Categories: Watchlist

Tirasemtiv phase IIB powers up

clock December 14, 2012

 

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.

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The oligodendrocyte, a new player in ALS?

clock July 19, 2012

oligodendrocyte myelin axons ALS

 

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

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

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

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

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

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

oligodendrocyte axons lactate ALS

 

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

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

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

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

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

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

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

References

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

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

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

Further Reading

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

 

 

 

 

 

 

 

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Rethinking ALS

clock June 7, 2012

Brain EF Agosta 300

 

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

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

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

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

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

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

The results are published this month in Neurobiology of Aging.

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

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

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

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

References

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

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

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

Further reading

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

 

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French team rethinks potential of the DPS

clock April 30, 2012

 

The NeuRX Diaphragm Pacing System. Image: Synapse Biomedical.

One of biggest challenges treating ALS is breathing difficulties which occur due to the gradual weakening and decline of the respiratory muscles.  Researchers nevertheless are working hard to develop treatment strategies to keep these respiratory muscles moving to help people with ALS breathe easier.

One potential strategy called phrenic pacing hopes to keep the diaphragm moving by boosting the stamina of the respiratory muscles through the implantation of a device that regularly stimulates the connecting nerves. The FDA-approved device, called the NeuRX diaphragm pacing system (DPS), is available by prescription for patients experiencing frequent trouble breathing (chronic hypoventilation).

But a group of physicians from Assistance Publique – Hôpitaux de Paris led by respiratory specialist Thomas Similowski MD PhD thinks that the NeuRX DPS could benefit a lot more people with ALS.  They suspect the device, introduced at the very first signs of breathing difficulties, might jump start the training of these muscles to keep the diaphragm moving even longer - postponing the need for non-invasive ventilation.

Now, the French team is gearing up to put their treatment strategy to the test in people with ALS.  The double-blind randomized clinical trial, called RespiStimALS, is to be conducted at the Pitié-Salpêtrière Hospital in Paris.  All participants are to be monitored three times monthly for 2 years.  Outcomes include: reductions in respiratory decline (forced vital capacity), improvements in sleep quality and overall survival.  74 people with ALS are expected to participate.

The trial is scheduled to begin in June 2012.

To learn more about the NeuRX DPS and how the device might help people with ALS, read DPS Sleep.  To read about the ongoing NeuRX DPS trial in the UK, check out UK Gears Up To Put DPS Through Its Paces.  To find out about other strategies to help people with ALS breathe easier, read CK-357, helping pALS live strong?

References

Gonzalez-Bermejo, J., et al. (2011) Diaphragm pacing improves sleep in patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis. doi:10.3109/17482968.2011. 597862  Abstract Full Text (Subscription Required)

Onders, R.P., et al. (2009) Complete worldwide operative experience in laparoscopic diaphragm pacing: results and differences in spinal cord injured patients and amyotrophic lateral sclerosis patients. Surgical Endoscopy, 23(7): 1433-1440.  Abstract | Full Text (Subscription Required)

Further Reading

Ducko, C. (2011) Clinical advances in diaphragm pacing. Innovations: Technologies and Techniques in Cardiothotacic and Vascular Surgery 6(5), 289-297. Abstract | Full Text (Subscription Required)

Marion, D.W. (2011) Diaphragm Pacing.  UpToDate.  Excerpt |  Full Text (Subscription Required)  

Patient Resources

Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation (RespiStimALS). Contact | ALS TDI Website 

Diaphragm Pacing in Motor Neuron Disease (DiPALS) Study. Contact | ALS TDI Website 

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The ABCs of ALS Therapies

clock April 27, 2012

blood brain barrier

 

Keep out.  The blood brain and spinal cord barriers fortify the walls of tiny blood vessels that snake through the brain and spinal cord - preventing toxic substances in the blood from entering the central nervous system. Image: Ben Brahim Mohammed, Wikimedia Commons.

More than 100 medicines have been tested as possible treatments for ALS. But only riluzole is FDA-approved: a drug that at best, moderately treats the disease.

A considerable obstacle toward developing more effective treatments for neurologic diseases including ALS is the blood brain and spinal cord barriers which in part, keep certain toxic substances circulating in the blood out of the central nervous system. These cellular-based barriers block potential medicines from getting into the brain and spinal cord. And, drug pumps called ABC transporters installed within these barriers kick drugs that sneak into ALS-ravaged nerves back out into the blood.

But according to a new study led by Thomas Jefferson University neuroscientist Davide Trotti PhD in Pennsylvania, creating medicines for ALS might be especially challenging because two of these drug pumps appear to kick into high gear over the course of the disease.  

The researchers found that levels of ABC transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) increased in people with ALS.  And in mice, these pumps appeared to kick out over 50% more drugs from the spinal cord.

These ABC transporters are the same drug pumps demonstrated previously by scientists at Université Paris-Sud in France to have the ability to kick riluzole out of the brain.

The results are published this month in Neurobiology of Disease.

The US team measured the levels and pumping action of 8 ABC transporters in the blood brain and spinal cord barriers in two mouse models of ALS.

drug efflux pharmacoresistance ALS p-glycoprotein

 

Going out?  Drug pumps (purple) embedded in the blood brain and spinal cord barriers may kick potential ALS medicines (blue) out of the central nervous system (CNS) over the course of the disease - rendering them much less effective.  Adapted from Osherovich, L. (2009), SciBX. Courtesy of Nature Publishing Group. All rights reserved.

The team found that the numbers of two of these drug pumps – P-glycoprotein and breast cancer resistance protein (BCRP) - appeared to increase at clinical onset - up to nearly doubling over the course of the disease. 

The drug pump boost appeared to be localized to the motor cortex (muscle-moving region of the brain) and the spinal cord.  The same regions ravaged by the disease.

The results demonstrate the importance of rigorous preclinical testing of emerging ALS drugs before making go/no-go decisions. This includes chronic dosing studies to determine the appropriate dosing strategy to use during testing to ensure adequate delivery to the brain and spinal cord throughout the course of the disease.    

Looking ahead, the team suggests testing combination therapies that include pump blockers such GlaxoSmithKline’s elacridar and Xenova’s tariquidar to boost CNS exposure and maximize drug efficacy.  First introduced as a potential therapeutic option for drug-resistant cancers, such strategies are also being tested as a possible treatment for antibiotic-resistant bacterial infections.

References

Jablonski, M.R., Jacob, D.A., Campos, C., Miller, D.S., Maragakis, N.J., Pasinelli, P. and Trotti D. (2012) Selective increase of two ABC drug efflux transporters at the blood-spinal cord barrier suggests induced pharmacoresistance in ALS. Neurobiology of Disease doi:10.1016/j.nbd.2012.03.040. Abstract | Full Text (Subscription Required)

Milane, A., Fernandez, C., Dupuis, L., Buyse,M., Loeffler, J.-Philippe, Farinotti, R.,Meininger, V. and Bensimon, G., 2010. P-glycoprotein expression and function are increased in an animal model of amyotrophic lateral sclerosis. Neuroscience Letters 472(3), 166–170. Abstract | Full Text (Subscription Required)

Milane, A., Vautier, S., Chacun, H., Meininger, V., Bensimon, G., Farinotti, R. and Fernandez, C. (2009) Interactions between riluzole and ABCG2/BCRP transporter. Neuroscience Letters 452(1), 12–16. Abstract | Full Text (Subscription Required)

Boston-Howes, W., Williams, E.O., Bogush, A., Scolere, M., Pasinelli, P. and Trotti, D. (2008) Nordihydroguaiaretic acid increases glutamate uptake in vitro and in vivo: therapeutic implications for amyotrophic lateral sclerosis. Experimental Neurology 213(1), 229–237. Abstract | Full Text

Milane, A., Fernandez, C., Vautier, S., Bensimon, G., Meininger, V. and Farinotti, R. (2007) Minocycline and riluzole brain disposition: interactions with p-glycoprotein at the blood–brain barrier. Journal of Neurochemistry 103(1), 164–173. Abstract | Full Text (Subscription Required)

Further Reading

Neuwelt, E.A. et al. (2011) Engaging neuroscience to advance translational research in brain barrier biology. Nature Reviews Neuroscience 12(3), 169-182. Abstract | Full Text (Subscription Required) 

Löscher, W. and Potschka, H. (2005) Drug resistance in brain diseases and the role of drug efflux transporter. Nature Reviews Neuroscience 6(8), 591-602. Abstract | Full Text (Subscription Required) 

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Neuralstem: surging immunosuppression?

clock April 12, 2012

human neural stem cells

 

Transplant stat.  Emory University School of Medicine neurosurgeon Nicholas Boulis MD injected between 0.5 and 1 million neural stem cells (above) in the lumbar section of ALS patients' spinal cords. Image: Corey Seehus, Brain Cells Inc for the 2010 GE Healthcare Image Competition.

Researchers estimate that more than 70% of motor neurons could be lost in people with ALS just one year after being diagnosed with the disease. To stem the tide of neurodegeneration, scientists are working hard to develop neuroprotective therapies to help keep their muscles moving.

One such potential treatment strategy, being developed by Maryland’s Neuralstem Inc., hopes to deploy neuronal bodyguards into the spinal cord that crank out protective substances which may shield the motor nerves from further destruction. The experimental stem cell transplantation procedure, performed during surgery, involves the direct injection of healthy neural stem cells into the spinal cord. The transplanted stem cells according to preclinical studies may give rise to populations of so-called interneurons that might plug directly into ALS-ravaged motor neurons, providing them life support.

In 2010, US physicians launched a phase I clinical trial to evaluate the safety of Neuralstem’s stem cell transplantation procedure. Patients received stem cell injections in the lumbar (leg-moving) region of the spinal cord. 12 people with ALS participated. 

Now, the team reports the first results from the phase I clinical trial.

The stem cell transplantation procedure appears to be safe and does not appear to aggravate the disease.  But, the immunosuppressants prescribed to prevent rejection of these transplanted stem cells were not well-tolerated by trial participants.

The results are published in the journal Stem Cells.

Emory University School of Medicine neurosurgeon Nicholas Boulis MD injected up to 1 million neural stem cells into the spinal cords of 12 ALS patients post-laminectomy.  Patients received anti-rejection medicines routinely used in whole organ transplants before and after surgery.

The team found that the procedure appeared to be safe and 6 to 18 months later did not rapidly worsen patients’ condition according to ALS-FRS, forced vital capacity and other functional measures. 

But researchers discovered that ALS patients could not tolerate the immunosuppressants (mycophenolate mofetil and tacrolimus) prescribed post-surgery.  Most trial participants had to drop or reduce the dosage of at least one of the two anti-rejection medicines due to chronic bloating, diarrhea and vomiting.  And, 2 out of 12 patients had to be taken off both drugs altogether due to the inability to control these symptoms through other medications.

adult mesenchymal stem cells from bone marrow

 

Under adult supervision. Scientists are creating potentially neuroprotective astrocyte-like cells from adult (mesenchymal) stem cells obtained from the patient's own bone marrow in hopes to slow down the disease. Image: Stem Cell Institute, Panama.

The jury is still out however whether a personalized stem cell therapy such as Brainstorm Cell Therapeutics’ NurOwn is a better way to go – particularly for people with inherited forms of ALS. The treatment strategy, which uses the patients’ own bone marrow to generate neurotrophin-producing cells, eliminates the need for immunosuppressants. But these transplanted cells according to some experts contain potentially ALS-triggering mutations which might also further contribute to the disease.

Neuralstem’s phase I clinical trial remains ongoing. Six people with ALS are expected to be implanted with stem cells in the cervical (diaphragm-moving) region of the spinal cord sometime this spring or summer. The trial is expected to be completed in October 2012.

Brainstorm Cell Therapeutics’ NurOwn phase I/II clinical trial is currently ongoing in Israel. Researchers are expected to launch a phase I/II ALS clinical trial in the US sometime in 2012.

References

Glass, J.D., Boulis, N.M., Johe, K., Rutkove, S.B., Federici, T., Polak, R., Kelly, C. and Feldman, E.L.(2012) Lumbar intraspinal injection of neural stem cells in patients with ALS: results of a phase I trial in 12 patients. Stem Cells, doi:10.1022/ stem.1079. Abstract | Full Text (Subscription Required)

Xu, L., Ryugo, D.K., Pongastaporn, T., Johe, K. and Koliatsos, V.E. (2009) Human neural stem grafts in the spinal cord of SOD1 transgenic rats: differentiation and structural integration into the segmental motor circuitry. Journal of Comparative Neurology 514(4), 297-309. Abstract Full Text

Xu, L., Yan, J., Chen, D. Welsh, A.M., Hazel, T., Johe, K., Hatfield, G. and Koliatsos, V.E. (2006) Human neural stem cell grafts amerliorate motor neuron disease in SOD-1 transgenic rats. Transplantation 82(7), 865-875. Abstract Full Text (Subscription Required)

Further reading

Boulis, N.M., Federici, T., Glass, J.D., Lunn, J.S., Sakowski, S.A. and Feldman, E.L. (2012) Translational stem cell therapy for amyotrophic lateral sclerosis. Nature Reviews Neurology 8(3), 172-176. Abstract Full Text (Subscription Required) 

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

Patient Resources

Human Spinal Cord Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis (ALS)  ALSTDI | Website | Contact

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

Note: We will update this information when details in regards to Brainstorm's US trial become available.

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ALS motor neurons made easy?

clock April 5, 2012

induced motor neurons ALS TDP-43

 

Lights camera action potential.  Scientists recreated diseased motor neurons by reprogramming skin cells from a person with a rare inherited form of ALS linked to a mutation in TDP-43. Adapted from Bilican, B et al. (2012). Courtesy of the National Academy of Sciences Press.  All rights reserved.

For more than 150 years, ALS has been recognized by experts as a motor neuron disease. But scientists still remain unsure why these cells are especially vulnerable to destruction in people with ALS or why they ultimately fail during the course of the disease.

An international group of neuroscientists led by University of Edinburgh’s Siddharthan Chandran MD PhD, King’s College London’s Christopher Shaw MBChB MD FRACP FRCP and Columbia University’s Tom Maniatis PhD hopes to begin to answer these questions by recreating ALS-ravaged motor neurons in laboratory dishes and studying their neurodegeneration.

Now, the UK-US research team reports that they have hit their first milestone: the generation of a so-called induced pluripotent stem (iPS) cell line created from an ALS patient skin biopsy that can be used to cook up motor neurons in the laboratory. Incredibly, the motor neurons induced appear to be in working order - capable of firing electrical signals used to 'tell' muscles to move - and exhibit tell-tale signs of the disease.

This is the first time that researchers have been able to recreate apparently functional motor neurons in the laboratory from a person with ALS.

The study is published this month in the Proceedings of the National Academy of Sciences.

ALS motor neuron iPS TDP-43 not mislocalized

 

Not an exact match. Researchers discovered that induced ALS motor neurons accumulate misfolded TDP-43 (green). But unlike more than 90% of people with ALS, these aggregates do not build up in the cytoplasm. Image: Bilican, B et al. (2012).  Courtesy of the National Academy of Sciences Press.  All rights reserved.

The UK-US research team created a 'line' of ALS iPS cells by turning back the cellular clocks of a patient's skin cells and culturing them. The scientists then splashed these iPS cells with a few chemicals to push them into motor neuronal mode.

Peering under the microscope, the researchers found that the resulting motor neurons somewhat resembled those in people with ALS. The cells were nearly 3-times more prone to degeneration. And, misfolded proteins accumulated in them.

Meanwhile, neuroscientists at Nationwide Children’s Hospital in Ohio hope to up the ante by introducing key inflammation instigators such as microglia and astrocytes into the mix to truly recreate ALS in laboratory dishes. Just last September, the research team led by neuroscientist Brian Kaspar PhD reported the successful reconstitution, using spinal cord tissue from ALS patients, of a key aspect of astrocytosis – the astrocyte-mediated destruction of neighboring motor neurons - which in part fuels the progression of the disease.

Looking ahead, these cellular systems could help scientists uncover underlying mechanisms of ALS and at the same time, pave the way toward the development of personalized therapies to treat the disease.

To find out more about how scientists hope to use stem cells to better understand why motor neurons degenerate in people with ALS, read Dishing ALS

References

Bilican, B. et al. (2012) Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proceedings of the National Academy of Sciences, doi:10.1073/ pnas.1202922109. Abstract | Full Text (Open Access)

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)

Further Reading

Son, E.Y., Ichida, J.K., Wainger, B.J., Toma, J.S., Rafuse, V.F., Woolf, C.J. and Eggan, K. (2011). Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell, 9(3), 205-218Abstract Full Text (Open Access)

Dimos, J.T. et al. (2008) Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218-1221. Abstract Full Text (Subscription Required)

Di Giorgio, F.P., Boulting, G.L., Bobrowicz, S., and Eggan, K.C. (2008). Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell, 3(6), 637-648. Abstract | Full Text (Subscription Required)

Marchetto, M.C., Muotri, A.R., Mu, Y., Smith, A.M., Cezar, G.G., and Gage F.H. (2008). Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell, 3(6), 649-657. Abstract | Full Text (Subscription Required)

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CK-357, helping pALS live strong?

clock March 6, 2012

 

Power gain.  CK-357 may boost the power of fast skeletal muscles by increasing their sensitivity to weak electrical impulses generated by deteriorating motor nerves. CK-357 might be particularly useful to boost diaphragm function because these muscles contain nearly 50% fast-twitch muscle fibers. Courtesy of Nature Publishing Group. All Rights Reserved.

In people with ALS, the diaphragm and intercostal muscles gradually weaken often leading to respiratory distress and failure.  In hopes to keep these muscles moving, Case Western University School of Medicine surgeon Raymond Onders MD FACS introduced a device, now approved by the FDA for people with ALS with breathing difficulties, called the NeuRX DPS which may boost the stamina of these muscles.  

But researchers from San Francisco’s Cytokinetics Inc. think that they might have a simpler solution: the experimental drug CK-2017357 (CK-357). Introduced in 2008, CK-357 might increase the strength of certain skeletal muscles including those needed for breathing. Now, Cytokinetics scientists reveal just how CK-357 works: the drug promises to make the most of weakening neuromuscular junctions by helping fast twitch fibers in skeletal muscles hold on to calcium, enabling more powerful contractions.  These so-called fast skeletal muscles are needed in part, to maintain a healthy breathing rate.

The Cytokinetics’ team anticipates that the drug could be beneficial in the treatment of number of neuromuscular diseases including ALS.

CK-357 increases the calcium affinity of fast skeletal muscle troponin

 

Sensitive muscle? Electrical signals from the motor nerves enable skeletal muscles to move by pulling the wrench out of the muscular works - troponin - through the release of calcium. CK-357 may strengthen muscles by increasing the affinity of fast skeletal troponin for calcium, boosting the power of these contractions. Adapted from Nature Education. Original source: Lehman, W. et al. (1994). Courtesy of Nature Publishing Group. All Rights Reserved.

Performance testing

Physicians are currently evaluating the safety and tolerability of multiple doses of CK-357 in people with ALS.  The multi-institutional US team, led by State University of New York neurologist Jeremy Shefner MD PhD, are also checking for improvements in patients’ muscle function including breathing ability.  The two 14 day placebo-controlled phase II clinical trials are expected to be completed by the end of March 2012. About 48 ALS patients are participating.

Meanwhile, researchers in England and France are gearing up to put the NeuRX DPS to the test to determine whether the device improves the quality of life and extends survival of people with ALS. The first results of these clinical trials are expected in early 2015.

Reference

Russell, A.J. et al. (2012) Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nature Medicine doi:10.1038/nm.2618. Abstract | Full Text (Subscription Required)

Further Reading

Hardiman, O., van den Berg, L.H. and Kiernan, M.C. (2011) Clinical diagnosis and management of amyotrophic lateral sclerosis. Nature Reviews Neurology 7(11), 639-649. Abstract | Full Text (Subscription Required)

Hardiman, O. (2011) Management of respiratory symptoms in ALS. Journal of Neurology 258(3), 359-365. Abstract | Full Text (Subscription Required)

Patient Resources

Please note: These clinical trials are ongoing but are not recruiting.

A Study to Evaluate the Effects of Multiple Doses of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS)  ALSTDI | Website | Contact

Dose Titration Study to Test Safety and Effects of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS)  ALSTDI | Website | Contact 

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C9ORF72 Comes Into Focus

clock February 28, 2012

FTD FTLD MRI

 

FTLD Explained.  FTLD occurs when certain regions of the brain including those involved in executive function - critical thinking, problem solving and complex decision-making - shrink (red) due to neuronal loss.  FTLD is also known as frontotemporal dementia (FTD).  Here, an MRI of a person with a form of FTLD similar to ALS-FTLD is shown. Adapted from Whitwell, J.L. and Josephs, K.A. (2012). Courtesy of Nature Publishing Group. All Rights Reserved.

Neurologists may need to keep an eye out for cognitive and behavioral changes in people showing signs of ALS, according to a new study. 

The research team, led by Trinity College Dublin neurologist Orla Hardiman MD FRCP, found that 50% of people examined with the most common form of familial ALS identified to date also showed signs of frontotemporal lobar degeneration (FTLD).  The brain disorder might result in difficulties in critical thinking, problem solving and making complex decisions.

The study, which included 20 people with familial ALS harboring repeat expansions in the C9ORF72 gene, is the first to clinically describe this form of ALS.

The results are published in the March issue of Lancet Neurology.

Scientists first suspected that ALS might fall on the same clinical spectrum as FTLD in 2000 when a research team led by Massachusetts General Hospital neurologist Robert Brown MD PhD identified families with a history of both diseases. Just last fall, two independent research teams discovered one such cause of this so-called ALS with FTLD: repeat expansions in the gene, C9ORF72. 

Now, researchers report that people harboring repeat expansions in the C9ORF72 gene might have a distinct subtype of ALS. The C9ORF72-linked form of ALS appears to be earlier onset, about twice as rapidly progressing and may result in certain cognitive and behavioral changes including increased indifference and difficulties in problem solving and making complex decisions.  The disease appears to be distinguished from other forms of ALS using advanced magnetic resonance imaging (MRI)

The study is one of three studies this month that confirms that repeat expansions in the C9ORF72 gene are the most common cause of inherited forms of ALS, ALS-FTLD and FTLD.

To test or not to test

Most people with C9ORF72-linked ALS identified by the team had a strong history of neurodegenerative disease.  But researchers caution that larger studies are needed to determine whether or not genetic testing is warranted - especially for family members of patients without any signs of either ALS or FTLD. The penetrance is variable.  Nearly one out of every three people with repeat expansions in the C9ORF72 gene (6 out of 20) lived into their 80s and 90s and showed no signs of the disease.  What’s more, researchers remain unsure how many of these repeat sequences in the C9ORF72 gene are needed to trigger the disease.

To further explore the role of the brain in ALS, check out MRI, Make that a double.  To learn more about the emerging role of C9ORF72 in ALS, read Silence is not golden

References

Byrne, S. et al. (2012) Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study.  Lancet Neurology 11(3), 232-240. Abstract | Full Text (Subscription Required)

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)

Hsiung, G.Y. et al. (2012) Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain doi: 10.1093/brain/awr354. Abstract | Full Text (Subscription Required)

Simón-Sánchez J, et al. (2012) The clinical and pathological phenotype of C9orf72 hexanucleotide repeat expansions. Brain doi: 10.1093/brain/awr353. Abstract | Full Text  (Subscription Required)

Whitwell, J.L. & Josephs, K.A. (2012)  Neuroimaging in frontotemporal lobar degeneration—predicting molecular pathology Nature Reviews Neurology doi:10.1038/nrneurol.2012.7.  Abstract | Full Text (Subscription Required)

Further Reading

Andersen, P.M. (2012) Mutation in C9orf72 changes the boundaries of ALS and FTD.  Lancet Neurology 11(3), 205-207.  Full Text (Subscription Required)

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

Learn more about cognitive and behavioral changes in people with ALS

 

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Categories: Watchlist

UK gears up to put DPS through its paces

clock February 13, 2012

 

The NeuRX Diaphragm Pacing System. Image: Synapse Biomedical.

Researchers in the UK will soon be putting the NeuRX diaphragm pacing system (DPS) to the test to determine whether the device in combination with non-invasive ventilation (NIV) improves the quality of life and extends survival of people with ALS experiencing respiratory weakness. The clinical trial, known as Diaphragm Pacing In Motor Neuron Disease (DiPALS), will be conducted at up to 10 National Health Service (NHS) hospitals in the UK. Trial participants will receive either NIV or NIV and be implanted with the NeuRX DPS.  108 people with ALS are expected to enroll.  The trial is expected to be completed in 2014.

To read more about the NeuRx diaphragm pacer and how the device might benefit people with ALS, read our recent feature DPS Sleep.

Further Reading

Scherer, K. and Bedlack, R.S (2012) Diaphragm pacing in amyotrophic lateral sclerosis: a literature review. Muscle and Nerve 46(1), 1-8. Abstract Full Text (Subscription Required)

Marion, D.W. (2011) Diaphragm Pacing. UpToDate.  Excerpt  Full Text (Subscription Required)  

Patient Resources

Diaphragm Pacing in Motor Neuron Disease (DiPALS) Study  Contact | ALS TDI  |  Website 

Update 1/25/13: The trial is now ongoing.  At least 7 sites in the UK are recruiting people with ALS MND including the Royal Free Hospital in London and the John Radcliffe Hospital in Oxford.

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