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: Podcast

Charting the course of ALS

clock January 31, 2014

ALS MND FTD FTLD C9orf72 prion spread TDP-43 TDP43

 

Follow the TDP-43 Road The spread of key proteins (red) between neurons in the brain and the spinal cord may in part explain the regional progression of the disease. Adapted from Braak, H. et al. (2013). Courtesy of Nature Publishing Group.

ALS occurs due to a progressive loss of motor neurons – the cells that enable muscles to move. One arm or leg may often be at first affected. But over time, the disease spreads throughout the body leading to paralysis and respiratory failure.

Researchers across the globe are working hard to understand how ALS spreads in hopes to develop more effective treatment strategies that stop the disease in its tracks. And, keep people with ALS moving.

One approach, led by University of Pennsylvania School Of Medicine’s John Trojanowski MD PhD, aims to retrace the ‘steps’ of ALS by tracking TDP-43, a protein that accumulates in motor neurons in more than 90% of people with the disease.

The strategy, pioneered by Universitätsklinikum Ulm neuroanatomist Heiko Braak MD in Germany, has provided insights into a growing number of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease and most recently, frontotemporal dementia (FTD).

Now, the US-German team reports that ALS may travel through key regions of the brain using the axons that connect them. And, classifies the progression of the disease, based on the trajectory of TDP-43, into four distinct stages.

The results may enable clinicians in the future to predict the course of ALS in their patients.  And, inform their care.

ALS Today’s Michelle Pflumm PhD talked with University of Pennsylvania School of Medicine’s Virginia Lee PhD and John Trojanowski MD PhD about their latest findings and their potential implications for people with ALS going forward.

***

To find out about emerging methods to track ALS in people with the disease, check out our American Association for the Advancement of Science (AAAS) 2013 meeting report A Brave New World.

References

Brettschneider, J. et al. (2013) Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Annals of Neurology 74(1), 20-38.  Abstract  |  Full Text  

Braak, H., Brettschneider, J., Ludolph, A.C., Lee, V.M., Trojanowski, J.Q. and Del Tredici, K. (2013)  Amyotrophic lateral sclerosis-a model of corticofugal axonal spread. Nature Reviews Neurology 9(12), 708-714.  Abstract  |  Full Text   (Subscription Required) 

Further Reading

Ravits, J.M. and La Spada, A.R. (2009) ALS motor phenotype heterogeneity, focality and spread. Neurology 73(10), 805-811.  Abstract  |  Full Text  

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Categories: Spotlight

Timeline: ALS 2013, A Year in Review

clock January 15, 2014

2013 has now come and gone. Lest the auld year be forgot, ALS Today turns back the clock - highlighting key advances in 2013 and key challenges going forward.

High-resolution ultrasound entered the ALS clinic, an emerging technique that aims to identify people with ALS with fewer EMGs. An ALS cognitive test, ECAS, was unveiled. A whole-brain imaging technique, MIDAS, emerged; opening the door to using MRS to monitor people with ALS. And, new insights into the spread of ALS may help physicians in the future to predict the course of their disease.

Potential therapies for ALS moved forward in the clinic. GlaxoSmithKline’s ozanezumab advanced to phase II across the globe. AB Science’s Masitinib neared phase III in Europe. And, potential stem cell treatments, Brainstorm’s NurOwn and Neuralstem’s NSI-266, reached phase II in Israel and the US.

New treatment strategies for ALS also emerged. In the US, Novartis’ Gilenya and the generic mexiletine moved into the ALS clinic. In China, the generic fasudil re-entered phase II. Misfolded SOD1-targeted antibodies including Neurimmune’s NI-204 entered the pipeline. And, GlaxoSmithKline’s potential ‘stress-buster’ GSK2606414 targeting PERK resurfaced.

Neurologists, however, remain divided on how to test these potential therapies in people with ALS. In the wake of the failure of Biogen-Idec/Knopp's dexpramipexole, a growing number of research teams launched phase IIA and larger phase IIB clinical trials to increase confidence in dose selection and phase II go/no go decisions. But others continue to evaluate these drugs in smaller phase II studies.

What's more, with the humanitarian device exemption looming large, neurologists remain at odds over recommending the NeuRX DPS and how best to evaluate its use.

Take a look back at 2013 by exploring our interactive timeline. Click on key advances to learn more.

Image Credits: Søren Storm Hansen, Flickr; Alice-Palace, Flickr; Judith Stoffer, National Institute of Genome and Medical Sciences; tnsasse, Flickr; Go, Dog,Go!, PD Eastman; Inside Star Wars Insider #133, Lucas Films LTD; Nature Publishing Group, UCDavis Biowiki and The Smithsonian Institution. 

Categories: Roundtable

Antisense and ALS sensibility

clock December 19, 2013

C9ORF72 Rademakers RNA foci repeat expansion motor neuron ALS MND FTD FTLD

 

Repeat offenders Expanded RNAs appear to tightly fold up (RNA foci, above) in the nuclei of motor neurons in people with C9orf72-linked ALS - keeping key regulatory proteins out of action. Image: Courtesy of Nature Publishing Group.

With the discovery of disruptions in C9orf72 in 2011, ALS began to emerge as a whole brain disease. Key network glitches, detected by MRI, could be traced back to structural changes in cognitive centers of the brain – potentially explaining key cognitive challenges including problem solving and complex decision making (executive function). And, key behavioral signs including apathy and assessing risk, characteristic of frontotemporal dementia (FTD), became more widely appreciated in people with ALS – further blurring the line between these diseases.

“We used to think of ALS and FTD as different diseases. But now it is becoming clear that it is a disease continuum,” says University of Leuven’s Wim Robberecht MD PhD.

C9orf72 is now one of ten genes implicated in both ALS and ALS/FTD according to University of Massachusetts’ Bob Brown MD PhD. And, repeat expansions in the gene appear to be linked to at least 1 out of 20 cases of ALS – including more than 40% of people with familial ALS (fALS) – across the globe.

“This is clearly the most common cause of neurodegeneration,” says Brown.

Key questions remain. Expanded RNAs appear to accumulate in people with C9orf72-linked ALS – potentially keeping regulatory proteins out on the cytoplasmic sidelines. But according to recent studies led by Deutsches Zentrum für Neurodegenerative Erkrankungen’s Christian Haass PhD and Mayo Clinic’s Len Petrucelli PhD, the disease may instead be a perfect storm of proteins and RNAs brewing in people with the disease. Repeat-associated proteins called C9RANTs also appear to build up in motor neurons in people with C9orf72-linked ALS – potentially fueling their destruction. And, the production of C9orf72 protein appears to be reduced in people with C9orf72-linked ALS and may also contribute to the disease.

But research teams led by University of California San Diego’s Don Cleveland PhD and Johns Hopkins University School of Medicine's Jeff Rothstein MD PhD remain undaunted – developing treatment strategies that aim to destroy expanded RNAs in people with the disease.

 

The Whole C9 Yards Explore our interactive timeline to learn more about C9orf72, the most common form of ALS identified to date.

Ahead of the 2013 meeting of the Society of Neuroscience, researchers gathered at the RNA Metabolism and Neurological Disease conference in San Diego to talk about the latest advances in C9orf72-linked ALS and emerging treatment strategies for the disease going forward.

Modeling workshop

The race is on to create a model of C9orf72-linked ALS – a key first step in generating a treatment strategy for the disease.

University of Massachusetts’ Bob Brown MD PhD is leading the pack - developing a mouse model of the disease. 

The transgenic mice, which harbors 580 repeats in the first intron of the C9orf72 gene, do not appear to develop paralysis.  But according to Brown, may have other emerging hallmarks of the disease.

“It is early days,” says Brown.

But whether these mice actually exhibit key symptoms of ALS makes no difference according to University of California San Diego’s Don Cleveland PhD, who is also developing them.

“We don’t care whether these mice develop full or partial disease,” says Cleveland.  “It is not a key feature to move forward.”

Researchers, however, need to keep trying to develop mouse models of C9orf72-linked ALS, says ALS Therapy Development Institute’s Fernando Vieira MD.

Although these mice will be helpful in validating emerging antisense treatment strategies for C9orf72-linked ALS, says Vieira, we don’t know what drives the disease. And, therefore we cannot be sure which therapy to develop.

“It is important to keep striving for models that actually recapitulate elements of ALS symptomatology,” says Vieira. “Then, we start to learn which pieces of the C9orf72 puzzle actually lead to the disease.”

Meanwhile, Johns Hopkins University School of Medicine’s Jeff Rothstein MD PhD is turning to stem cells to develop a treatment strategy for C9Orf72-linked ALS.

fibroblast reprogramming stem cell ALS

 

Skin to skin A growing number of scientists are turning to stem cells, recreated from skin cells (above) from people with C9orf72-linked ALS, in hopes to discover more effective medicines for the disease. Image: Ankur Singh PhD, Georgia Institute of Technology.

Motor neurons are recreated from people with ALS by reprogramming their skin cells. And, the cells scoured for key signs of disease.

The approach aims to identify key phenotypes that can be used to develop medicines that help weather these motor neurons from the C9orf72 storm by detoxifying them. 

The strategy is the same strategybeing developed by Cedar Sinai’s Bob Baloh MD PhD and University of California San Diego’s Clotilde Lagier-Tourenne PhD.

“We do not need a mouse to move a treatment forward,” says Rothstein.

Motor neurons do appear to exhibit tell tale signs of disease. Expanded C9orf72 RNAs and C9RANTs can be detected according to Mayo Clinic's Len Petrucelli PhD and University of Florida College of Medicine's Laura Ranum PhD.  And, according to Johns Hopkins University School of Medicine’s Chris Donnelly PhD, the motor neurons may also be more vulnerable – at least to increased levels of glutamate which occurs in many people with the disease.

But whether this model alone can be used to develop treatments for the disease remains an open question according to Mayo Clinic’s Rosa Rademakers PhD. Thousands of repeats appear to be embedded in the C9orf72 gene in key cells in the brain and spinal cord.  But only at most 700 – 800 repeats can be detected in skin cells – the cells researchers use to model C9orf72-linked disease.

“I think it is extremely important to keep this in mind,” says Rademakers.

Storm Troopers

In 2011, research teams led by Mayo Clinic’s Rosa Rademakers PhD and National Institutes of Health’s Bryan Traynor MD PhD fingered toxic RNA as the prime suspect behind C9orf72-linked ALS.

Repeat-rich RNAs appear to be detected in motor neurons of people with C9orf72-linked ALS.  And, suspected researchers, kept key regulatory proteins out of commission – leading to the disease.

The same underlying mechanism that leads to progressive muscle weakness in people with myotonic dystrophy.

c9rants ran translation C9ORF72 ALS MND

 

RANT and rave? RNAs appear to tightly fold up in people with C9orf72-linked ALS - enabling the synthesis of potentially toxic short proteins called C9orf72 non-ATG translated peptides (C9RANTs). RANTs are emerging as a potentially key feature in a growing number of diseases including myotonic dystrophy (above). Image: Courtesy of the Public Library of Science.

With the discovery of short dipeptide repeat proteins in people with C9orf72-linked ALS in 2012, however, researchers began to realize that the disease is much more complicated.

As many as six dipeptides appear to accumulate in key neurons in the brain in people with C9orf72-linked ALS and ALS/FTD according to studies led by University of Florida College of Medicine’s Laura Ranum PhD. And, at least one of these short proteins according to cell culture studies presented by Mayo Clinic’s Len Petrucelli PhD may damage them.

The short dipeptides are emerging as a characteristic feature of a growing number of RNA repeat-associated diseases including myotonic dystrophy I (DM1) and fragile X-associated tremor/ataxia syndrome (FXTAS).

“We need to start thinking about RAN translation,” says University of Florida College of Medicine’s Laura Ranum PhD. “And, their role in these diseases.”

But although there are a lot of lessons that can be learned from these RNA repeat-associated diseases, says Hospital of Sick Kids’ Christopher Pearson PhD, researchers still need to prove that the same underlying mechanisms lead to ALS.

At least 7 regulatory proteins appear to be kept out of action by C9orf72 expanded RNAs in the brain and spinal cord according to Johns Hopkins University School of Medicine’s Chris Donnelly PhD.  But whether the loss of any of them contributes to ALS remains an open question. 

What’s more, researchers remain unsure what role if any C9RANTs play in the disease.

“Toxicity is a question that is looming over all of us,” says Johns Hopkins School of Medicine’s Jeff Rothstein MD PhD.

 

Eye of the C9 Storm Researchers hope to identify key proteins that rescue the rough eye phenotype (top, right) of C9orf72 fruit flies in hopes to unravel underlying mechanisms of C9orf72-linked ALS. Image: Courtesy of the National Academy of Sciences.

To begin to tackle this question, the Johns Hopkins University School of Medicine team is turning to an emerging model of C9orf72-linked ALS in hopes to identify key sequestered proteins that may contribute to the disease. 

The transgenic fruit flies, which produce expanded repeats in key regions of the eye, sustain a progressive loss of key ocular neurons which leads to a “rough” appearance.  

The team hopes to identify key proteins benched by repeat-rich C9orf72 RNAs by increasing their levels in the eye.  And, looking to see whether their eyes are restored.

“Some RNA-binding proteins appear to reduce the rough eye phenotype,” says Johns Hopkins’ Christopher Donnelly PhD.

The GAL4 UAS fruit fly model, developed by Zihui Xu PhD, now at Huazhong University of Science and Technology, is one of the first to recreate neuron loss, a key feature of the disease.

Meanwhile, scientists including Mayo Clinic’s Len Petrucelli PhD are trying to figure out whether dipeptide repeat proteins also contribute to the disease.

“We are trying to understand what C9RANTs are doing,” says Mayo Clinic’s Len Petrucelli PhD, “whether they are toxic.”

Target Practice

A potential treatment strategy for C9orf72-linked ALS appears to be safe and well tolerated – at least in mice according to University of California San Diego’s Clotilde Lagier-Tourenne PhD.

 

Search and destroy Antisense oligonucleotides directed against the repeat expanded form of C9orf72 RNA bind these potentially toxic molecules- tagging them for destruction. Image: Courtesy of Rockefeller University Press.

The approach, developed by ISIS Pharmaceuticals, deploys antisense oligonucleotides (ASOs) known as gapmers to search for expanded C9orf72 RNAs and target them for destruction.

The emerging treatment strategy does appear to reduce levels of repeat-rich C9orf72 RNAs in motor neurons recreated from people with the disease.

Treatment with antisense oligonucleotides appear to reduce levels of expanded C9orf72 RNAs (RNA foci) to nearly 50% according to University of California San Diego’s Clotilde Lagier-Tourenne PhD. And, according to Johns Hopkins University School of Medicine’s Chris Donnelly PhD, may help protect them from potentially toxic buildup of glutamate (excitotoxicity) – a potential contributor to the disease.

What's more, many of these antisense oligonucleotides do not appear to further reduce expression of the C9orf72 gene.

The results add to growing evidence that this emerging treatment strategy may be helpful to people with C9orf72-linked disease.

“It is really encouraging – going forward with this strategy in C9orf72 ALS,” says Lagier-Tourenne.

But whether antisense is the best approach to treat C9orf72-linked ALS remains an open question. Existing dipeptide repeat proteins remain untouched. Expanded RNAs tightly fold up into stable quadruplexes according to studies led by Hospital of Sick Kids’ Christopher Pearson PhD – making them potentially less vulnerable to oligo attack. And, the battle may need to be waged in the nervous system.  ASOs are deployed intrathecally – directly into the spinal cord.

Small molecules may be a better choice to keep key regulatory proteins in action according to Scripps Institute’s Matthew Disney PhD.  Small molecules can often be taken by mouth.  And, may bind more tightly – burying themselves in the expanded RNA’s unique folds.

 

Foursquare Researchers hope to design small molecules that hide out in the unique folds of the expanded C9orf72 RNA 'quadruplexes' in people with ALS -to keep regulatory proteins in action. Image: Reprinted with permission from Gunaratnam, M. et al. (2009). Copyright 2009 American Chemical Society.

“We are targeting secondary structure,” explains Disney.  “This is more selective than oligonucleotides.”

But designing small molecules that target these RNAs may be tricky to do.  Small molecule libraries contain few compounds that bind RNAs according to Disney.  And, no antimicrobial or antiviral substance (natural product) has been discovered to date that target RNAs - providing no clues to create them.

To overcome these challenges, the Scripps Institute team introduced a new method to design molecules that target expanded RNAs to treat disease.

The library vs library approach involves the identification of key small molecules that target the RNA. And, tweaking them using computational-based methods to optimize their abilities to bind and detoxify them.

The resulting small molecules can then be displayed on peptide-like scaffolds to enable them to bind cooperatively to the repeat-rich RNAs – maximizing their efficacy.

The approach is currently being used to develop potential treatments for rare muscles diseases known as myotonic dystrophies.

Efforts to create expanded C9orf72 repeat-rich RNA-targeted small molecules are now underway.

***

To learn more about antisense and its potential for people with C9orf72-linked ALS, tune into our podcast with Jeff Rothstein MD PhD. To find out more about C9orf72-linked ALS and potential stem cell treatments for the disease, check out Astrocytes for the people?

References 

Donnelly, C.J. et al. (2013)  RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention.  Neuron 80(2), 415-420.  Abstract  |  Full Text  (Subscription Required)

Lagier-Tourenne, C. et al. (2013) Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration.  Proceedings of the National Academy of Sciences 110(47), E4530-4539.  Abstract  |  Full text  (Subscription Required)

Sareen, D. et al. (2013) Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion.  Science Translational Medicine 5(208), 208ra149.  Abstract  |  Full Text (Subscription Required)

Zu, T. et al. (2013)  RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proceedings of the National Academy of Sciences 110(51), E4968-E4977.  Abstract  |  Full Text

Mori, K. et al. (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS.  Science 339(6125), 1335 – 1338.  Abstract  |   Full Text  (Subscription Required)

Ash, P.E. et al. (2013)  Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS.  Neuron 77(4), 639-646.  Abstract  |  Full Text  (Subscription Required)

Xu, Z.  et al. (2013)  Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration.  Proceedings of the National Academy of Sciences  110(19), 7778–7783.  Abstract  |  Full Text

Reddy, K., Zamiri, B., Stanley, S.Y., Macgregor, R.B. Jr and Pearson, C.E. (2013) The disease-associated r(GGGGCC)n repeat from the C9orf72 gene forms tract length-dependent uni- and multimolecular RNA G-quadruplex structures.  Journal of Biological Chemistry 288(14), 9860-9866.Abstract|Full Text (Subscription Required)

Majounie, E. et al. (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurology 11(4):323-30. Abstract | Full Text  

DeJesus-Hernandez, M. et al. (2011) Expanded GGGGCC hexanucleotide repeat in a noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS Neuron 72(2), 245-256. Abstract | Full Text (Subscription Required)

Renton, A.E. et al. (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72(2), 257-268. Abstract | Full Text (Subscription Required)

Further Reading

van Blitterswijk, M., DeJesus-Hernandez, M. and Rademakers R. (2012)  How do C9ORF72 repeat expansions cause amyotrophic lateral sclerosis and frontotemporal dementia: can we learn from other noncoding repeat expansion disorders?  Current Opinion in Neurology 25(6), 689-700.  Abstract  |  Full Text  (Subscription Required)

Disney, M.D. (2013)  Rational design of chemical genetic probes of RNA function and lead therapeutics targeting repeating transcripts.  Drug Discovery Today 18(23-24), 1228-1236.  Abstract  |  Full Text (Subscription Required)

 

 

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Categories: Meeting Report

ALS, Plan B2?

clock November 26, 2013

EphA4 antagonist blocker ale zebrafish modifier

 

Irreconcilable differences Key genetic changes called modifiers may explain why some people with ALS may get the disease later or live longer. Image: Kam2y, Flickr.

Many people with ALS survive 3-5 years. But at least 10% of people with ALS live for more than 10 years. And, many of them harbor the same mutations in the same genes.

"There is no straight line between  cause and clinical outcome in ALS," says University of Leuven's Wim Robberecht MD PhD.  

The reason, in part, is that key changes buried in their genomes may determine when the first signs of ALS appear and the progression rate of their disease.

Identifying these genetic modifiers may enable researchers to pinpoint key targets of ALS. And, develop more effective treatments for the disease.

Ephrin receptor A4 (EphA4), an emerging modifier of ALS, appears to be upregulated in people with rapidly progressing ALS.  And, lowering its production, at least in two people with ALS, may explain in part, their extended survival after being diagnosed with the disease. 

The discovery, reported by Wim Robberecht MD PhD in 2012, suggested that reducing ephrin signaling may be a potential treatment strategy for ALS.

This month, researchers gathered at the 2013 meeting of the Society of Neuroscience (SfN13) in San Diego to discuss the emerging role of ephrins in neurological conditions including ALS. And, the latest ephrin blockers being developed to treat them.

Gone Fishing

Researchers across the globe are working hard to decode the genomes of 1000 people with ALS. The multi-institutional partnership, led by HudsonAlpha’s Rick Myers PhD, in part, aims to ferret out modifiers of ALS in hopes to identify new treatment strategies for the disease. The project is expected to take about 5 years.

EphA4 antagonist blocker ale zebrafish modifier

 

Go fish Scientists cast out for modifiers of ALS by looking for genetic changes in a zebrafish that protected them from developing key features of the disease.  Image: Carnegie Mellon University.

Wim Robberecht MD PhD, however, chose a simpler approach.  He sent his research team fishing.

The University of Leuven team developed a zebrafish SOD1 model of ALS. And, screened for key genetic changes that protected the fish from developing key aspects of the disease.

Their biggest catch: EphA4.

The reduction of EphA4 appeared to slow ALS – at least in mice.  A mouse model of ALS that produced 50% of normal levels of EphA4 appeared to experience about a 40% reduction in decline in motor coordination/performance.  And, the survival of these mice appeared to be extended more than 50% after showing the first signs of disease.

What’s more, reduced expression of EphA4 may be a key compensatory mechanism that may extend the survival of some people with the disease. People that expressed lower levels of EphA4 appeared to live longer with ALS.  And, two of them harbored key mutations in the EphA4 receptor gene.  

But why levels of EphA4-mediated signaling impacted the outcome of people with ALS remained unclear.

Now, neuroscientist Lies Schoonaert of the University of Leuven reports that ephrin B2, a protein which binds and activates EphA4, may in part, explain its role in modifying the disease.

Ephrin B2 appears 'to relocate' to astrocytes after disease onset in a G93A SOD1 mouse model of ALS.  And, fuel the progression of the disease. 

G93A SOD1 mice harboring activated astrocytes lacking ephrin B2 appear to progress more slowly.  And, live more than two weeks longer with the disease.

The results follow at the heels of a 2013 study led by University of Rochester School of Medicine’s Maiken Nedegaard MD DMSc which fingered ephrin B2 as a key obstacle blocking the repair and regeneration of axons in a mouse model of spinal cord injury.

astrogliosis

 

Signals crossed? Researchers suspect that ephrin B2 produced by reactive astrocytes (above) binds ephA4 decorating motor neurons - contributing to ALS. Image: Gerry Shaw, Wikimedia Commons.

Together, the results suggest that ephrin-B2 may prevent the repair of motor neurons damaged by ALS– accelerating the progression of disease.

Now, Robberecht’s team hopes to identify key downstream targets of ephrin B2 in motor neurons in hopes to identify new targets of ALS.  And, develop more effective treatment strategies for the disease.

Check Angiogenesis’ List

Sanford Burnham Medical Research Institute’s Elena Pasquale PhD suspected long ago that targeting EphA4 may help stop cancer in its tracks.

The activation of EphA4 triggers the growth of new blood vessels – fueling the growth of tumors. And, accelerates its spread.

In more recent years, however, this strategy is emerging as a potential treatment for a wide range of neurological conditions – including ALS. 

The reason, according to a growing number of studies, is that EphA4-mediated signaling appears to be a key barrier blocking the repair of damaged nerve cells in the brain and spinal cord.

EphA4 blockers and decoys may help lift this ‘brake’ in people who suffered a spinal cord injury or stroke - enabling the wiring to be repaired and reconnected. And, in people with ALS, these ‘antagonists’ may help the motor nerves plug back into muscles.

But targeting EphA4 is tricky to do.

EphA4 plays a number of key roles – including helping to keep bones healthy, regulate glucose intake and maintain the blood supply to the brain, heart and lungs.

“Targeting ephrin is hard,” says ALS Therapy Development Institute’s Steve Perrin PhD. “There is a lot to think about when converting it into a clinical candidate for ALS.”

EphA4 blockers may need to be targeted to key tissues affected by ALS to minimize side effects.

What's more, potent highly-selective small molecule blockers continue to remain elusive according to Sanford-Burnham Medical Institute’s Elena Pasquale PhD. And, existing peptides that target EphA4 are extremely instable- insufficient for therapeutic use.

To overcome these obstacles, Elena Pasquale PhD turned to Sanford-Burnham structural biologist Stefan Riedel PhD in hopes to design more stable EphA4 blockers that could potentially be used in the clinic. 

The plan: Take snapshots of peptide-bound EphA4 at molecular resolution. By understanding how these peptides grab hold of EphA4, the team could get a better sense of their plan of attack. And, design and deploy more effective ones that keep EphA4 out of action.

The Sanford-Burnham team captured EphA4 bound to three peptides, APY, KYL and VTM at atomic resolution.  By taking a look at these molecular snapshots, the team found that these peptides burrowed into EphA4.  And, blocked its ability to bind ephrins - including potentially ephrin-B2.

But Scripps Research Institute synthetic chemist Philip Dawson PhD saw room for improvement. The peptides, he reasoned based on computational calculations, could be redesigned and reimagined to be both stable and more effective.

EphA4 antagonist blocker als

 

Be rational Researchers took a snapshot of EphA4 bound to APY in hopes to design cyclic peptides more suitable for therapeutic use. 

Under the laboratory hood, Dawson’s team created cyclic peptides that bound more tightly to EphA4. And, subsequently modified them to boost their stability.

One highly selective cyclic peptide, called APY-d3, appears to be potent (IC50 = 27 ± 6.5 nM). And, “extremely stable” both in CSF and in circulation (t1/2 > 72 hours) -  at least in mice.

The cyclic peptide was introduced just one day after State University of New York's Jing An MD PhD unveiled TYY, an EphA4-targeted cyclic peptide being developed by her team as a potential treatment for certain cancers.

Now, Pasquale’s team hopes to develop this cyclic peptide-based strategy as a potential treatment for neurological conditions including ALS.

Key obstacles remain. These peptides needs to be chemically modified to enable delivery into the brain.  And, maximize its stability in circulation.

But Elena Pasquale PhD remains hopeful that her team can overcome these challenges.

“Cyclic peptides are a particularly promising approach,” says Pasquale.

Signal Ahead

The Ephrin A4 receptor (EphA4) is emerging as a key regulator of the regeneration of the central nervous system.  And, a formidable obstacle in the repair of the brain and spinal cord upon injury or disease.

Increased Eph/ephrin signaling is implicated in a growing number of neurological conditions including ALS.  And, may accelerate the progression of the disease.

What’s more, reduced EphA4 signaling may be a potential compensatory mechanism that may help protect the motor nerves in some people with the ALS. Reducing this signaling with emerging EphA4 antagonists and decoys may be helpful to extend survival of people with the disease.

But key challenges remain.  EphA4 blockers may need to be targeted to key systems affected by ALS to minimize side effects. And, modified to ensure delivery to many of these tissues – including the brain and spinal cord.

Key downsteam targets of Eph/ephrin signaling also need to be elucidated according University of Melbourne’s Ann Turnley PhD. Identifying these targets will enable scientists to better understand why the nervous system ‘hits’ the brakes when damaged.  And, create treatment strategies to lift them to allow repairs to take place.

“There’s a lot of work that still needs to be done.  But the future looks promising,” says Ann Turnley PhD.

References

Van Hoecke, A. et al. (2012) EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans.  Nature Medicine 18(9), 1418-1422.   Abstract   |  Full Text   (Subscription Required)

Ren, Z., Chen, X., Yang, J., Kress, B.T., Tong, J., Liu, H., Takano, T., Zhao, Y. and Nedergaard, M. (2013) Improved axonal regeneration after spinal cord injury in mice with conditional deletion of ephrin B2 under the GFAP promoter.  Neuroscience 241, 89-99.  Abstract  |  Full Text  (Subscription Required)

Han, X., Xu, Y., Yang, Y., Xi, J., Tian, W., Duggineni, S., Huang, Z. and An, J. (2013) Discovery and Characterization of a Novel Cyclic Peptide That Effectively Inhibits Ephrin Binding to the EphA4 Receptor and Displays Anti-Angiogenesis Activity.  PLoS One 8(11), e80183.   Abstract  |  Full Text

Further Reading

Noberini, R., Lamberto, I. and Pasquale, EB. (2012)  Targeting Eph receptors with peptides and small molecules: progress and challenges.  Abstract  |  Full Text  

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Categories: Roundtable , Watchlist

SfN13: Astrocytes for the people?

clock November 19, 2013

astrocyte als

 

A starry knight? The introduction of healthy astrocytes in people with ALS may help keep existing motor neurons 'alive' by reducing levels of potentially toxic substances including glutamate. Image: Jonathan Cohen PhD, National Institute of Child Health.

More than 10 stem cell strategies are being developed for ALS across the globe.  One of these potential treatments, known as astrocyte replacement, is approaching the clinic. The strategy aims to protect motor neurons by introducing healthy astrocytes in people with ALS in hopes to detoxify the nervous system.

But according to recent preclinical studies, this approach may be limited because astrocytes may be a key player in ALS in only certain forms of the disease.

Now, a US team led by Nationwide Children’s Hospital’s Brian Kaspar PhD reports that astrocytes may contribute to motor neuron loss in people with C9ORF72-linked ALS.

The results suggest that strategies targeting astrocytes might benefit many people with ALS – including those with the most common form of the disease identified to date.

Nationwide Children’s Hospital neuroscientist Katherine Meyer PhD presented the results last week at the 2013 meeting of the Society of Neuroscience in San Diego.

Clinicians first turned to stem cells in the late 1990s in hopes to treat ALS. The strategy aimed to help people with ALS keep moving by replacing motor neurons destroyed by the disease.

But this approach turned out to be too tricky to do. Motor neurons must plug into the central nervous system. And, their axons need to be extended nearly 3 feet to reach the muscles.

astrocyte als

 

Appetite for destruction? Astrocytes (green) may contribute to ALS in part by failing to regulate levels of glutamate in motor neurons. Image: Hajime Hirase PhD, RIKEN Brain Science Institute.

This stem-cell based procedure could take 2-3 years by some estimates to potentially take effect– too late for many people with the disease.

In the mid 2000s, researchers turned to astrocytes as a more feasible approach to treat the disease. The potential stem cell treatment, known as astrocyte replacement, involves injection of astrocyte precursors directly into the spinal cord.

The strategy aims to protect existing motor neurons in people with ALS by restoring the balance of key neuronal substances including glutamate in the brain and spinal cord.

One approach, known as Q cells, according to preclinical studies led by Johns Hopkins University School of Medicine's Nicholas Maragakis MD appears to delay onset and extend survival of the G93A SOD1 mouse model of ALS. 

Astrocyte replacement is now at the IND-enabling stage - the final step before entering the clinic.  At least three strategies are being developed.   An IND could be filed as early as February 2014 according to Cedar Sinai's Clive Svendsen PhD.

But which people might benefit from astrocyte replacement remains an open question. 

Astrocytes regenerated from skin cells from people with SOD1-linked ALS appear to contribute to motor neuron loss.  But according to studies led by Johns Hopkins University School of Medicine’s Nicholas Maragakis MD and University of Edinburgh’s Siddharthan Chandran PhD, motor neurons appear to emerge unscathed when co-cultured with astrocytes harboring mutations in TDP-43, a protein mislocalized in most people with the disease.

astrocyte als ips stem cell

 

Replacement, Ltd? Astrocytes harboring mutations in TDP-43 appear to leave motor neurons untouched - at least in mice. But according to preliminary co-culture results from Nationwide Children’s Hospital’s Katherine Meyer PhD, these astrocytes may contribute to motor neuron loss – at least under certain conditions. Image: Robert Krencik, University of Wisconsin.

Now, researchers from Nationwide Children’s Hospital report that astrocytes in people with C9Orf72-linked ALS may be a key player in the disease.

The “induced” astrocytes, directly converted from skin cells from three people with C9Orf72-linked ALS, reduced survival of mouse motor neurons by at least 50%.

The preliminary co-culture findings come at the heels of previous studies from Amanda-Haidet Phillips PhD, now at Johns Hopkins University School of Medicine, and Columbia University’s Virginia Le Verche PhD which suggest that astrocytes may contribute to motor neuron loss in certain forms of sporadic ALS.

Together, the results suggest that astrocytes may be a key player in ALS in many people with the disease. And, potential treatments directed at astrocytes may be of benefit to them.

Clinicians hope to launch phase I studies of astrocyte replacement sometime next year. 

***

To learn more about astrocyte replacement, tune into our podcast with Johns Hopkins University School of Medicine’s Nicholas Maragakis MD, A new player in the stem cell Q? To find out about other stem cell strategies being developed the disease, check out our report from the 2013 meeting of the International Society of Stem Cell Research, ALS, Stem to Stern.  

 

References

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

Haidet-Phillips, A.M. et al. (2011) Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nature Biotechnology,29(9), 824-8. Abstract Full Text (Subscription Required)

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

Yamanaka, K., Chun, S.J., Boillee, S., Fujimori-Tonou, N., Yamashita, H., Gutmann, D.H., Takahashi, R., Misawa, H. and Cleveland DW. (2008)  Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis.  Nature Neuroscience 11(3), 251-253.  Abstract  |  Full Text

Further Reading

Robberecht, W. and Philips, T. (2013)  The changing scene of amyotrophic lateral sclerosis.  Nature Reviews Neuroscience 14(4), 248-264.  Abstract  |  Full Text  (Subscription Required)

Papadeas, S.T. and Maragakis, N.J. (2009) Advances in stem cell research for Amyotrophic Lateral Sclerosis.  Current Opinion in Biotechnology 20(5), 545-551.  Abstract  |  Full Text  (Subscription Required)

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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.

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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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