Categories: In The Pipeline , Watchlist

ALS clinical trial nears T off

clock March 10, 2014

regulatory T cell FOXp3 antigen presenting cell dendritic cell ALS MND

 

Par-foxP3? Regulatory T cells (red) may help protect motor neurons in people with ALS in part by reducing the production of inflammatory substances by key immune cells (blue) including effector T cells that infilitrate the CNS. Image: John R James PhD and Ron Vale PhD. Courtesy of Howard Hughes Medical Institute. All rights reserved. 

More than 200,000 people are diagnosed with ALS every year around the globe. About 10% of people with ALS will live at least 5 – 10 years. But many more survive only 2 -3 years with the disease.

Researchers are working hard to understand why certain people may live longer with ALS in hopes to design therapies that slow progression of the disease. 

An emerging competitive advantage in the ALS fight is a high number of regulatory T cells, key immune cells that help keep inflammation in check.  

People who survive at least 6 years after diagnosis according to Methodist Neurological Institute’s Stan Appel MD PhD appear to have three times the number of regulatory T cells in circulation compared to those that live at most 2-3 years. What’s more, the larger the number of regulatory T cells that are on ‘the course’ in people with ALS, the slower the progression of their disease. 

The results suggest that increasing populations of regulatory T cells may help more people with ALS be on their 'A' game. But how to boost these cells in people with ALS remains unclear.

A growing group of clinicians in France suspect that low dose interleukin 2 (IL-2) may help expand regulatory T cells in people with ALS.  And, thereby slow the progression of their disease. 

The treatment strategy, originally developed to fight transplant rejection, is one of the first potential ALS treatments to be tested in the clinic that aims to supe up regulatory T cells in people with the disease.

A phase I/II clinical trial is scheduled to begin in April of 2014.

regulatory T cell FOXp3 ALS MND

 

Bump and run? The surface of regulatory T cells are highly decorated with high affinity receptors that tightly bind IL-2 - enabling them to be potentially selectively expanded by lose doses of IL-2. Image: NIAID.

In the mid 2000s, Dana Farber Cancer Institute’s Jerome Ritz MD turned to IL-2 in hopes to promote tolerance in stem cell transplant recipients at high risk of developing grafts versus hosts disease (GVHD).

The growth substance, at low doses, according to studies led by Ritz, appears to stimulate the expansion of regulatory T cells. But leave troublesome effector T cells, lacking high affinity IL-2 receptors, untouched.

The treatment strategy, according to a growing number of phase I and phase II clinical studies, appears to double numbers of circulating regulatory T cells - at least in people at high risk of GVHD. And, boost levels of FOXP3 – a key regulatory substance critical to help these cells keep inflammation in check.

The approach is being developed to help combat transplant rejection in people with certain blood diseases. And, people battling complications of certain viral infections.

Now, Assistance Publique – Hôpitaux de Paris’ Gilbert Bensimon MD PhD is gearing up to put low dose IL-2 to the test in people with ALS in hopes to increase numbers of regulatory T cells and thereby slow progression of their disease.

A phase I/II randomized placebo-controlled clinical trial is to take place in France. Participating sites include Centre Hospitalier Régional Universitaire de Nîmes and Centre Hospitalier Régional Universitaire de Montpellier.

The 6 month study aims to evaluate the safety and tolerability of low doses of IL-2 in people with ALS.  And, determine the ability of the drug to boost regulatory T cells in people with the disease.

24 people with ALS are expected to participate.

The first results are expected sometime in 2015.

***

To learn more about the role of regulatory T cells in ALS, check out Regulating ALS. To find out about other emerging treatment strategies to boost them in people with ALS, check out ALS, extracellular matrix reloaded? and Emerging potential of HDACIs in ALS.

Patient Resources

Immunomodulation in ALS (IMODALS): A phase I/II of safety and activity of low dose interleukin in ALS.  Contact | ALS TDI | Website 

References

Kennedy-Nasser, A. et al. (2014) Ultra low-dose IL-2 for graft-versus-host disease prophylaxis after allogeneic HSCT mediates expansion of regulatory T cells without diminishing anti-viral and anti-leukemic Activity.  Clinical Cancer Research  doi:10.1158/1078-0432.CCR-13-3205 Abstract | Full Text  (Subscription Required)

Matsuoka, K. et al. (2013) Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease.  Science Translational Medicine 5(179), 179ra43.  Abstract  |  Full Text  (Subscription Required)

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

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

Saadoun, D., Rosenzwajg, M., Joly, F., Six, A., Carrat, F., Thibault, V., Sene, D., Cacoub, P. and Klatzmann, D. New England Journal of Medicine 365(22), 2067-2077.  Abstract  Full Text

Koreth, J. et al. (2011) Interleukin-2 and regulatory T cells in graft-versus-host disease.  New England Journal of Medicine 365(22), 2055-2066.  Abstract  |  Full Text

Zorn, E. et al. (2006) IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo.  Blood 108(5), 1571-1579.  Abstract  |  Full Text

Further Reading

Bluestone, J.A. (2011) The yin and yang of interleukin-2-mediated immunotherapy. New England Journal of Medicine 365(22), 2129-2131.  Abstract  |  Full Text (Subscription Required)

 

 

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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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US team puts NeuRX DPS through its paces

clock October 22, 2013

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

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

stem cell induced pluripotent iPS ALS Neuralstem Brainstorm Q Therapeutics Corestem

 

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

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

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

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

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

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

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

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

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

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Categories: Watchlist

Actemra for ALS?

clock October 22, 2013

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

ALS MND potential therapies clinic

 

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

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

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

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

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

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

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Categories: Watchlist

Immunosuppressants revisited

clock October 22, 2013

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

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

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

immunosuppressant CellCept mycophenolate mofetil ALS

 

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

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

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

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

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

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

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

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

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

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

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Neuralstem phase II begins

clock October 22, 2013

 

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

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

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

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

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

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

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

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

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

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What's in the ALS pipeline -2013?

clock August 30, 2013

ALS MND potential therapies clinic

 

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

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

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

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

A long and winding road

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

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

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

mitochondria dysfunction ALS

 

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

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

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

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

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

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

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

Patient Resources

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Mexiletine in Sporadic ALS   Contact   |   ALS TDI    |    Website

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

Gilenya in Amyotrophic Lateral Sclerosis   Contact   |   ALS TDI    |    Website     

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

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

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Categories: Featured , From The Bench , Watchlist

Modeling ALS: The Game's A FUS

clock August 5, 2013

mouse model ALS

 

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

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

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

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

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

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

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

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

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

An RNA world?

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

FUS ub inclusions als

 

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

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

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

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

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

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

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

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

***

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

References

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

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

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

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

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

Further reading

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

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Categories: From The Bench , Watchlist

Regulating ALS

clock April 18, 2013

Treg regulatory T cells FOXP3 ALS

 

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

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

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

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

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

The study is published next month in Biochemical Pharmacology.

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

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

high-throughput screening ALS drugs

 

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

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

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

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

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

***

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

References

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

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

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

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

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Categories: Watchlist

Can the NeuRX DPS boost survival?

clock December 14, 2012

 

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.

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