RoIP

Like VoIP (Voice over IP) for phones, the Internet also carries "Radio" over IP. I will be participating in an online radio show, The Global Voice with Susan Piontek. I will be joining ferocious advocate Michele Dupree of Carnival for PALS, Mike Miller, the founder of ROALS, and Mike Shannon of ALS-TDI. The show will air tomorrow, Wednesday, September 1, at 5pm PDT. This may be "today" for those of you who subscribe to this blog via email. The subject will, of course, be ALS and I will be providing my view of things from the perspective of a PALS. This show will actually be Part 2 of last week's show which ran out of time as the subject has so many facets. That show is archived online at this link. Because I am on a vent and can't speak, I have prepared responses to some questions which were provided in advance. My wife, Claire, will read them live and I will edit this post on Thursday to include them (as well as a direct link to the archive). Listen live and either call in with questions or type into the simultaneous web chat. Maybe you'll hear me do my Stephen Hawking impersonation! [edit] The archived version of Part Two can now be found here. My Q&A transcript follows below: Q: Tell us about yourself and how ALS has changed your life? A: At the time of diagnosis I was 36 years old, had a wonderful career in Information Technology and had just taken a position to manage the computer network infrastructure of the US research and development program for an automobile manufacturer. I had a little house on the shore where my wife and I could walk down the hill to celebrate our wedding anniversary by surfing together (also our first dating activity). I had everything I wanted and was extremely happy in my life. Then all of that was removed piece by piece. I am now quadriplegic, we are about to move to my parents' house, and I require a machine just to breathe. Fortunately the Internet is a great physical equalizer so I can continue my online life somewhat unchanged. Unfortunately, I now have plenty of time for Facebook. Q: What would you like people to know about ALS; the disease, the current research, the expense? A:Words will never be able to adequately express the pure horror that is ALS. You can feel pain but not move to avoid it. You can feel hunger and thirst but never consume to slake. Dignity is utterly destroyed. There is no other condition with the same combination of helplessness and misery. There is no risk factor or behavior which brings this curse, and not nearly enough is being done to end it. There are many fine people working to solve this but their work isn't supported enough and there aren't enough of them. PALS don't have time to wait. The technology is recently available to adequately study the problem so the only thing needed is money. As Dr. Stan Appel testified before Congress, "ALS isn't incurable, it's underfunded." The research is beginning to zero in on things that can make truly effective therapies and a few promising clinical trials are just starting or will soon. For the meantime, medicine has gotten quite good at dealing with the symptoms of ALS and Medicare pays for it. However, on the most crucial aspect only half measures are available. While ventilators and supplies are paid for, the people necessary to maintain the equipment, handle alarms, and assist with personal issues are not. Family members, when they exist, are destroyed from the combined physical and emotional strain. The cost for attendants is high and has bankrupted me. PALS can be productive in society with proper support and I am living proof. In addition to other activities I have begun to lobby ALSA to be more aggressive in public education and to persuade Congress to amend Medicare to pay for in-home vent care. Q: What can people do to help? A: The easiest way to help is to support an organization like TDI. But that is too passive. Our society likes to write a check, push a button, take a pill, then forget about the initial problem. That level of commitment doesn't cut it. In _addition_ to a financial contribution, more people need to follow the lead of the 3 Ms and agitate. Write a letter to ALSA demanding national television PSAs with a current A-list celebrity. Write a letter to your Congresscritter demanding changes to Medicare so PALS don't opt for death in the face of daunting costs (I have a year-long debate going with a friend who is facing ventilation). If you know of someone with ALS, keep that person's name in the local press. Write to the TV news networks demanding more coverage of this silent crisis. The more people who are aware of ALS, the more demand for a solution results in more action, more funding, and more participation from the industry. And use social media to reach out and coordinate activities. 10 voices are easy to ignore. 10,000 not so much. I and a group of PALS use social media every day to connect and coordinate. The services are free, very easy to set up, and have global reach. I have my blog and a Facebook page to recruit an A-list celebrity. If I can do this, someone with functional hands certainly can.

Salty Dog

As discussed in a previous post, immune modulation appears to be a promising pathway to attack ALS. Recently, a company called Neuraltus has commenced a Phase I clinical trial of a substance they code-named NP001. This substance also works as an immunomodulator by reverting immune system cells from hostile to nurturing. For some time, chronic inflammation has been recognized as an important factor in ALS (though the cause remains elusive) and many attempts have been made to control it. This appears to be another promising method. It can be deduced from the press release that NP001 manipulates the cytokines in the body which signal the various reactions to injury or infection. But what is NP001 and how does it work? Neuraltus isn't revealing the secret sauce so I went on a treasure hunt through PubMed. One of the chronologically earliest results of searching on the Neuraltus founder Michael McGrath reveals that he has been investigating immunomodulation since 2002 (actually earlier, but this study serves as a good starting point which will become clear later). In 2004 he co-authored another paper investigating the immunomodulatory effects of WF10. WF10 is interesting because it down-regulates pro-inflammatory cytokines by reacting with hemoproteins to form hypochlorous acid which then reacts with taurine to form TauCl which inhibits the inflammatory cytokines. WF10 seems to also have some drawbacks so another, "gentler", chlorine ion donor is probably desirable. In 2006 another paper was published, co-authored by Dr. McGrath and Dr. Robert G. Miller (the principle investigator in the NP001 trial) which investigated the role of defective macrophages in Sporadic ALS which expanded upon their 2005 paper. This research is doubly interesting as it looks directly at SALS as well as posits functional biomarkers which can be used to gauge drug efficacy instead of the clumsy ALSFRS (the NP001 trial lists this as a secondary outcome measure). A paper in 2009, again co-authored by Drs. McGrath and Miller, not only investigated immune activation in SALS but posits a cause. I hope to talk about that in future posts but for now I digress. With the evidence for immune system involvement in ALS and the evidence that a chlorite-based drug can neutralize some of the cytokines that promote inflammation, it seems to make sense to investigate whether such a drug can address the neuroinflammation of ALS. I have an unconfirmed report that sodium chlorite is the active ingredient in NP001 (the chlorine ion donor). Also, according to this 2006 patent issued to Dr. McGrath, TCDO (WF10) and sodium chlorite are both considered for ALS treatment in dose-dependent manner. I am intrigued and hopeful that this drug could have a positive impact in ALS. By reducing the amount of "attack" signals (cytokines), the "nurture" signals might help to end the damage caused by the neuroinflammation. Unfortunately my search for any of Neuraltus' preclinical (animal) research served a bagel so we have to wait for human results to evaluate beyond speculation. Of course, as always, remember that I am not a doctor or biochemist so take my words with a grain of salt (NaCl, sodium chloride, table salt.. get it? I apologize).

Shah Den Froi Duh

There is a game show on ABC I enjoy called Wipeout. This is because I enjoy seeing people with a full set of NMJs get pummeled by padded machinery. It is the ultimate in schadenfreude television!

Poor SOD

There has been a question whether SOD1 plays a part in sporadic ALS (SALS) as well as familial ALS (FALS), in which one of a large number of inherited defects in the SOD1 gene cause alterations (misfolding) of the SOD1 enzyme which it encodes. A recent study published in PLoS ONE suggests that misfolded SOD1 is present in all cases of ALS, not just in those involving genetic defect. Some previous studies have had similar results while others have not. Apparently this study used a fairly aggressive set of antibodies to detect inclusions (flaws) in the motor neurons which consisted of SOD1. Whether the misfolded SOD1 or the inclusions/aggregates that result are the cause of disease is still being questioned, although disease effects can be seen prior to visible aggregates forming. Two things about this study I found interesting: First, the study reported that the inclusions were found mostly in the axon hillock which makes me wonder if this can be related to the slowing of axonal transport which is a very early event in ALS. Second, if you look at the diagram in the SOD1 link above, you can see that it is a rather tight and highly complicated enzyme to fold. A mutation may make it more difficult or impossible for a lysosome to break down. Lysosomes are rather important cellular components. The subject study indicates that the misfolded SOD1 found in the motor neurons co-localized with lysosomes, suggesting that the lysosomes were choking on the mutant enzymes. Lysosomal dysfunction has already been linked to several diseases, including neurological. It is known that lysosomal function degrades with age, and ALS is an age-related disease (both SALS and FALS begin after decades of otherwise normal life). At least one study is being conducted, attempting to address ALS by means of increasing lysosomal function. Of course, this assumes a "neurocentric" view of the disease, where the pathogenesis is in the neuron itself. Recent research suggests this may not be the case, and that some upstream event triggers the cascade that leads to distress and death of the motor neurons. It is this "missing link" that continues to confound researchers.

Build A Cell

Ever wanted to build your own pet cell piece by piece, feed it and defend it from hazards both external and internal? Well now you can! This engaging little game (built using Flash) entertains and educates simultaneously. While you are building your cell, each component's function is explained and demonstrated with practical applications. As your cell becomes increasingly more complex, so do the hazards come faster and more dangerous. Keep it fed, keep it producing energy and raw materials for growth and regeneration, and watch out for viruses! The game teaches you cell biology and mechanics while you play. There is a bit about transpermia as the goal is to build the cell, train it up, and send it to another planet to ensure the survival of a species of rather clever and industrious platypuses... Note that I have not made it through the end of the game because the action becomes too frenetic for my optical control system to control. My cell gets killed by virus attack. I try not to take it as an omen...

Baby Steps

I recently came across a video of a talk given by Dr. Hans Keirstead, whose work I have mentioned in a previous post. In the video, posted June 29, 2009 (almost exactly a year ago), Dr. Keirstead showcases his research on a stem cell therapy for SMA. He shows how he was able to grow functional motor neurons (proving it by showing them innervating muscle fibers) and explaining the then-current status of a proposed human trial to replace damaged tissue. The proposed trial is for infants who suffer from Type 1 SMA. SMA (Spinal Muscular Atrophy) occurs from a malfunctioning SMN gene and the Type 1 (infantile) version is rapidly fatal. Like with a form of ALS called PMA (Progressive Muscular Atrophy), the motor neurons between the spinal cord and muscles die leaving the person paralyzed. When the diaphragm muscle is eventually denervated the person dies of respiratory failure. Regenerative medicine offers a way to replace lost tissue and restore function. In lab and animal tests it appears Dr. Keirstead has been successful. now for the next step. There seem to be good reasons to try this in SMA infants. I am going to be coldly blunt but I beg the reader to take a breath and stay with me. First, the infants are going to die very soon so the trial length is short; you will see quick benefit or have rapid access to post-mortem tissue (also the reason Neuralstem included late-stage ALS patients in its trial). Because of the infants small size, the grafted neurons don't have far to go to innervate muscle. In an adult such as myself motor neurons would have to grow a bit over a meter to reach fingers and toes. Even the phrenic nerve (the "money" nerve in neurodegenerative disease) would need to grow nearly half a meter to innervate my diaphragm muscle. Nerves grow slow so that could take as much as two years (for the more distal muscles). Infant bodies are still also in a rapid growth mode which may assist the grafts (mentioned in the Stanford study in a previous post). I could also guess that an immature immune system may be beneficial for anti-rejection purposes (pure speculation on my part). Time is in critically short supply in SMA (and ALS) so having short trial lengths is crucial. June 22, 2010 update on program progress. Because SMA is so similar to ALS, if this trial goes well it would be huge news for PALS. In fact, ALS is the next disease in line for this treatment. With this program and the concurrent ongoing programs by Brainstorm, TCA, and Neuralstem either soon to be or currently in trial, I have great hope for regenerative medicine. As always I invite responsible comments or questions.

Because Someone Has To

A few years ago a report came out claiming some fantastic results involving Lithium's efficacy in ALS. The paper was published in a respectable journal. However, reaction was surprisingly cool. Because Lithium has been used for years in much higher doses for maintenance of bipolar disorder and was cheap and easy to get, many PALS started their own off-label "trial" which collected valuable data (unfortunately to the contrary of the results of the original study). This first in history patient-driven trial forced multiple professional clinics to stage real, placebo controlled, clinical trials (with results which matched the patient-driven trial). Recently there has been interest in a natural bile acid which has anti-apoptotic effects, specifically in the mitochondria. There are two companies already in clinical trials with proprietary substances intended for mitochondrial support. Ursodeoxycholic Acid (UDCA) is found to be anti-apoptotic, easily crosses the blood-brain barrier, has an excellent safety profile, and is inexpensive and easy to obtain. A Phase 1 trial was already done which showed excellent safety for ALS patients. A few scattered PALS have been safely using UDCA and some anecdotal reports from S. Korea (using a version with a starch binder) have indicated efficacy. Unfortunately no clinic is interested in performing the trials necessary to fully investigate UDCA. So I have created the second patient-driven clinical trial intended to provide some good data on the efficacy of UDCA as a treatment for ALS. While not a true clinical trial it should be a decent indicator. I did this because the risk is low and the potential benefit high. I did this because doing nothing gets you nothing. I did this because someone has to.