Wednesday, August 17, 2011

ALS - Linda's thoughts and information about research

My friend Linda has her insight and understanding of the havoc ALS can wreak on a person. This is what she has to say -

             Any thoughts that you'd like to share with us?

ALS strikes as many people as does MS, but people are not as aware of it since "people with ALS" (PALS) do not live as long as people with MS. 


For instance, people with MS, are able, for the most part, to live relatively normal lives with medication and experience periods of remission. But those with ALS, are unable to continue as functioning members of society. We don't see them being able to carry on their jobs, walk, participate in their community - in short, they become invisible far too quickly due to the nature of the disease, confining them to their beds, wheel chairs, and being hooked up to ventilators.

Imagine, having an itch that you can't scratch. Imagine, having to move your eyes to spell out your passions. Imagine, not being able to speak or move, alone with your own thoughts. This is the reality of ALS, Amyotrophic Lateral Sclerosis. It affects the nervous system and is characterized by muscle wasting, paralysis, speech loss and eventually, the inability to swallow or breathe.

The Discovery of ALS more than 1 1/2 centuries ago and the general course of the disease

ALS has been a death sentence ever since its discovery a centruy and a half ago by Jean Martin Charcot. In France it is still called Charcot's disease. In America it goes by the name of its most famous victim, Lou Gehrig, the NY Yankee baseball player.

In ALS, nerves in the spine begin to die one by one. These are what are known as the motor nerves, because they carry signals from the brain to the muscles of the body. Without signals from these motor nerves, the muscles wither and atrophy. As more nerves die in the spine, the body becomes progressively paralyzed. The damage travels up and down through the spinal cord until it reaches the brain stem, which controls the muscles that allow a human body to breathe and swallow. Even then, patients remain wide-awake and fully conscious.They can still see and hear, feel and reason. They become prisoners in their own minds forced to spell out words to communicate by moving the only part of their body not paralyzed, their eyes. (Although an unfortunate 4% lose their eye movement becoming completely locked in.) They watch their muscles wither away until they can no longer breathe, and they suffocate to death.

New gene discoveries have quickened the pace of research on the causes of ALS.

Research on the cause of ALS is being conducted on many fronts, including the ALS Association, Motor Neurone Disease Association (MND), Muscular Dystrophy Association (MD), scientists, University professors and researchers, academic Medical Centers, Biotechnology startup companies, hospitals.  But as new genes have been discovered in recent years, the ALS picture has grown more complex suggesting that there may be multiple primary causes of the disease. 

The ALS Association aggressively supports investigations to uncover the cause of ALS and find innovative treatments

Paramount is the study of the effects of mutations in genes, currently being explored in a variety of models, each chosen to highlight one or more aspects of the disease process. The hope is that this multi-pronged approach has the best chance of revealing the true problem each mutation causes. Coupled with the variety of intense research and investigations (as outlined below), and cooperation with agencies, institutions and individuals, it is an exciting time. All are desperately striving to find the cause/causes of ALS which will lead to means of prevention, and to slow and stop, (and even reverse?!) the progression of the disease in existing cases.

·                     Cause and prevention of ALS
·                     Stem cell research
·                     Gene therapy Drug screening and drug development
·                     Identification of new genes
·                     Development of model systems (worms, flies and zebra fish)
·                     Biomarkers-surrogate markers of disease
·                     Small pilot studies and clinical trials

SODI, the first gene discovered for ALS is still the most common genetic cause known, but two other genes, TDP-43 and FUS, were discovered within the past two years and have become the subject of intense research. Another recently discovered gene, called optineurin, is only found in a handful of families, but researchers are hoping it may reveal disease mechanisms common to many forms of ALS. Mutations in optineurin are known to increase inflammation, a process that may damage motor neurons, through another molecule called TNF-alpha. “If this hypothesis is true,” said Ryuji Kaji, M.D., of Tokushima University in Japan, “inhibition of TNF-alpha may be a key to disease-modifying therapy.” He pointed out that there are many drugs already known to inhibit this molecule, suggesting it may be possible to quickly test this possibility. “There are still more ALS genes to be discovered,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D. She noted that the most recently discovered gene, VCP, which occurs on chromosome 9, is not the only ALS-causing gene there. 
Further work will be needed to discover this still-unknown gene and to identify others that cause the disease. “By finding these genes, and understanding the pathways each works in, we can piece together a picture of ALS that will lead us to new treatments. Each gene we discover brings us closer to that goal.”

The discovery of TDP-43 has had an enormous impact on the understanding of neurodegenerative diseases. Mutations of TDP-43 can also cause another neurodegenerative disease, called frontotemporal dementia, suggesting the two diseases are two ends of a single spectrum. In addition, the involvement of TDP-43 points to RNA processing as a potentially central mechanism in disease. Cells use RNA for a variety of processes, most importantly for relaying genetic messages from the nucleus, where they are stored, to the cytoplasm, where they can be used to create protein. Both TDP-43 and FUS are RNA-binding proteins, meaning they interact with RNA to help it do its job. It is not yet clear how mutations in these two proteins cause disease, but researchers are looking closely at the protein-RNA interactions, to see whether the mutations that cause disease disrupt the normal activity of RNA as a result.

“The more we understand these pathways, the better we can use the information to identify new targets for treating ALS. This is a really exciting time for learning more about the causes of ALS, and trying to find disease-modifying therapies,” Dr. Lee said. Virginia Lee, Ph.D, of the University of Pennsylvania, is co-discoverer of the TDP 43 gene). Tom Maniatis, Ph.D., of Harvard University, is examining the effect of TDP-43 and FUS mutations on gene expression in motor neurons. The goal is to find “the needle in the haystack,” the change in expression that leads to disease, rather than the many others that are a result of it. For reasons that are not yet clear, TDP-43 mutations appear to cause changes in expression that are opposite to those of FUS mutations, despite the fact that both cause ALS. Further research may uncover the link between the two that sheds light on a common pathway.

Nigel Leigh MD, Ph.D is a Professor at the Institute of Psychiatry at King’s College in London (UK). He has been a leader in both clinical and scientific research in ALS, and colleagues have made a start at defining subtypes relevant for clinical trials by analyzing outcomes among a large group of patients and looking for factors that best predict prognosis. They found that two factors predicted most of the variability among groups: site of symptom onset (bulbar or limb) and delay from first symptom to diagnosis, with longer delay predicting longer survival. He's hopeful that his work may provide a jumping-off point for further refinement, with the goal of defining natural divisions among cases of ALS that can speed clinical trials.

Unfortunately with ALS there is an inherent problem in doing Clinical Trials. Often either the participant dies before he/she can finish the trial, or he/she becomes unable to continue taking a drug if it requires swallowing or ingesting by mouth due to paralysis of those muscles. Feeding tubes can provide a solution to the swallowing problem as the drugs can be given to patients who already have a feeding tube.

 Thank you Linda and the wonderful people from the ALS Salem Support Group. Thanks for your time, the well researched information, the willingness to share the story of your life, and most of all, your determined spirit.

Quick links-

Checks can be made out to - 
ALS Association of Oregon and SW Washington 
Mailing address:
ALS Association of Oregon & SW Washington
700 NE Multnomah Ave, Suite 870
Portland, OR 97232





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