Categories: Featured , Postcards

Neuralstem Phase 2 Clinical Trial Results Annouced

clock March 13, 2015

Neuralstem recently announced via press release results from a Phase 2 clinical trial of their fetal-derived stem cell treatment, NSI-566. According to their statement, only one person in the 15-person study failed to tolerate the surgical procedure involving the injection of up to 16 million stem cells directly into the spinal cord. The primary endpoint defined for the study was safety. From early analysis of the data, the company reports that endpoint was met. An earlier clinical trial conducted in ALS patients also reported similar results regarding safety.

Nerualstem also included early analysis on the effects of their stem cell treatment on the progression of ALS.  According to their press release, nearly half of the people in the trial responded to the treatment in a positive way. A positive response is defined by Neuralstem as a positive change in the rate of progression as measured by ALSFRS-R or a positive change in grip strength tests. No further details were provided about this cohort, which they term the responder group. The other half of the patients in the trial, termed the nonresponder group, saw a negative change in rate of progression as measured by ALSFRS-R or a negative change in grip strength tests.  Nowhere in the release did they describe an objective measure that could differentiate a responder from a non-responder before enrolling a patient in the trial. That work is ongoing according to several of the investigators quoted in the company's press release.

While the trial was not intended to measure efficacy, the data in the press release seemed to suggest that Neuralstem wanted to communicate on that topic. There was no placebo arm in this study and no attempt to compare the data to a standard of care or placebo arm was made in the press annoucements. All patients were given some amount of modified stem cells which the company hoped would engraft into the spine, replacing cells lost to the disease and providing support to remaining motor neurons, however specific dosing for each patient or across the proposed reponder and nonresponder groups were not provided in the press statement. That is not a surprise and Neuralstem stated that it planned to produce more data later in the year at scientific conferences for example.

One analyst who wrote on the Nerualstem press release, compared the reported ALSFRS-R changes in the Phase 2 clinical trial to a historical dataset, PRO-ACT. According to that person's analysis, when the data from all participants are analyzed together against the historical control group, it indicates the treatment may have had an overall adverse effect on disease progression. Such use of historical controls in lieu of placebo control arms in drug trials remains a controversial topic. Principal investigator, Eva Feldman, MD, PhD, states clearly in the company’s release that she intends to move the proposed treatment into a larger controlled trial, which could be interpreted as one including a placebo or standard of care arm. She suggested that the trial may open for enrollment as early as this summer.

It is the opinion of the ALS Therapy Development Institute that the Phase 2 clinical trial was not designed to measure the efficacy of NSI-566. However, we are encouraged by this additional trial finding the treatment and treatment procedure to be safe and tolerable, in general, in people diagnosed with ALS. We believe that Neuralstem should continue its efforts with this treatment, including the organization and execution of additional clinical trials.

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Categories: In Translation , Postcards

TMS: a headstart for PALS?

clock June 19, 2013

NeuRX DPS diaphragm pacing ALS

 

A headstart program? Corticomotor hyperexcitability testing may help clinicans diagnose ALS earlier and develop more effective treatments for the disease.  Learn more by tuning into our Postcard from Sydney.

More than 20 potential treatments for ALS are being tested in the clinic.  But for many people with ALS, the medicines developed may be too little too late.  More than 70% of motor neurons by some estimates are lost in people with ALS one year after the first signs of muscle weakness – the time the disease often takes to be diagnosed.

A growing number of researchers are developing tools to identify people with ALS more quickly in hopes to more effectively treat their disease.  One of these techniques, called threshold tracking transcranial magnetic stimulation (TMS), enables clinicians to measure increased levels of activity of key motor neurons in the brain and spinal cord. The changes, known as corticomotor hyperexcitability, may be an early step in ALS.

The test, developed by Neuroscience Research Australia’s Steve Vucic PhD and Matthew Kiernan MBBS, PhD, DSc, FRACP, may also help clinicians identify people that will likely develop familial ALS - months before the first signs of disease.

Brainstorming ALS

In 1992, Vancouver General Hospital’s Andrew Eisen MD proposed that the overactivity of motor neurons in the brain and spinal cord could lead to ALS by contributing to their destruction.

To put Eisen’s theory to the test, Neuroscience Research Australia’s Steve Vucic PhD and Matthew Kiernan MBBS, PhD, DSc, FRACP, turned to TMS.  The technique enables researchers to measure the activity of key motor neurons by stimulating the motor cortex, the motion-enabling regions of the brain. 

 

Fire when ready  In TMS, a series of magnetic pulses is used to stimulate key circuits of the brain in order to evaluate them. The technique is currently being developed to diagnose and monitor a number of conditions including stroke. Video: Oliver Ende.

The researchers found that increased activity could be detected early in people with ALS – including C9ORF72, the most common form of the disease.  What’s more, these changes according to a small study appeared months before the clinical onset of familial ALS – at least in SOD1-linked disease. 

The results suggest that cortical hyperexcitability could be a general feature of ALS.  And, these changes could be an early sign of disease.

Furthermore, TMS appears to distinguish ALS from other outwardly similar disorders – suggesting that this technique may help diagnose people with the disease.  No significant increases in activity could be detected in people with key neuromuscular disorders often confused with ALS including multifocal motor neuropathy (MMN), spinal muscular atrophy (SMA) and Kennedy’s disease.

Now, the Neuroscience Research Australia team is working hard to bring TMS to the ALS clinic.  The test could be in ALS clinics as early as next summer.

***

To learn more about emerging tools to diagnose ALS, read Imaging ALS.  To find out about potential early treatments of ALS that may reduce hyperexcitability, check out Channeling ALS?

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Categories: Postcards

Cognition in ALS – Measure for Measure

clock June 19, 2013

ECAS cognition executive dysfunction verbal fluency ALS

 

Rethinking cognition in ALS A new multi-domain screening measure aims to identify cognitive changes in people with ALS. Learn more by checking out our Postcard from Scotland.

Nearly 50% of people with ALS by some estimates experience cognitive challenges. But for many people with ALS, these changes can often be undetected. 

Existing screening measures frequently look for difficulties in critical thinking and problem solving (executive function) – overlooking potential challenges including expressing thoughts, interpreting emotions and producing words. What’s more, many of these tools were designed for people with other neurological conditions.  And, do not account for physical challenges inherent to the disease.

Now, University of Edinburgh neuropsychologist Sharon Abrahams PhD hopes to change that by introducing the multi-domain Edinburgh Cognitive and Behavioral Screen (ECAS).  The 15 to 20 minute test, designed to be administered by health professionals, aims to identify people with cognitive challenges as quickly as possible in hopes to better manage their disease.

Ahead of the European Network for the Cure of ALS (ENCALS) 2013 meeting, ALS’s Michelle Pflumm PhD talked to Sharon Abrahams PhD about our growing understanding of cognitive changes in ALS and the impact of the ECAS going forward.

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Categories: Postcards

ALS, Out of Africa

clock November 6, 2012

Africa Kiri

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 SandTo learn about efforts to identify the genetic and environmental contributors of complex genetic diseases in Africa, check out NIH and Wellcome Trust’s H3Africa.

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Categories: Postcards

Climb every mountain

clock July 5, 2012

 

Postcard from Quito Miriam Bucheli PhD talks about ELA-Ecuador and how she hopes the project will help the nation.

Physicians knew children in the 1920s lived in a “lead world”.  Mild cases of colic and muscle spasms were commonplace due to the ingestion of paint chips.  And, children were sickened by drinking water delivered by lead pipes.

Lead became tightly regulated.  By 1978, only lead-free paints could be found at the local hardware store. Cars could run on unleaded gasoline. Copper pipes delivered drinking water. And, lead-free earthenware could be found on dinner tables throughout the US.

But high in the Andean mountains, the indigenous peoples of Ecuador cling to the old ways.  Huddling around bubbling cauldrons of molten lead now salvaged from old car batteries, potters continue to create shiny ceramic lead-glazed roof tiles that Ecuadorian homeowners crave.

The lead levels, estimated to be more than 10 times higher than the limit recommended by the US' Centers for Disease Control and Prevention, have been linked to learning deficits.  And, scientists suspect, may even predispose people later in life to develop ALS.

Now, researchers from the San Francisco University of Quito in Ecuador led by neuroscientist Miriam Bucheli PhD hope to determine whether chronic lead exposure contributes to ALS and results in increased cases of the disease. 

“A link to ALS could create awareness [and] encourage people to change their lifestyles because the disease is so debilitating” says Bucheli.

 

Team ELA-Ecuador. Project coordinator Ivan Sisa MD and epidemiologist Marco Fornasini MD PhD.  Also pictured left to right, USFQ medical students Priscila Villalba, Alejandra Mendoza, Diana Chicaiza, Carolina Franco, Barbara Mantilla and Amelia Calderon. Image courtesy of Miriam Bucheli PhD. Reproduced with permission.

The study is part of a growing effort, called ELA-Ecuador, to unravel the genetics and environmental influences that contribute to the disease.

Nearly 20 genes by some estimates are linked to ALS. But mutations in these genes alone, scientists suspect, may not result in ALS. Other factors such as chemical exposures, lifestyle choices and viral infections are also speculated to contribute to the onset of the disease.

Scientists hope to identify these risk factors in part, by interviewing people at high risk for developing the disease.

In the US, researchers at the University of Miami led by neurologist Michael Benatar MD PhD hope to pinpoint what triggers ALS in people harboring familial ALS-associated mutations.  And, a multi-institutional US team led by Duke University School of Medicine epidemiologist Silke Schmidt DSc MS hopes to discover why US veterans appear to be about twice as likely to develop the disease.

Now, the ELA-Ecuador team is turning to the same epidemiologist, Stanford University School of Medicine's Lorene Nelson PhD, to conduct the same kinds of interviews, in hopes to identify risk factors including lead exposure in people from the Andean region.

“We are using the same questionnaires,” explains Bucheli, “so that we can eventually compare the data from other countries.”

Southern Exposure

 

Lead overexposed. High lead exposure is common in people who live in the Andes mountains. Video: S. Allen Counter DMSc PhD, Harvard University.

Lead exposure has been suspected for decades to be a possible risk factor for ALS because the toxic substance can damage the central nervous system.  

Some studies suggest that higher lead levels could increase the risk of developing ALS. But other studies have been inconclusive. 

A big part of the problem is that these studies are extremely difficult to do. Circulating lead levels can increase during the disease course due to bone breakdown making total levels tricky to estimate. And the difference in lead levels can be difficult to determine because the levels in circulation are relatively small.

By studying a large population of people exposed daily to high levels of lead, Bucheli hopes to be able to finally determine whether or not lead exposure contributes to ALS. And at the same time, help people reduce their risk of developing the disease.

“If you know you have a higher risk for ALS, you may choose to change rather than continue old practices,” says Bucheli.

References

Counter, S.A., Buchanan, L.H. and Ortega F. (2005) Neurocognitive impairment in lead-exposed children of Andean lead-glazing workers. Journal of Occupational and Environmental Medicine 47(3), 306-312. Abstract | Full Text (Subscription Required)

Counter, S.A. et al. (2000). Environmental lead contamination and pediatric lead intoxication in an Andean Ecuadorian village.  International Journal of Occupational and Environmental Health 6(3), 169-176. Abstract | Full Text (Subscription Required)

Counter, S.A., Buchanan, L. H., Ortega, F., and Rifai, N. (2000). Blood lead and hemoglobin levels in Andean children with chronic lead intoxication. Neurotoxicology 21(3), 301-308. Abstract | Full Text (Not Online)

Counter, S.A., Buchanan, L.H., Rosas, H.D. and Ortega F. (1998) Neurocognitive effects of chronic lead intoxication in Andean children. Journal of Neurological Sciences 160(1), 47-53.  Abstract | Full Text (Subscription Required)

Fang, F. et al. (2010) Association between blood lead and the risk of amyotrophic lateral sclerosis. American Journal of Epidemiology 171(10), 1126-1133. Abstract | Full Text 

Haley, R.W. (2003) Excess incidence of ALS in young Gulf War veterans. Neurology 61(6), 750-756. Abstract | Full Text 

Horner, R.D. et al. (2003) Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. Neurology 61(6), 742-749. Abstract | Full Text 

Ruddock, J.C. (1924) Lead poisoning in children. Journal of the American Medical Association 82(21), 1682-1684.  Full Text

Schmidt, S. et al. (2008) Genes and environmental factors in veterans with amyotrophic lateral sclerosis: the GENEVA study. Neuroepidemiology 30(3), 191-204. Abstract | Full Text 

Further reading

Ahmed, A. and Wicklund, M.P. (2011) Amyotrophic lateral sclerosis: what role does environment play? Neurologics Clinics 29(3), 689-711. Abstract | Full Text (Subscription Required)

Callaghan B., Feldman D., Gruis K. and Feldman, E. (2011) The association of exposure to lead, mercury, and selenium and the development of amyotrophic lateral sclerosis and the epigenetic implications. Neurodegenerative Diseases 8(1-2), 1-8.  Abstract | Full Text (Subscription Required) 

Patient Resources

ELA-Ecuador.  Contact ALS TDI | Website

The Pre-Familial Amyotrophic Lateral Sclerosis (Pre-fALS) StudyContact | ALS TDI |  Website

 

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Categories: Podcast , Postcards

TROPALS, Circle In the Sand

clock June 21, 2012

 

Postcard from Burkina FasoThere are only 5 neurologists in Burkina Faso.  But that doesn’t stop Athanase Millogo MD from making a difference for people with ALS beyond his nation’s borders. Photo courtesy of Athanase Millogo MD.  All rights reserved.

With the opening of dozens of specialized ALS clinics and the establishment of multipractice care programs, nearly 1 out of every 5 people with ALS in the US now lives at least 5 years after being diagnosed with the disease.  And, nearly 1 out of 10 survives more than a decade.

But in Africa, ALS is instead a neglected non-communicable disease.  Few general practitioners recognize motor neuron disorders.  And, most people cling to traditional healing practices resulting in treatments being prescribed according to a recent analysis as much as 4.5 years after the first signs of the disease.

A group of neurologists, called TROPALS, however is determined to turn things around for people with ALS in Africa.  The team has launched an unprecedented multicenter longitudinal study to describe ALS in Africa.  And, at the same time identify key challenges facing these populations in hopes to ultimately to develop interventions to improve their quality of life.

“We are working for the patients,” explains Athanase Millogo MD, head of the Department of Medicine, Bobo-Dialousso Teaching Hospital in Burkina Faso. “We are not sitting in our offices making computations.  We hope to improve the outcome of people with the disease.”

Reference

Marin, B. et al. (2012) Juvenile and adult-onset ALS/MND among Africans: incidence, phenotype, survival: a review. Amyotrophic Lateral Sclerosis 13(3), 276-283.  AbstractFull Text  (Subscription Required)

Researcher Resources

Etude Epidémiologique de la Sclérose Latérale Amyotrophique sous les Tropiques (TROPALS) Email | Website

Study of Amyotrophic Lateral Sclerosis Under the Tropics (TROPALS) Email | Website

 

 

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Categories: Postcards

ALS, a brief history of more time

clock June 21, 2012

 

Postcard from Chandigarh Akshay Anand PhD talks about how he hopes to discover the secret behind the longevity of certain people with ALS/MND.

Inspired by physicist Stephen Hawking, Post Graduate Institute of Medical Education and Research (PGIMER) neuroscientist Akshay Anand PhD is determined to find out why certain people with ALS live longer with the disease.  Turning his attention to his hometown of Chandigarh, he hopes to discover why people with ALS in India live nearly ten years longer with the disease.

He suspected that higher levels of the blood vessel-forming substance VEGF could be a possible reason people from India live longer with ALS.  Lower levels of VEGF appear to increase the risk of getting ALS.  And, reduced VEGF according to preclinical studies results in neurodegenerative disease.

“All neurons would be happy to have more supply of nutrients coming from blood vessels,” explains Anand.  “Any disruption in the supply of blood [however] could lead to neurodegeneration.”

 

Soakin' Up the VEGF.  Blood vessels are formed at the right place and at the right time in part by restricting the levels of VEGF (yellow) available through the VEGF scavanger receptor VEGF-R1/FLT1 (green). Image: Journal of Biological Chemistry.

To put his theory to the test, he teamed up with PGIMER neurologist Sudesh Pradhakar MD to take a look at levels of VEGF circulating in people with ALS.  The researchers focused on 100 people from Northern India – including 50 people with ALS. The team found that the levels of VEGF appeared to be more than three-times higher in the spinal cord of people with definite ALS compared to people without the disease.

These results suggested that increased nourishment, delivered by additional blood vessels via astrocytes, may help ALS-ravaged motor neurons stay alive longer, slowing down the disease.

The team subsequently found, in a study that included 36 people with ALS from Northern India, that the boost in VEGF might be explained by reduced levels of the VEGF “sponge” VEGF-R1/FLT1.

Now, the PGIMER team hopes to look at more people with ALS to determine whether or not circulating levels of VEGF or VEGF-R1/FLT1 correlate with the stage and severity of the disease.  And, at the same time, evaluate whether VEGF-R1/FLT1 could be used as a biomarker to identify people who live longer with the disease.

“Who knows?  This could be the molecule,” says Anand.  “The suppression, reduction or inhibition [of VEGF-R1/FLT1] could actually if not curb the fatality of the disease, at least extend the survival time.”

References

Anand, A., Gupta, P.K., Sharma, N.K. and Prabhakar, S. (2012) Soluble VEGFR1 (sVEGFR1) as a novel marker of amyotrophic lateral sclerosis (ALS) in the North Indian ALS patients. European Journal of Neurology 19(5), 788-792. Abstract | Full Text

Gupta, P.K., Prabhakar, S., Sharma, S. and Anand A. (2011) Vascular endothelial growth factor-A (VEGF-A) and chemokine ligand-2 (CCL2) in amyotrophic lateral sclerosis (ALS) patients. Journal of Neuroinflammation 8, 47. Abstract | Full Text

Gupta, P.K., Prabhakar, S., Abburi, C., Sharma, N.K. and Anand A. (2011) Vascular endothelial growth factor-A and chemokine ligand (CCL2) genes are upregulated in peripheral blood mononuclear cells in Indian amyotrophic lateral sclerosis patients. Journal of Neuroinflammation 8, 114.  Abstract | Full Text

Lambrechts, D. et al. (2003) VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nature Genetics 34(4), 383-394.  Abstract | Full Text (Subscription Required)

Oosthuyse, B. et al. (2001) Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nature Genetics 28(2): 131-138.  Abstract | Full Text (Subscription Required)

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Categories: Postcards

Breaking the ice

clock June 21, 2012

 

Postcard from Reykjavik  ALS/MND International Alliance Chairman Guðjón Sigurðsson talks about how he hopes to make life better for people with ALS. He has been the head of MND Iceland since 2005.

Many people find extra energy going to the gym.  ALS/MND International Alliance Chairman Guðjón Sigurðsson, however, finds his second wind helping to improve the quality of life for people with ALS and to rid the world of this "damned" disease.

"Helping people with ALS every way I can,” says Sigurðsson. "That’s what keeps me going.”

Guðjón Sigurðsson was diagnosed with ALS in 2004. But despite an uncertain future, he had no doubt he could make a difference for people with the disease.

Now the head of MND Iceland,  Sigurðsson has worked with health professionals, government officials and other patient advocacy groups around the world to raise awareness about ALS and provide better care for the people with the disease.  He has helped put in place a patient registry in Iceland.  He has helped deliver wheelchairs to people with ALS in Mongolia. And, most recently, he has teamed up with ALS health professionals in China to encourage acceptance of people with the disease.

“We have to work together,” says Sigurðsson, “we cannot afford to go solo.”

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