases emerged as a key instigator of neuronal destruction. And, these experimental medicines became recruited in an even larger war: stroke, spinal cord injury (SCI), traumatic brain injury (TBI) and neurodegenerative disease.

Matrix metalloproteinases appear to rise up in the central nervous system in a number of neurological conditions leading to blood brain barrier breakdown, infiltration of T cells, monocytes and macrophages, and neuroinflammation.

Some of the same mechanisms that ultimately destroy motor neurons in people with ALS.

matrix metalloprotease 9 MMP-9 MMP9 ALS MND

 

An oracle of the disease? The levels of MMP-9 appear to correlate with the progression rate of ALS suggesting that the enzyme may play a role in the disease.

MMP-9 appears to be in the right place at the right time to contribute to ALS. The enzyme builds up in the motor centers of the brain and spinal cord according to studies led by University of Southern California's Zoltan Tökés PhD And, the levels of MMP-9 appear to correlate with the rate of progression of the disease according to studies led by Universitätsklinikum Ulm's Johannes Brettschneider MD.

What’s more, according to preclinical results from University of Arkansas College of Medicine’s Mahmoud Kiaei PhD, these enzymatic uprisings appear to break out in motor neurons –key cells ravaged by ALS. And, in microglia, key instigators of inflammation, which fuel the progression of the disease.

”MMP-9 could be an important player that could contribute to motor neuron death,” says Kiaei. "It is an exciting molecule that could allow us to learn a lot about ALS."

Now, MMP-9 is fingered as a key player in the destruction of key subsets of motor neurons in ALS – at least in mice. 

Motor neurons producing high levels of MMP-9 appear to be preferentially lost during the course of the disease. And, increasing the levels of the enzyme in motor neurons appeared to accelerate their destruction.

 

A radical architect at work? Free radicals and inflammatory substances released by microglia may activate MMP-9 causing activated enzyme levels to build up during the course of the disease. Image: Urs Meyer MD, Swiss Federal Institute of Technology.

What's more, re-introducing MMP-9 into G93A SOD1 mice lacking the enzyme appeared to increase their vulnerability to the disease.

“Other motor neurons will eventually be destroyed in ALS,” explains Henderson. “We are talking about the first motor neurons to go.”

The results suggest that MMP-9 may mark motor neurons for destruction in people with ALS.  And, reducing levels of the enzyme may protect them from the disease.

ALS Potion Number 9?

But targeting MMP-9 is tricky to do.

Research teams developed more than 50 matrix metalloproteinase inhibitors to date. All of these experimental medicines appear to be intolerable. And, all of them appear to be ineffective in treating cancer, rheumatoid arthritis and heart disease.

“Matrix metalloproteinases are a bit like zombies.  They resurface again and again from pharmaceutical graveyards.” says ALS Therapy Development Institute’s Matvey Lukashev PhD. “But without much success.”

The reason, in part, is that most of these experimental medicines target many matrix metalloproteinases.

Enzymes that are essential to build new blood vessels and repair muscles – critical in people with neurological conditions including ALS.

"Unfortunately, the inhibitors that we need are not out there yet," says University of Arkansas College of Medicine's Mahmoud Kiaei PhD. 

matrix metalloprotease 9 MMP-9 MMP9 inhibitor SB-3CT derivative ALS MND

 

Dodging bullets? Emerging inhibitors of gelatinases may help protect motor neurons in ALS by reducing levels of MMP-9 - an enzyme that may make them vulnerable to the disease. Image: Clive Svendsen PhD, Cedars-Sinal Medical Center. ©University of Wisconsin-Madison University Communications.

However, inactivating MMP-9 alone in people with ALS is extremely difficult to do.

More than 20 matrix metalloproteinases have been discovered to date. All of these enzymes are highly structurally related. And, many of them are produced in the brain and spinal cord. 

What’s more, many of these matrix metalloproteinases use the same strategies to remodel and repair our tissues.

But University of Notre Dame chemists Shahriar Mobashery PhD and Mayland Chang PhD remain undaunted.

In 2000, Mobashery’s team introduced SB-3CT, a drug that targets gelatinases: matrix metalloproteinase 2 and 9. The drug, known as a suicide substrate, binds deep in the active site of these enzymes – keeping them out of action.

SB-3CT, redesigned and reimagined by Chang’s team, can now be directly introduced and absorbed into the blood. And, appears to be readily delivered into the central nervous system.

The strategy is now being developed as a potential treatment for traumatic brain injury and stroke.

“We are trying to get this drug into the clinic,” says University of Notre Dame’s Mayland Chang PhD.“We think it could be beneficial for a number of neurological diseases.”

The drug, according to preclinical studies led by University of Missouri School of Medicine’s Zezong Gu MD PhD, appears to protect damaged neurons from degenerating. And, stabilizes the vasculature after traumatic brain injury and stroke.

The potential treatment strategy, however, may do much more for people with ALS.

The emerging gelatinase blocker appears to decrease infiltration of activated monocytes, macrophages and T cells – emerging instigators of inflammation, the fuel that drives the progression of the disease.

matrix metalloprotease 9 MMP-9 MMP9 inhibitor SB-3CT derivative ALS MND

 

A matrix reboot? Emerging gelatinase inhibitors may need to be delivered acutely to enable the repair of injured motor neurons and re-innervation into muscle. Image: Greg Valdez PhD, now at Virginia Tech Carilion Research Institute and Joshua Sanes PhD, Harvard Medical School.

Treatment with SB-3CT appears to lower numbers of monocytes and macrophages that invade the injured spinal cord about 30% according to preclinical studies led by University of San Francisco’s Linda Noble-Hausslein PhD. And, significantly reduce effector T cell infilitration– at least in a model of transplant rejection according to studies led by Indiana University David Wilkes MD.

What’s more, the emerging gelatinase blocker may supe up regulatory T cells, key immune cells that help keep ALS in check early in the disease. And, boost numbers of oligodendrocytes – an emerging life-line for motor neurons disrupted in the disease.

But how to use these emerging medicines to regulate levels of MMP-9 in people with ALS remains an open question.

MMP-9 appears to contribute to the destruction of motor neurons. But these same enzymes may ultimately be needed to enable recovery from the disease. 

Matrix metalloproteinases appear to facilitate the repair and regeneration of axons – a key first step to plug motor neurons back into muscles.

Enzymes including MMP-9 appear to degrade key sugar-coated proteins in the surrounding debris known as chondroitin sulfated proteoglycans (CSPGs) that block the regrowth of axons. And, according to preclinical studies, at least MMP-2 is required to repair damaged motor neurons in the spinal cord.

Emerging gelatinase inhibitors may therefore need to be administered acutely at the right place and at the right time during the course of the disease.

A similar strategy is being developed to treat traumatic brain injury, spinal cord injury and stroke.

"There is no such thing as a safe drug," says Chang.  "There is always a balance between risk and benefit."

Morphing MMPIs

Matrix metalloproteases are beginning to emerge as a key player in a growing number of neurological conditions – including ALS.

Motor neurons that produce these enzymes appear to be selectively destroyed by ALS. And, microglia fuel the MMP9 outbreak – leading to blood brain barrier breakdown, infiltration of immune cells, inflammation and motor neuron loss.

 

The blue or the red pill? Reduction of MMP-9 may be one of many strategies needed to treat ALS. Image: Fernando Prieto, Flickr.

Reducing MMP9 may be a potential strategy to slow progression of the disease. But how to quell these enzymatic uprisings in people with ALS remains an open question.  Most MMP-targeted medicines tested in the clinic to date appear to be intolerable.  And, painful side effects preclude their long-term use.

Pharmaceutical companies, burned by multiple failures, appear to be closing the MMP books. But researchers remain undaunted. Emerging sub-selective inhibitors of gelatinases appear to protect neurons and reduce inflammation – at least in mice.  And, strengthen the vasculature.

Their short-term use, however, in combination with other therapies, may be necessary to enable the repair of injured motor neurons and reconnect them to muscles.

By understanding how MMP-9 is activated and the role of the enzyme in the disease, researchers hope to develop more effective treatments for ALS.  And, encourage industry leaders to repurpose existing experimental medicines already in their freezers.

“I think MMP-9 is one of a small number of targets," says Henderson, "that is definitely worth further investigation in clinical trials."

References

Kaplan, A., Spiller, K.J., Towne, C., Kanning, K.C., Choe, G.T., Geber, A., Akay, T., Aebischer, P. and Henderson, C.E.. (2014) Neuronal matrix metalloproteinase-9 is a determinant of selective neurodegeneration.  Neuron 81(2), 333-348.  Abstract  |  Full Text  (Subscription Required)

Lim, G.P., Backstrom, J.R., Cullen, M.J., Miller, C.A., Atkinson, R.D. and Tökés, ZA. Matrix metalloproteinases in the neocortex and spinal cord of amyotrophic lateral sclerosis patients.  Journal of Neurochemistry 67(1), 251-259.  Abstract  |  Full Text (Subscription Required)

Fang, L. et al. (2009) Linking neuron and skin: matrix metalloproteinases in amyotrophic lateral sclerosis (ALS).  Journal of Neurological Sciences 285 (1-2), 62-66.  Abstract  |  Full Text  (Subscription Required)

Kiaei, M., Kipiani, K., Calingasan, N.Y., Wille, E., Chen, J., Heissig, B., Rafii, S., Lorenzl, S. and Beal, M.F.  (2007) Matrix metalloproteinase-9 regulates TNF-alpha and FasL expression in neuronal, glial cells and its absence extends life in a transgenic mouse model of amyotrophic lateral sclerosis. Experimental Neurology 205(1), 74-81.  Abstract  |  Full Text (Subscription Required)

Lorenzl, S., Narr, S., Angele, B., Krell, H.W., Gregorio, J,. Kiaei, M., Pfister, H.W. and Beal, M.F.  (2006)  The matrix metalloproteinases inhibitor Ro 28-2653  extends survival in transgenic ALS mice.  Experimental Neurology 200(1), 166-171.  Abstract  |  Full Text  (Subscription Required)

Song, W. et al. (2013) Water-soluble mmp-9 inhibitor prodrug generates active metabolites that cross the blood-brain barrier.  ACS Chemical Neuroscience 4(8),  1168-1173.  Abstract  |  Full Text  (Subscription Required)

Brown, S., Bernardo, M.M., Li, Z.-H., Kotra, L.P., Tanaka, Y., Fridman, R. and Mobashery, S. (2000) Potent and Selective  Mechanism-Based Inhibition of Gelatinases. Journal of the American Chemical Society 122:6799–6800. Abstract  |  Full Text  (Subscription Required)

Further Reading

Vandooren, J., Van den Steen, P.E. and Opdenakker G. (2013) Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): the next decade. Critical Reviews of Biochemistry and Molecular Biology 48(3), 222-272.  Abstract  |  Full Text  (Subscription Required)

Zhang, H., Chang, M., Hansen, C.N., Basso, D.M. and Noble-Haeusslein, L.J. (2011) Role of matrix metalloproteinases and therapeutic benefits of their inhibition in spinal cord injury. Neurotherapeutics 8(2), 206-20.  Abstract  |  Full Text

 

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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: Featured , From The Bench , Watchlist

Modeling ALS: The Game's A FUS

clock August 5, 2013

mouse model ALS

 

Mousehunt Researchers are working hard to create mouse models of ALS to identify and evaluate potential medicines for the disease. Image: Rama, Wikimedia.

More than 30 potential therapies for ALS have been tested in the clinic.  But only riluzole is FDA-approved to treat the disease.  And, boosts survival of people with ALS just 2 to 3 months.

In hopes to change that, researchers are working hard to develop new mouse models of ALS to help identify and prioritize potential therapies to push forward into the clinic.

Now, an international research team led by Cardiff University neuroscientist Natalia Ninkina PhD, introduce a new mouse model of ALS. The transgenic mouse, which produces a truncated form of the protein Fused In Sarcoma (FUS), exhibits key signs of ALS including progressive muscle atrophy and paralysis.  And, accumulates key delocalized proteins in the brain and spinal cord.

The mouse is the first FUS-linked model of ALS to be published that exhibits key signs of ALS and key histological features of the disease.

The study is published this month in the Journal of Biological Chemistry.

In 1994, Northwestern University’s Mark Gurney PhD introduced the first mouse model of ALS in hopes to develop treatments for the disease.  The transgenic mouse, which harbors an ALS-associated mutation in the superoxide dismutase 1 (SOD1) gene, exhibits key signs of ALS including muscle decline and paralysis.  And, dies due to respiratory failure. 

Nearly two decades later, however, riluzole remains the only drug identified to date that benefits people with ALS.  One reason, argues some scientists, is that ALS is an extremely heterogeneous disease.  More than 20 genes by some estimates appear to be linked to familial ALS.   And, the survival of people with ALS is extremely variable – just months to more than a decade.

Multiple mouse models of ALS may be needed to identify treatments that benefit people with such a heterogeneous disease.

An RNA world?

In the mid-2000s, researchers turned their attention to TDP-43, a protein that appears to buildup in the brain and spinal cord of more than 90% of cases of ALS.  What’s more, TDP-43 appears to be altered in about 1 in 20 cases of inherited form of the disease.

FUS ub inclusions als

 

A big FUS? Many people with ALS accumulate FUS in the cytoplasm of motor neurons, suggesting that its deregulation may contribute to the disease. Image courtesy of Nature Publishing Group.

But the TDP-43 mouse models of ALS published to date do not appear to fully recapitulate the disease.  Progressive motor neuron loss could be detected.  And, walking appears to be affected.  But death appears to be due to defects in the gut – uncharacteristic of the disease.

A growing group of research teams are now setting their sights on the transcription factor FUS in hopes to develop additional mouse models of the disease.  The protein, like TDP-43, appears to be altered in about 1 out of 20 cases of familial ALS.  And, appears to aggregate in the cytoplasm of motor neurons in many more cases of ALS – including sporadic disease.

Now, researchers at Cardiff University in Wales introduce a new FUS model of ALS.  The transgenic mice, which produce a truncated form of the protein, exhibit key symptoms of ALS including progressive muscle weakness – often beginning in a single limb.  And, rapidly develop paralysis.

Taking a look under the microscope, the motor neurons of these mice appear to sustain extensive damage due to inflammation leading to the crumbling of the neuromuscular junctions – much the same as in people with the disease.

The jury, however, is still out whether these mice can be used to develop drugs for ALS.  The onset of disease is extremely variable.  The first signs of muscle weakness occur at any time during a 2 month period – as compared to about 2 weeks in the G93A SOD1 mouse model of the disease. 

The mice may nevertheless help prioritize potential ALS therapies to advance to the clinic by helping to validate them.

In the meantime, a US team led by University of California San Francisco’s Eric Huang MD PhD is taking a more conventional approach to develop a FUS model of ALS.  The transgenic mice, which harbors the R521C ALS-associated mutation in the FUS gene, display key signs of ALS including spasticity, synaptic loss and motor decline according to results presented at SfN 2012.  And, exhibit certain histological hallmarks of disease including delocalized FUS in the spinal cord.  Analysis is ongoing.

***

To learn more about emerging mouse models of ALS, check out SfN12: ALS, Down on the Bayou.  To find out about stem cell models of ALS and their potential to discover medicines for the disease, check out iPS ready, set, screen.

References

Shelkovnikova TA et al. (2013) Fused in Sarcoma (FUS) Protein Lacking Nuclear Localization Signal (NLS) and Major RNA Binding Motifs Triggers Proteinopathy and Severe Motor Phenotype in Transgenic Mice. Journal of Biological Chemistry, doi: 10.1074/jbc.M113.492017  Abstract  |  Full Text  

Mitchell, J.C. et al. (2013) Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion.  Acta Neuropathologica 125(2), 273-288. Abstract  |  Full Text  

Huang, C., Zhou, H., Tong, J., Chen, H., Liu, Y.J., Wang, D., Wei, X. and Xia, XG.  (2011) FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genetics 7(3), e1002011.  Abstract  |  Full Text  

Kwiatkowski, T.J. et al. (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323(5918), 1205-1208.  Abstract  |  Full Text  (Subscription Required)

Vance, C. et al. (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.  Science 323(5918), 1208-1211. Abstract  |  Full Text  (Subscription Required)

Further reading

McGoldrick, P., Joyce, P.I., Fisher, E.M., Greensmith, L. (2013) Rodent models of amyotrophic lateral sclerosis.  Biochimica Biophysica Acta 1832(9), 1421-36. Abstract  |  Full Text  (Subscription Required)

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Categories: From The Bench , Watchlist

Regulating ALS

clock April 18, 2013

Treg regulatory T cells FOXP3 ALS

 

Damage control. Regulatory T cells (Tregs) help quiet down certain immune cells – reducing the production of substances that damage the motor nerves. Image: Kathryn T. Iacono PhD, University of Pennsylvania School of Medicine.

Many people with ALS survive two to five years. But at least 10% of people with ALS live at least 10 years after being diagnosed with the disease.

Some scientists suspect that the reason some people might be more vulnerable to ALS may be in part due to kinks in their cellular armor. People who progress more quickly appear to have fewer numbers of regulatory T cells (Tregs). Key watchdogs that help keep neuroinflammation in check – potentially slowing down the progression of the disease.

Now, a US research team led by Georgia Regents University’s Jin-Xiong She PhD introduce a method to rapidly identify medicines that boost the numbers of Tregs and their policing abilities.

The strategy may help researchers identify new drugs for ALS – including existing FDA-approved medicines that can be more rapidly evaluated as treatment strategies for the disease.

The study is published next month in Biochemical Pharmacology.

Tregs may help keep ALS in check by reducing inflammation– the fuel that drives progression of the disease. The immune cells quiet down microglia and other cellular invaders that infilitrate the brain and spinal cord – reducing the production of neurotoxic substances that further damage the motor nerves. 

A growing number of researchers therefore suspect that boosting populations of Tregs might help slow ALS in its tracks. Infusions of Tregs reduce astrocyte and microglia-mediated destruction of the motor nerves in mouse models of disease. And, appear to delay disease onset and slow muscle decline. 

high-throughput screening ALS drugs

 

Screening room A new method may enable researchers to more quickly identify potential medicines for ALS. Image: Maya Schuldinger PhD, Weizmann Institute of Science, Israel.

What’s more, increasing numbers of Tregs might extend survival of people with the disease.  People with ALS who live at least six years post-diagnosis appear to have at least three times the number of these cells in circulation compared to those who survived at most two years with the disease.  And, their progression rate appears to correlate with the number of Tregs racing through their bloodstream.

But how to effectively boost Tregs and/or their anti-inflammatory abilities in people with ALS remains unclear.

Now, researchers introduce a method to identify medicines that might do just that.  The ‘high-throughput’ technique is expected to enable researchers to rapidly screen tens of thousands of potential drugs for the disease.

The strategy may also help scientists identify treatments for a wide-range of medical conditions including cancer, diabetes, multiple sclerosis and transplant rejection.

***

To learn more about the role of the immune system in ALS and emerging immunomodulators to treat the disease, check out Gilenya, giving ALS the fingo? and  NP001, a quiet riot for ALS? 

References

Henkel, J.S., Beers, D.R., Wen, S., Rivera, A.L., Toennis, K.M., Appel, J.E., Zhao, W., Moore, D.H., Powell, S.Z. and Appel, S.H. (2013) Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Molecular Medicine 5(1), 64-79.  Abstract  |  Full Text

Beers, D.R., Henkel, J.S., Zhao, W., Wang, J., Huang, A., Wen, S., Liao, B. and Appel, S.H. (2011) Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis.  Brain 134(5), 1293-1314.  Abstract  |  Full Text

Banerjee, R., Mosley, R.L., Reynolds, A.D., Dhar, A., Jackson-Lewis, V., Gordon, P.H., Przedborski, S. and Gendelman, H.E. (2008)  Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. PLoS One 3(7), e2740.  Abstract  |  Full Text

Beers, D.R., Henkel, J.S., Zhao, W., Wang, J. and Appel, S.H. (2008) CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS.  Proceedings of the National Academy of Sciences 105(40), 15558-15563.  Abstract  |  Full Text

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Categories: From The Bench

SFN12: ALS, Down On The Bayou

clock November 30, 2012

Society for Neuroscience SfN12 New Orleans NOLA

The identification of a common link between repeat expansions in the C9ORF72 gene and ALS one year ago kick-started a race to develop diagnostic tools and therapeutic strategies for this form of ALS. The introduction of antisense treatment strategies however is only one of a number of key advances in ALS that topped the lineup at the 2012 meeting of the Society of Neuroscience (SfN12). 

New stem cell technologies open the door toward the identification of new drug targets. New tools enable researchers to discover potential medicines for ALS.  And, emerging animal models of ALS might help scientists in future bring more effective treatment strategies to the clinic.

The meeting, which took place in New Orleans, highlighted the latest advances in a wide-range of neurological diseases including ALS. More than 30,000 neuroscientists and neurologists participated.

The livin’ ain’t easy

New models of ALS, unveiled at SfN12, show key signs of ALS opening the door toward the study of sporadic ALS and the development of new strategies to treat the disease.  University of California – San Francisco (UCSF) School of Medicine’s Haiyan Qiu PhD introduced a transgenic mouse, harboring an ALS-associated R521C FUS mutation, that showed key ALS symptoms including muscle spasticity and motor deficits.  And, the mice sustained a modest but progressive loss of motor neurons in the spinal cord.

TDP-43 inclusions brain ALS pathology

Building up. More than 90% of people with ALS accumulate TDP-43 (brown) in the cytoplasm of neurons in the brain and spinal cord. Models of TDP-43 ALS therefore might provide insight into more cases of the disease. Image: Tsuji, H. et al. Brain (2012). Courtesy of Oxford University Press.

Hoping to bridge the mouse to man gap, Louisiana State University School of Medicine’s Ronald Klein MD PhD is working hard to develop a non-human primate TDP-43 model of ALS.  Introduced at SFN12, the rhesus macaques appear to show tell-tale signs of ALS including muscle denervation and deficits completing motor tasks according to a preliminary analysis.  “We are trying to make more relevant models,” says Klein, “to discover therapies that we might have [otherwise] missed.”

But key challenges remain. Many models resemble ALS but do not fully replicate the disease. FUS mouse models of ALS developed by University of Massachusetts’ Larry Hayward MD PhD appear to accumulate clumps of FUS protein in the cytoplasm of motor neurons in the spinal cord.  But only a subset of these mice exhibit occasional motor coordination deficits and moving difficulties. And, transgenic mutant FUS mice developed by the UCSF team die due to complications outside of the respiratory system including the blood. “We can’t say that they die due to neurodegeneration,” says Qiu.

What’s more, some models of ALS show few signs of the disease. A ubiquillin 2 mouse model of ALS according to results presented by Northwestern University School of Medicine’s Han-Xiang Deng MD PhD accumulates clumps of proteins largely in the brain - exhibiting behavioral challenges resembling frontotemporal dementia (FTD). “We waited two years,” says Deng. “We didn’t see a motor phenotype.”

Laissez les cellules souche rouler

Stem cells may be a promising alternative to study ALS and discover new drugs for the disease according to some experts.

Induced pluripotent stem (iPS) cell-derived motor neurons appear to exhibit tell-tale signs of ALS according to researchers from the lab of Harvard University’s Kevin Eggan PhD. The motor neurons, generated from skin biopsies from 2 people with SOD1-linked ALS, accumulate aggregate-destroying vacuoles and appear to be more vulnerable to degeneration according to Harvard University’s Evangelos Kiskisnis PhD.  The mitochondria of these cells also appear to be malfunctioning (swollen) and struggle to get around the axon. Such power plant delivery interruptions, first observed in mouse SOD1 models of ALS, are speculated by scientists to contribute to the unplugging of the motor nerves from skeletal muscle in a growing number of motor neuron diseases.

“Induced pluripotent stem cells are a robust, reliability technology to study ALS,” says Kiskisnis.

What’s more, these cultured motor neurons appear to fire spontaneously and more frequently according to electrophysiological patch clamp analysis presented by Harvard University neuroscientist Brian Wainger MD PhD. Extracellular arrays of these motor neurons enable 100s of these cells to be characterized simulataneously according to Wainger - opening the door to screen for drugs that could reduce this so-called hyperexcitability – one of the earliest signs of the disease.

Creating motor neurons from induced pluripotent stem cells, however, takes time and can be tricky to do – particularly at large-scales needed to discover potential medicines for ALS.  So, Harvard University’s Justin Ichida PhD is hoping to use a shortcut – create motor neurons directly from skin biopsies and screen for substances that the protect them from the damage that occurs due to the disease.  A pilot screen, presented at SfN12, identified one potential drug, kenpaullone, which appears to boost survival of these so-called ALS induced motor neurons. 

ips induced pluripotent stem cell astrocyte ALS

Search and destroy. Scientists hope to identify new ALS targets by uncovering astrocytes' weapons of motor neuron destruction in iPS-based models of ALS. Image: Courtesy of Robert Krencik, University of Wisconsin-Madison.

Meanwhile, other research teams are working to recreate ALS in dishes by introducing other cells such as astrocytes and microglia and studying their weapons of motor neuron destruction.  The results might help researchers identify new targets that can be used to identify potential medicines for the disease.

New methods might help scientists regenerate these so-called glial cells from people with ALS to kickstart studies of the disease.  A technique developed by the team of Nationwide Children’s Hospital’s Brian Kaspar MD PhD enables ALS-ravaged astrocytes to be made more quickly – by directly generating them from skin biopsies.  And, a method developed by the lab of University of Rochester’s Steven Goldman MD PhD generates myelinating-capable oligodendrocytes from human iPS cells helping researchers to unravel their emerging role in the disease.

What’s more, the first fully humanized stem cell-based model of ALS developed by the team of Columbia University’s Serge Przedborski MD PhD opens the door toward unraveling underlying mechanisms of the human disease. “We can really recapitulate in a dish,” says Columbia University neuroscientist Virginia Le Verche PhD, “what we see in patients.”

But the jury is still out whether stem-cell based strategies can be used to treat ALS.  The transplantation of neural stem cells into the cervical (diaphragm-moving) region of the spinal cord appears to be safe according to preclinical studies from the research team of Cedars Sinai Medical Center’s Clive Svendsen PhD.  But these strategies do not appear to improve muscle function or increase survival – at least in a SOD1–linked rat model of ALS. The findings add to growing evidence which suggests that multiple injections into multiple regions might be needed to maintain the connections between the brain, descending motor tracts and lower spinal cord to keep muscles moving. “All of these structures need to be functional and connected properly," explains University of California San Diego's Martin Marsala MD, “in order for people to walk.”

Tech po’boy

als neuromuscular junction NMJ motor neuron muscle nerve terminal

Structural support. A new technique might enable scientists to identify potential ALS medicines that stabilize muscle-motor nerve connections - possibly slowing the onset of muscle weakness and paralysis. Image: Rockefeller University.

Researchers, however, continue to introduce new tools to discover and develop new potential treatment strategies for ALS.

Neuromuscular junctions (NMJs) can now be recreated in the laboratory paving the way toward the discovery of new ALS medicines that protect and stabilize these connections. The technique, developed in the lab of Dalhousie University’s Victor Rafuse PhD, enables stem cell-derived motor neurons to plug directly into muscle fibers – just like in our muscles.  What’s more, connections recreated between SOD1 ALS motor neurons and muscle cells appear to be much more unstable.  Existing techniques regenerate NMJs using cultured muscle cells.  Whether these motor neurons retain their muscle moving abilities (to fire action potentials) remains to be determined.

Protein aggregate clearance via autophagy can now be monitored in single neurons - opening the door toward ALS “clinical trials in dish” according to UCSF’s Steve Finkbeiner MD PhD.  Initial studies identified four destruction-stimulating substances which increase the survival of motor neurons recreated from skin cells from people with ALS.  These so-called autophagy inducers appear to protect neurons at least in part, by reducing a potential key source of toxicity associated with the disease. “We not only improve survival,” says Finkbeiner, “we seem to be able to accelerate the clearance of TDP-43.” 

What’s more, this drug discovery strategy is potentially promising for a growing number of neurodegenerative diseases including ALS.  The inability to destroy misfolded proteins through these mechanisms appears to be a key contributor to the disease according to new studies presented by Northwestern University School of Medicine’s Teepu Siddique MD and his team.  “If we can modulate proteostasis, we may be able to convert a fatal disease into a long term disability,” says Siddique.

Meanwhile, University of Missouri-Columbia speech pathologist Teresa Lever PhD is developing quantitative tests to help diagnose and treat dysphagia (difficulties swallowing).  Existing techniques rely on qualitative approaches or are measured on a self-reporting scale. The tests, which include fluoroscopic, histological and video analysis, are currently being evaluated by the University of Missouri team in animal models of ALS.  Looking ahead, these methods might help scientists discover and develop the next Nuedexta, a medicine that is soon to be tested in the clinic for its ability to improve speaking and swallowing in people with ALS.

* * *

To learn more about how scientists hope to use stem cells to discover new therapies for ALS, read: iPS, ready, set screen.  To find out more about the challenges of using stem cells to treat ALS, check out Neuralstem, surging immunosuppression?  To learn more about treatment strategies currently being developed for C9ORF72-linked ALS, tune into our podcast with Jeff Rothstein MD PhD, ALS dressed to the C9s.

 

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ALS: Much Ado About Oligodendrocytes

clock August 20, 2012

oligodendrocyte oligodendroglia myelin motor neuron ALS

 

Plan B. Oligodendrocytes (green) appear to deliver energy-rich metabolites to motor neurons (purple) during periods of high energy usage. Image: Alan Hoofring, Medical Arts Design Section, National Institutes of Health.

Oligodendrocytes are the tuners of the central nervous system, which busily insulate the nerves' axons to optimize the performance of the brain and spinal cord.

But when energy levels drop, these cellular handymen take on a second job. Oligodendrocytes supply nerve cells with energy-rich metabolites such as lactate to help keep the power on. 

Recent studies suggest however that these intercellular deliveries might be interrupted in people with ALS.  And, this break in the metabolic supply chain may contribute to the onset and progression of the disease.

ALS Today's Michelle Pflumm PhD talked to Max Planck Institute of Experimental Medicine neuroscientist Klaus-Armin Nave PhD about oligodendrocytes, their emerging role in ALS and potential treatment strategies going forward.

 

To learn more, check out our watchlist: The oligodendrocyte, a new player in ALS?

References

Fünfschilling, U. et al. (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485, 517-521. Abstract  |  Full Text

Lee, Y. et al. (2012) Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature, doi:10.1038/nature11314.  Abstract  |  Full Text

Kang, S.H., Fukaya, M., Yang, J.K., Rothstein, J.D. and Bergles DE. (2010)  NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron 68(4), 668-681.  Abstract  |  Full Text

Griffiths, I. et al. (1998)  Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280, 1610-1613. Abstract  |  Full Text   

Further Reading

Nave, K.A. (2010)  Myelination and the trophic support of long axons. Nature Reviews Neuroscience 11(4), 275-283. Abstract  |  Full Text  


 

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The oligodendrocyte, a new player in ALS?

clock July 19, 2012

oligodendrocyte myelin axons ALS

 

Insular Messaging. Oligodendrocytes ensure that messages are delivered by neurons quickly and efficiently by insulating (myelinating) them.  Adapted from Aubourg, P. (2007), Nature Genetics. Courtesy of Nature Publishing Group. All rights reserved.

In people with ALS, the motor nerves deteriorate leading to muscle weakness and paralysis.  Astrocytes and microglia, entrusted to support and protect these cells, turn traitor spewing out neurotoxic cytokines, contributing to disease progression.

ALS, however, is fueled by much more than a perfect storm of neurotoxic substances.  Motor neurons face an energy crisis.  And, scientists suspect, are without a plan B.  Oligodendrocytes, which may help keep the power on in motor neurons, are also disappearing over the course of the disease.

Now, researchers from Johns Hopkins University School of Medicine led by neurologist Jeff Rothstein MD PhD report that oligodendrocytes appear to be the main supplier of energy-rich lactate to nerve cells.  And, cutting off the supply of this critical metabolite may lead to neurodegenerative disease.

These results add to growing evidence that the loss of oligodendrocytes in the brain and spinal cord may contribute to the onset and progression of ALS.

The results are published online this month in the journal Nature.

oligodendrocyte axons lactate ALS

 

Power hungry. Scientists found that ALS-ravaged motor cortex (a) expresses less than half the level of lactate exporters MCT1 and MCT4 than unaffected regions of the brain (b) in people with ALS suggesting that an interruption in the supply chain might contribute to the disease. Image: Lee, Y. et al. (2012), Nature. Courtesy of Nature Publishing Group.All rights reserved.

The Johns Hopkins University School of Medicine team found that the principal lactate transporter, MCT1, is primarily produced by oligodendrocytes.  And, in people with ALS, this delivery vehicle appears to be expressed over 50% less in disease-ravaged regions of the brain.

Together, these findings suggest that reduced delivery of energy-rich lactate by oligodendrocytes may contribute to ALS.

To put this theory to the test, the researchers disrupted the delivery of this energy-rich metabolite via injecting oligodendrocyte-specific MCT1 RNA-interfering lentiviruses in the mouse spinal cord.  The team found that more than 50% of motor neurons near the injection site degenerated.

The results come just three months after a Max Planck Institute of Experimental Medicine team led by neuroscientist Klaus Armin-Nave PhD reported that oligodendrocytes may switch to lactate-producing mode to help neurons in energy need.

Looking ahead, these studies suggest that treatments which boost numbers of oligodendrocytes which can deliver this critical energy-rich metabolite may slow the progression of the disease.

To learn more about the emerging role of oligodendrocytes in ALS, check out Jeff Rothstein’s talk at the 2011 ALS TDI Summit.  To find out about approaches scientists are exploring to increase oligodendrocyte populations, read our recent feature, Exercise: stretching the limits of ALS care.

References

Fünfschilling, U. et al. (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485, 517-521. Abstract  |  Full Text

Kang, S.H., Fukaya, M., Yang, J.K., Rothstein, J.D. and Bergles DE. (2010)  NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron 68(4), 668-681.  Abstract  |  Full Text

Lee, Y. et al. (2012) Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature, doi:10.1038/nature11314.  Abstract  |  Full Text

Further Reading

Nave, K.A. (2010)  Myelination and the trophic support of long axons. Nature Reviews Neuroscience 11(4), 275-283. Abstract  |  Full Text  

 

 

 

 

 

 

 

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Help Wanted: Istanbul

clock July 3, 2012

 

Postcard from Istanbul  Rachael Marsden RN MSc talks about the biggest challenges facing people with ALS/MND in Turkey.  Photo courtesy of  Rachael Marsden RN MSc.  

University of Oxford MND Specialist Nurse Rachael Marsden RN MSc saw the note on the board at the 2007 ALS/MND Meeting in Toronto. Coşkun Özdemir MD, President of KASDER, a neuromuscular disease association based in Istanbul, needed help caring for people with ALS/MND in Turkey.

“We said we would have a go at helping. That’s how it started,” says Marsden.

She did not know what to expect when she arrived in Istanbul.  But what she found was a small group of nurses determined to improve the care and quality of life for people with ALS/MND. And, the nurse training program she helped put in place inspired a nation to put plans together to create more than a dozen care centers devoted to neuromuscular diseases including ALS/MND.

 

Class in session.  Nurses learn how to care for people with ALS/MND in Istanbul. Photo: Courtesy of Rachael Marsden RN MSc. Reproduced with permission. 

Further Reading

Tsou, A.Y., Karlawish, J., McCluskey, L., Xie, S.X. and Long, J.A (2012). Predictors of emergent feeding tubes and tracheostomies in amyotrophic lateral sclerosis (ALS). Amyotrophic Lateral Sclerosis 13(3): 318-325. Abstract | Full Text (Subscription Required)

People with ALS/MND who get a feeding tube electively have a better outcome according to this study.

Andersen, P.M.  et al. (2012) EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)-revised report of an EFNS task force.  European Journal of Neurology 19(3) 360-375.  Abstract  |  Full Text  (Subscription Required)

Regular multidisciplinary care is highly recommended for people with ALS/MND according to these recent guidelines issued by the European Federation of Neurological Societies (EFNS).

Patient Resources

Türkiye Kas Hastalıkları Derneği (KASDER) Contact | Website

ALS-MNH Derneği   Contact | Website 

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Rethinking ALS

clock June 7, 2012

Brain EF Agosta 300

 

Think tank.  Researchers discovered that functional changes in certain regions of the brain (blue) may help some people with ALS maintain cognition.  Image: Agosta et. al (2012), Neurobiology of Aging.  All rights reserved.

ALS is a progressive neurodegenerative disease in which the motor nerves deteriorate resulting in muscle weakness and paralysis.

A growing number of studies suggest however that ALS extends well outside the motor cortex, the region of the brain that controls the movement of muscles.  Neuroinflammation, triggered by the disease, spreads throughout the brain, possibly short-circuiting other key control centers including those that contribute to cognition.

Nevertheless, all people with ALS struggle with muscle weakness.  But only about half of these patients show any signs of cognitive impairment.

Now, a new study led by San Raffaele Scientific Institute neuroimaging specialist Massimo Filippi MD in Milan may explain why cognition might be spared in some people with ALS. The scientists discovered using resting state functional magnetic resonance imaging (rs-fMRI) that unaffected regions of the brain might “step up to the plate” to help maintain critical thinking abilities.

This is the first study to correlate functional changes in the ALS-ravaged brain to levels of cognition.

The results are published this month in Neurobiology of Aging.

The research team examined the brains and thinking abilities of 16 people with probable or definite sporadic ALS without frontotemporal dementia (FTD). 

The scientists found that people with ALS who performed better on executive function tests exhibited higher levels of functional connectedness in the default mode and frontoparietal networks of brain.  These areas of the brain are critical for a number of cognitive abilities including planning, remembering and thinking ahead.

The results suggest that certain networks in the brain might kick into overdrive to help maintain cognitive function in people with ALS over the course of the disease.  Larger studies however are needed to confirm these conclusions.

To learn more about how cognition might be affected in people with ALS, read C9ORF72 Comes Into Focus.  To find out how resting state fMRI could help neurologists better understand and diagnose the disease, check out MRI Make That a Double.

References

Agosta ,F., Canu, E., Valsasina, P., Riva, N., Prelle, A., Comi, G. and Filippi M.J. (2012) Divergent brain network connectivity in amyotrophic lateral sclerosis. Neurobiology of Aging, doi: 10.1016/j.neurobiolaging.2012.04.015. Abstract  |  Full Text  (Subscription Required)

Phukan, J,. Elamin, M., Bede, P., Jordan, N., Gallagher, L., Byrne, S., Lynch, C., Pender, N. and Hardiman O.  (2012) The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. Journal of Neurology, Neurosurgery and Psychiatry 83(1), 102-108. Abstract  |  Full Text

Brettschneider, J., Libon, D.J., Toledo, J.B., Xie, S.X., McCluskey, L., Elman, L., Geser, F., Lee, V.M., Grossman, M. and Trojanowski, J.Q. (2012) Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral sclerosis. Acta Neuropathologica 123(3), 395-407.  Abstract  |  Full Text  (Subscription Required)

Further reading

Phukan, J, Pender, N.P. and Hardiman O.  Cognitive impairment in amyotrophic lateral sclerosis.  Lancet Neurology 6, 994-1003.  Abstract  |  Full Text  (Subscription Required)

 

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