The year 2012 has now drawn to a close.  ALS Today turns back the clock - highlighting key advances in 2012 and key challenges going forward.

Monocytes, T-cells and oligodendrocytes emerged as potentially key players that could be targeted in ALS. Advances in induced pluripotent stem (iPS) cell technologies opened the door toward the discovery of new medicines for the disease.  Emerging antisense-based treatment strategies surfaced for C9- ALS, the most common form of ALS identified to date. GSK’s potential neuromuscular junction protector Ozanezumab (anti-NOGO A) approached phase II. And, Avanir’s emotionality-regulator Nuedexta, Novartis’ T cell sequesterer fingolimod (Gilenya), and the potential neuronal excitability-reducer mexiletine re-entered the pipeline – phase II clinical trials expected to begin sometime in 2013.

Key challenges, however, remain.  The first clinical reports of C9-ALS reawakened the debate about how to define inherited forms of the disease (fALS) and test for them. Clinical trials launched in 2012 hope to establish evidence-based clinical practice guidelines for the NeuRX, NIV and feeding tube to help clinicians best meet their ALS patients’ respiratory and nutritional needs. And, the failure of ceftriaxone and dexpramipexole fueled the debate about which drugs to push forward in the clinic and how best to evaluate them.

Take a look back at 2012 by exploring our interactive timeline. Click on key advances and challenges ahead to learn more.

Images courtesy of Arcadian, Bradford Timeline, East Birmingham Hospital's Graham Beards MD, NIGMS' Judith Stoffer.

CNS Invaders. In people with ALS, increased numbers of cytotoxic macrophages (pictured above) might enter the central nervous system and damage the motor nerves - contributing to disease progression. Image: MRC National Institute of Medical Research.

Macrophages help keep our tissues healthy and free from infection.  But in people with ALS, increased numbers of these immune cells may go into attack mode and enter the central nervous system– spewing toxic cytokines on the motor nerves.

Scientists are working hard to develop treatments that quiet down these cellular attack dogs in hopes to slow down ALS. One of these emerging medicines, Neuraltus Pharmaceutical’s NP001, is soon to be evaluated in the clinic.  The phase III clinical trial is scheduled to launch in the second half of 2013.

At the 2012 International Symposium on ALS/MND in Chicago, ALS Today’s Michelle Pflumm PhD talked to California Pacific Medical Center’s Forbes Norris ALS Clinic Director Robert Miller MD to learn more about NP001 and its potential to treat ALS going forward.

To learn more about other emerging medicines for ALS, check out the end of this podcast and our ALS/MND 2012 meeting report ALS Clinical Trials and Tribulations.

 

The NeuRX Diaphragm Pacing System. Image: Synapse Biomedical.

Diaphragm pacing might extend survival of some people with ALS according to a new study led by California Pacific Medical Center’s Jonathan Katz MD.  The study found that ALS patients implanted with the NeuRX DPS phrenic pacer appeared to live about 16 months (60%) longer vs. historical controls – after the initiation of noninvasive ventilation. 77 people with ALS participated. 

“The procedure may work,” says Katz. “But more studies need to be done.”

A key question is whether healthier people with ALS are in some way selected for diaphragm pacer implantation – patients who could live longer otherwise unassisted.  

“Until that’s excluded, we need to have a great deal of caution,” says Katz. “We need to study [the DPS] a lot more. We need randomized trials.”

A randomized controlled phase II clinical trial to further evaluate the potential benefits of the NeuRX DPS for people with ALS is now planned.  180 people with ALS are expected to participate.  Sites include California and New York.  Clinical trials are currently ongoing in England and France.

To learn more about the NeuRX DPS, check out DPS Sleep.  To find out about other emerging treatments for ALS, check out our full International ALS/MND Symposium meeting report ALS Trials and Tribulations.

 

Power up? Tirasemtiv may increase the power generated from fast skeletal muscle according to SUNY Medicine's Jeremy Shefner MD. Courtesy of Nature Publishing Group. All Rights Reserved.

Cytokinetics’ potential muscle booster tirasemtiv (CK-357) appears to be safe and tolerated.  But riluzole dosages need to be reduced 50% due to the drug’s ability to block riluzole breakdown according to phase IIa clinical trial results presented by State University of New York Medical University’s Jeremy Shefner MD PhD. “The evidence thus far supports the further evaluation of tirasemtiv,” says Shefner.

A phase IIB 20-week randomized, double-blind placebo-controlled clinical trial is now recruiting.  400 people are expected to participate.  Sites include clinics in US and Canada.

To learn more about tirasemtiv, read CK-357, helping pALS live strong? To find out about other emerging treatments for ALS, check out our full International ALS/MND Symposium meeting report ALS Trials and Tribulations.

The discovery and development of ALS medicines is picking up steam. In 2012 alone, at least 15 emerging treatments are being put to the test in the clinic – including 7 at the phase II and phase III stage.

Stem-cell based strategies including Neuralstem and Brainstorm hope to protect the motor nerves from further destruction. Mitochondrial-targeted medicines including Biogen-Idec’s dexpramipexole hope to treat ALS by keeping the energy flowing in the motor nerves. Immune system modulating drugs including Novartis’ Gilenya and Neuraltus’ NP001 hope to slow ALS in its tracks by reducing neuroinflammation. And, potential muscle boosters including Cytokinetics’ tirasemtiv (CK-357) hope to keep muscles moving.

Experts gathered at the International Symposium on ALS/MND in Chicago this month to discuss emerging treatment strategies currently being tested in the clinic and the challenges evaluating them going forward.

NP001

Neuraltus Pharmaceutical’s NP001 appears to be safe and tolerable according to phase II results presented by California Pacific Medical Center’s Robert Miller MD.  Some signs of benefit were detected in ALS patients that took the highest dose (2 mg/kg).  These include “modest” hints of reduced progression.  136 people with ALS participated.

“Our primary endpoints were not a home run,” says Miller.  “They were a bunt or a base hit.  But they were in the right direction.”

A second look at the phase II results, inspired by observations from doctors and trial participants, indicated that the progression appeared to “level off” in a significantly increased subset of people on the highest NP001 dose (27%) compared to placebo (including historical controls) (11%) during the 6 month treatment period. The strategy, called a post-hoc analysis, has been used previously to evaluate certain emerging cancer medicines.

“We feel the results justify the further development of NP001,” says Miller.

A phase III clinical trial is planned. Enrollment is expected to begin sometime in the second half of 2013.

To learn more about NP001 and its potential to treat ALS, tune into our podcast NP001: A quiet riot for ALS? with Robert Miller MD.

 

The NeuRX Diaphragm Pacing System. Image: Synapse Biomedical.

NeuRX DPS

Diaphragm pacing might extend survival of some people with ALS according to a new study led by California Pacific Medical Center’s Jonathan Katz MD.  The study found that ALS patients implanted with the NeuRX DPS phrenic pacer appeared to live about 16 months (60%) longer vs. historical controls – after the initiation of noninvasive ventilation. 77 people with ALS participated. 

“The procedure may work,” says Katz. “But more studies need to be done.”

A key question is whether healthier people with ALS are in some way selected for diaphragm pacer implantation – patients who could live longer otherwise unassisted.  

“Until that’s excluded, we need to have a great deal of caution,” says Katz. “We need to study [the DPS] a lot more. We need randomized trials.”

A randomized controlled phase II clinical trial to further evaluate the potential benefits of the NeuRX DPS for people with ALS is now planned.  180 people with ALS are expected to participate.  Sites include California and New York.  Clinical trials are currently ongoing in England and France.

To learn more about the NeuRX DPS, check out DPS Sleep.

Neuralstem

Neural stem cell transplantation into the spinal cord appears to be safe according to initial phase I clinical trial results presented by Emory University’s Jonathan Glass MD.  Stem cells could be detected in the spinal cord of autopsied tissue of some trial participants suggesting that engraftment occurred.  No significant changes appeared to be detected in rates of functional decline (including ALS-FRS) according to a recently published phase I analysis. “There is no indication that the treatment accelerated disease progression,” says Glass.  15 people with ALS participated.

A phase II ALS clinical trial is now planned.  Neural stem cells at higher doses will be injected into the cervical (diaphragm-moving) region of the spinal cord. The clinical trial is likely to include ALS patients with measurable functional decline and not be placebo-controlled according to Glass.  “We are awaiting FDA approval to move forward,” says Glass.

To learn more about stem cell transplantation and ALS, read Neuralstem, surging immunosuppression?

Tirasemtiv

 

Power up? Tirasemtiv may increase the power generated from fast skeletal muscle according to SUNY Medicine's Jeremy Shefner MD. Courtesy of Nature Publishing Group. All Rights Reserved.

Cytokinetics’ potential muscle booster tirasemtiv (CK-357) appears to be safe and tolerated.  But riluzole dosages need to be reduced 50% due to the drug’s ability to block riluzole breakdown according to phase IIa clinical trial results presented by State University of New York Medical University’s Jeremy Shefner MD PhD. “The evidence thus far supports the further evaluation of tirasemtiv,” says Shefner.

A phase IIB 20-week randomized, double-blind placebo-controlled clinical trial is now recruiting.  400 people are expected to participate.  Sites include clinics in US and Canada.

To learn more about tirasemtiv, read CK-357, helping pALS live strong?

SOD1-RX

Isis Pharmaceutical’s potential misfolded superoxide dismutase 1 (SOD1)-lowering therapy appears to be safe and tolerable according to initial phase I double-blind placebo-controlled clinical trial results presented by Washington University’s Timothy Miller MD PhD.  Patients received at least one dose of SOD1-directed 'gapmer' over a 12 hr period intrathecally - directly into the spinal cord.  21 people with SOD1-linked fALS participated.  Key side effects include headaches, backpain and nausea – typical of lumbar puncture.  The antisense oligonucleotide is now being redesigned in hopes to optimize its SOD1-lowering abilities.  “It is hard to predict when the next trial will be,” says Miller.

To find out about potential SOD1-directed strategies to treat sporadic ALS, check out our watchlist: Antibodies for sALS.

***

Enrollment in clinical trials remains challenging according to Duke University School of Medicine’s Rick Bedlack MD PhD MS. But other key obstacles to push ALS medicines forward also emerged at ALS MND Chicago 2012.

Ceftriaxone

Potential neuroprotective antibiotic ceftriaxone reduced functional decline more than 30% according to phase II double-blind placebo-controlled study results presented by Massachusetts General Hospital’s Merit Cudkowicz MD MSc. The drug was subsequently withdrawn in August of 2012 due to insufficient efficacy at the phase III stage. 513 people with ALS participated.

The results raise key questions about enrollment, the number of people with ALS needed to participate and study duration – particularly to inform and empower phase II go/no go decisions.

Olesoxime

Powerbar? Scientists hope to create mitochondrial-directed ALS medicines to boost energy levels in the deteriorating motor nerves. Image: David Furness PhD, Wellcome Images.

Better clinical trial outcome measures may be needed to evaluate emerging ALS medicines according to olesoxime study investigator and Hôpital de la Pitié-Salpêtrière neurologist Timothée Lenglet MD. The putative mitochondrial protectant failed to significantly extend life of people with ALS according to final randomized double-blind placebo-controlled phase III results presented at ALS MND 2012.  512 people with ALS participated.

“It may be difficult to detect a significant survival advantage in an 18 month clinical trial,” says Lenglet.

Clinical trial outcome measures including survival were a key subject of debate later that evening at Biogen-Idec’s ALS clinical trial roundtable.

“We have not really done well using survival as an endpoint,” says Carolinas Medical Center’s Benjamin Brooks MD.

Montreal Neurological Institute’s Angela Genge MD FRCP agrees. “We need a new endpoint that says that there is an effect and that the effect is worthwhile.”

An emerging technique called joint rank analysis may enable clinicians to do just that according to Genge. The combined functional survival measure is currently being used to help clinicians evaluate Biogen-Idec’s emerging ALS medicine dexpramipexole at the phase III stage. The initial results are anticipated by the end of 2012.

***

In the meantime, clinicians are working hard to care for people with ALS. Soft foods and thickened fluids help people with ALS meet their nutritional needs. Noninvasive ventilation helps ALS patients breathe easier, sleep better and boosts survival. And, certain medicines might help control emotionality and reduce spasticity.

But physicians remain divided on whether to recommend exercise for people with ALS.  A growing group of neurologists suspect that workouts can improve the quality of life and might even help fight the disease.  But others remain skeptical according to new results presented at ALS/MND 2012.

 

Exercise does a body good? Researchers at the University of Lisbon are developing treadmilling-based exercise regimens for people with ALS. Image: LuluLemon Athletica, Flickr.

Aerobic and Resistance Exercise

Certain forms of exercise including swimming might be safe for people with ALS according to a retrospective analysis of 234 patients’ hospital records led by the Hospice of Special Care’s Jinsy Andrews MD. No significant decline in survival was detected in people with ALS who exercised. What’s more, patients that exercised tended to experience slower functional and respiratory decline.

But key obstacles remain. Nearly 1 out of 4 health professionals are reluctant to routinely recommend exercise to people with ALS due to concerns of fatigue, falls and increased muscle weakness according to a survey from University of Pennsylvania’s Michele Lewis DPT.  And, workouts must be tailored to each ALS patient according to Northwestern Memorial Hospital’s Margaret McGovern-Denk MS OTR/L - making the design of general clinical practice guidelines challenging.

A big part of the problem is that there is insufficient evidence to indicate which exercises are the best choice for people with ALS.  A clinical trial of certain forms of exercise including stationary cycling and weightlifting led by Johns Hopkins University School of Medicine neurologist Nicholas Maragakis MD is ongoing. 60 people with ALS are expected to participate.

To learn more about exercise and ALS MND, check out Stretching the Limits of ALS Care.

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.

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. 

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

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.

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

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

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

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

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

Can MRI be implemented today to help diagnose ALS?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

***

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

References

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

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

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

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

Further Reading

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

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

Turner, M.R. (2011). Towards a neuroimaging biomarker for ALS. Lancet Neurology. 10(5), 400-403. Full Text (Subscription Required)

Patient Resources

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

The Pre-Familial Amyotrophic Lateral Sclerosis (Pre-fALS) Study. Contact | Website

Inside Africa. ALS/MND may occur earlier in Africa and be more common in men. Image: Fêtes des Masques à Kiri, Bobo Dioulasso, Burkina Faso, Guillaume Colin & Pauline Penot, Flickr.

Nearly 20% of people with ALS in the US live at least 5 years after being diagnosed. But in Africa, according to a recent analysis, people show the first signs of ALS earlier, are diagnosed later and die more quickly from the disease.

A group of neurologists and epidemiologists led by Université de Limoges’ Philippe Couratier MD hopes to change that by identifying people with ALS/MND throughout Africa and studying their disease.  The multinational, longitudinal study, called TROPALS, aims in part, to identify key prognostic factors that enable physicians to better manage the disease.

The collaboration is one of a growing number of partnerships that hopes to better understand, recognize and treat complex genetic diseases in Africa.

ALS Today’s Michelle Pflumm PhD caught up with participating neurologist Athanase Millogo MD of Burkina Faso at a networking meeting at the NIH’s Fogarty International Center in Maryland to learn more about TROPALS and its potential impact on people with ALS/MND in Africa going forward.

To find out more about the challenges of treating ALS/MND in Africa, read ALS, Circle in the Sand. To learn about efforts to identify the genetic and environmental contributors of complex genetic diseases in Africa, check out NIH and Wellcome Trust’s H3Africa.

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.

Repeat expansions in the C9ORF72 gene appear to be the most common cause of ALS identified to date – potentially explaining nearly 40% of cases of the inherited form of the disease.  Researchers, however, remain unsure why these repeat sequences within the first intron of the gene trigger ALS. 

Some scientists suspect that the repeat expanded C9ORF72 RNA might act as a sponge – soaking up transcription factors in motor neurons needed to keep these muscle-moving cells healthy.  But the loss of function of C9ORF72 alone could also potentially result in the disease.

Researchers hope to distinguish these possibilities by developing human induced pluripotent stem cell (iPS) and mouse models of C9ORF72-linked ALS and studying the underlying mechanism of the disease.

A growing number of scientists, however, are hedging their bets by developing antisense-based strategies that reduce these potentially toxic RNAs in hopes to create a treatment more quickly for this form of ALS. These small oligonucleotides, called gapmers, bind specifically to these repeat expanded RNA molecules – intracellularly targeting them for destruction.

ALS Today‘s Michelle Pflumm PhD talked to Johns Hopkins University School of Medicine neurologist Jeff Rothstein MD PhD about C9ORF72 and potential treatments for this form of ALS going forward.

To learn more about C9ORF72, check out our interactive timeline.

Alterations in nearly 20 genes have been linked to ALS.  But according to a growing number of studies, chemical changes to the genome might also be contributing to the disease.

Scientists are now looking to emerging cancer medicines in hopes to reset many of these so-called epigenetic switches in people with ALS.  But the drugs tested to date appear to be ineffective in the clinic. Some researchers suspect that these medicines simply cannot be given at high enough doses to be effective.  Their amounts strictly limited due to potentially harmful side effects.

Now, a growing number of scientists are developing so-called “next-generation” histone deacetylase (HDAC) inhibitors in hopes to create safe and more effective epigenetic medicines.  More selective drugs are currently being tested in the cancer clinic. And, central nervous system (CNS)-available medicines are being developed for the treatment of neurodegenerative diseases.

This month, experts met up at Discovery on Target 2012 to share the latest epigenetic therapeutic strategies and their potential in the clinic going forward.

The meeting, which took place on October 1-2 2012 in Boston, highlighted emerging medicines for a wide-range of medical conditions including diabetes, sickle cell anemia and cardiovascular disease. 

 

Overcoming obstacles Researchers first looked at general histone deacetylase inhibitors including trichostatin A in hopes to boost levels of neuroprotective substances in people with ALS. Image: Riken Institute, Japan.

Researchers first looked to epigenetic strategies in the late 1970s to treat cancer – hoping to stop the disease in its tracks by switching on tumor suppressive and tumor-killing genes. General HDAC-targeting medicines appeared promising in preclinical studies.  But concerns of heart problems slowed their entrance into the clinic. Only two HDAC blockers are currently FDA-approved for use and only for the treatment of a rare form of the disease. 

“The field is littered with failures,” says oncologist Kapil Dhingra MBBS. “Let’s call it a failure of blind enthusiasm.”

The field, however, appears to be turning a corner according to Dhingra, former head of Roche Oncology.  A growing number of emerging HDAC-targeting medicines appear to be safe and exhibit “acceptable” toxicity profiles.  But drug developers still remain in “phase II exploration mode” – looking largely for optimal combinations with other medicines to treat specific forms of the disease.

For researchers developing treatments for neurodegenerative conditions, however, the generation of safe and effective medicines are not the only challenges according to Repligen’s Senior Director of Preclinical Development Vincent Jacques PhD.  These medicines need to be efficiently and effectively delivered into the central nervous system. “Most histone deacetylase inhibitors on the market today do not cross the blood brain barrier,” explains Jacques.

To meet these challenges, a growing number of scientists are looking to specific structural classes of histone deacetylase inhibitors such as benzamides which appear to be relatively safe, tolerable and can get into the brain and spinal cord. 

Broad Institute's Stanley Center Director of Medicinal Chemistry Edward Holson PhD introduced drugs that appear to be primarily targeting HDAC3 that might be helpful in Alzheimer’s disease according to preliminary preclinical studies presented at DOT 12.  And, Repligen’s Vincent Jacques PhD presented a clinical update on their lead candidate, RG2833, targeting HDAC1 and HDAC2 which currently is in phase I clinical trials for Friedrich’s ataxia. Whether a next-generation pan or selective HDAC-targeting medicine is the best choice is an open question and remains hotly debated in the field.

No study published to date has evaluated the benefits of any of these emerging medicines in ALS.

 

Tubastatin A Researchers are developing derivatives of HDAC6 blocker tubastatin A in hopes to generate medicines that help  prevent transplant rejection and/or complications. 

Protect and serve

Researchers first looked toward epigenetic medicines as a potential treatment for ALS in hopes to boost the production of potentially ALS-slowing neuroprotective substances. But a growing number of scientific studies suggest that inhibiting these histone-modifying enzymes might do much more to help fight the disease. 

Treatment with HDAC6 blockers might “wake up” certain populations of regulatory T cells (Tregs), according to Children’s Hospital of Philadelphia (CHOP) organ transplant pathologist Wayne Hancock MBBS PhD, reducing inflammation. Elimination of HDAC6 appears to prevent transplant arteriosclerosis, a major life-threatening complication of heart transplants that occurs post-surgery according to preclinical studies Hancock presented at DOT12. What’s more, treatment with HDAC6 inhibitors appears to boost Treg function and protect mouse models against heart transplant rejection. Now, studies are underway at CHOP to determine if these same medicines can also help prevent heart transplant complications.

“These are the cells that keep you on the straight and narrow,” explains Hancock. 

Including potentially people with ALS.  Recent studies from Houston’s Methodist Hospital neurologist Stan Appel MD found that Tregs appear to help protect the motor nerves from destruction – reducing microglial-based neuroinflammation and extending survival in mouse models of disease.  What’s more, the larger the numbers of circulating Tregs in people with ALS, the lower the progression rate of their disease according to a 2011 study. Treating people with ALS with HDAC6-targeting medicines therefore might boost the abilities of these cells to help keep neuroinflammation in check and thereby slow down the disease.

But according to Duke University School of Medicine research scientist Tso-Pang Yao PhD, the generation of HDAC4 inhibitors still remains a high priority – particularly for those developing treatment strategies for ALS.  The deacetylating enzyme appears to be turned up in ALS and activates the production of proteins in skeletal muscle - resulting in muscle atrophy according to his studies. Potential HDAC4 blockers therefore might boost muscle strength in people with the disease.

To learn more about emerging medicines that may help reset chemical switches in people with ALS, check out our recent feature: Breaking the code of silence in ALS.  To find out about the emerging role of T cells in ALS, tune into our podcast Symphony in M with Houston Methodist Hospital neurologist Stan Appel MD.

References

Beier, U.H., Wang, L., Han, R., Akimova, T., Liu, Y., Hancock, W.W. Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms. Science Signaling 5(229), ra45. Abstract | Full Text (Subscription Required)

Kalin, J.H., Butler, K.V., Akimova, T., Hancock, W.W. and Kozikowski, A.P. (2012) Second-generation histone deacetylase 6 inhibitors enhance the immunosuppressive effects of Foxp3+ T-regulatory cells. Journal of Medicinal Chemistry 55(2), 639-651. Abstract | Full Text

de Zoeten, E.F. et al. (2011) Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3(+) T-regulatory cells.  Molecular and Cell Biology 31(10), 2066-2078. 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, 1293-1314. Abstract | Full Text

Zhao W, Beers DR, Liao B, Henkel JS, Appel SH. (2012) Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms. Neurobiology of Disease 48(3), 418-428. 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. Abstract | Full Text (Subscription Required)

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

Further Reading

Kazantsev, A.G. and Thompson, L.M. (2008) Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nature Reviews Drug Discovery 7(10): 854-868. Abstract | Full Text (Subscription Required)