It has been known for some time that chronic neuroinflammation is a primary driver of disease in ALS and its “cousins” Alzheimers, Parkinsons, etc. Many attempts have been made to address it by using anti-inflammation drugs without success. Recently a study was published using a “prodrug” in animal models of Alzheimer’s and Huntington’s diseases. In this study, the drug 2-(3,4-dimethoxybenzenesulfonylamino)-4-(3-nitrophenyl)-5-(piperidin-1-yl)methylthiazole (JM6) inhibited the action of KMO, which is involved in the metabolism of tryptophan. This causes tryptophan to metabolize into kynurenic acid (KYNA), a neuroprotective substance, instead of quinolinic acid (QUIN), a neurotoxic substance. This degradation of tryptophan is called the kynurenine pathway (KP). It is one of the major regulatory pathways of the immune response and is known to be active in neuroinflammation. In HD, AD, and PD (Parkinson) there is decreased KYNA and increased QUIN. In multiple studies, changing the KYNA/QUIN balance in favor of KYNA is neuroprotective via a variety of methods.
Of interest to the ALS Community is that the same imbalances are seen in ALS. Strong evidence suggests that dysregulation of the KP leads to the type of neuronal damage from chronic neuroinflammation seen in many neurodegenerative diseases. In vitro testing with rodent motor neuron cells revealed a functional KP, that degeneration increased with duration and magnitude of exposure of QUIN, and that KYNA was protective against damage to neurons. It is known that QUIN is an NMDA receptor agonist (activator) and that KYNA is an antagonist (inhibitor). NMDA receptor-mediated excitotoxicity via calcium (Ca+) influx is a known cause of motor neuron death in ALS. This means that inhibition of KMO (aka kynurenine 3-hydroxylase) should be beneficial in ALS as well. Fortunately, K3H/KMO has been characterized for some time. In a study done in 2000, KMO (referred to as K3H) was found to be inhibited by Cl- (chloride). Luckily for PALS, there is already a chlorine drug in trial. This drug creates Taurine Chloramine (TauCl) which modulates the pro-inflammatory response seen in ALS, and also appears capable of rerouting KP to a beneficial product rather than harmful.
From the above it appears that previous attempts at modulating neuroinflammation failed because they were targeting symptoms rather than underlying cause (like treating a headache with aspirin when the cause is a tumor). By boosting the body’s endogenous TauCl production a clearly malfunctioning immune response can be guided to its secondary, nurturing, state. At the same time, multiple targets identified in ALS can be struck with a single weapon: Excitotoxic calcium influx from glutamate receptors (currently treated with little effect by Riluzole), mitochondrial distress (currently the target of other drugs in trial), and the neuroinflammation which is one of the main drivers of disease progression in ALS.
While all roads may lead to Rome, it appears that in neurodegenerative disease they may lead to KP moderation by chloramines.
In 2006, mouse fibroblasts were successfully transformed from a fully differentiated state to a state of pluripotency. These cells were designated induced pluripotent stem cells (iPSC).Since that news, human cells were successfully transformed and techniques to increase the safety and efficiency of production have been found. Other techniques have been developed which can correct genetic defects in iPSCs with the eventual goal of repairing or replacing defective tissues.
iPSCs still have issues to be resolved such as:
- certain methods of inducing pluripotency are tumorigenic
- iPSCs appear to have “memory” of their original cell type
- there is some data showing that iPSCs express certain proteins on their surface resulting in immune rejection even in cells donated from the host’s own tissue
- other complications such as efficiency (allowing sufficient numbers of cells to be generated within a clinically acceptable time at a clinically acceptable cost).
Some of these issues are already being addressed and quite frankly the pace of research has been astonishingly rapid. iPSCs are already being used to model disease and aid drug discovery. Due to the novelty of cell-based therapies and the fact that implanted cells are difficult or impossible to remove (unlike dosages of drugs which can be ceased in the event of adverse reaction), regulatory hurdles are necessarily high. However, as more trials are performed giving more data on safety these hurdles can be lowered somewhat and/or more easily surmounted. There are cell-based therapies already in or going through the regulatory process for trials using a variety of stem cell types. Not only do these prospective treatments face regulatory hurdles, they must also cross the Valley of Death of pharmaceutical research. Some researchers are finding ways of doing this on their own with intellectual property partnerships, and the NIH has been working to bridge the gap with new programs such as TRND.
This is a very exciting time for regenerative medicine.
For some time it appeared that the inclusions found in the cytosol of neurons in degenerative disease were causing the disease, likely due to disruption of movement of organelles and proteins up and down the axons. But evidence is now suggesting that may not be the case. With TDP-43, it appears that depletion of it from the nucleus is the cause of disease. With SOD1, an unknown toxic gain of function is still theorized. However, a recent study reported that mutant SOD1 interacts with TDP-43 where normal SOD1 did not. Conflicting previous studies have found and not found misfolded SOD1 inclusions in the motor neuron cytoplasm of sporadic ALS patients, though a study using novel antibodies specific for denatured SOD1 reported small inclusions in all tested SALS patients. SOD1 is a highly complex protein and such are easily misfolded. Usually this is no problem as either chaperones refold the protein or intracellular autophagy destroys the errant protein. But age and stress can cause autophagy to decrease in effectiveness, possibly leaving errant proteins in the cell where they can do damage. So assuming that mutant SOD1 is present either by genetic mutation or routine misfolding not corrected or cleared by the cell, and assuming interactions between mutant SOD1 and TDP-43 where TDP-43 is depleted from the nucleus, it could be held that mutant or misfolded SOD1 causes disease through depletion of nuclear TDP-43.
Activation of the glial cells (astrocytes, microglia, etc.) is a driving force in ALS progression. Experiments where mutant SOD1 was limited solely to the glia demonstrated the ability to drive disease on their own. In the case of inherited forms of ALS where particular mutated genes produce mutated forms of proteins throughout the body it is easy to imagine disease spreading rapidly once initiated. But what drives the more common sporadic forms? A clue might be found by looking at prion disease. In fact, a recent study shows that Huntington’s Disease may very well spread this way, and it may be applicable to other neurodegenerative diseases. Indeed another study found that extracellular SOD1 can induce microglia to release pro-inflammatory cytokines and free radicals which promote motorneuron damage. A more recent study showed that introduced mutant SOD1 can induce disease. The biotech company Amorfix makes antibodies against extracellular mutant SOD1 and is now in trials to use these antibodies as a vaccine against ALS.
So with mutant or misfolded SOD1 we have multiple paths for disease as well as a likely pathway for spread of disease. Each of these questions are comparatively easy to test and seemingly easy to intercept in the extracellular space. I look forward to more studies to further illuminate these questions.
In June I posted a discussion about a prospective regenerative therapy. On December 1, I received a press release that the company developing this therapy has filed an IND with the FDA. This is a huge step forward for people suffering from motor neuron disease (especially late-stage PALS like myself). However, it is but the first baby step in the clinical trial journey. Let’s hope that the FDA acts swiftly and positively on this IND.
Today (10/12/2010), Geron began a Phase-I clinical trial using embryonic stem cells to treat spinal cord injury. While not directly applicable to ALS, a successful safety trial should open up approvals for similar subsequent trials utilizing human embryonic stem cells. Already there is favorable preliminary information coming from the Neuralstem trial (which uses fetal neural precursors, not embryonic stem cells) and several more are in the approval pipeline.
Meanwhile, in Israel, Brainstorm received approval to begin its trial for ALS. As discussed previously, Brainstorm engineers autologous cells to secrete neural growth factors and then implants them in muscle to promote axonal growth and nourish the cell body via axonal uptake. It’s a novel approach which doesn’t require risky surgery.
These are just a few very interesting things going on in research and clinical trials. But keep in mind that they are happening now.
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).
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.
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.
In a previous post I made mention of the Neuralstem clinical trial currently ongoing at Emory University. Recently, CNN ran a story on the trial which provided welcome news to the ALS community. Three implantations had been performed with no complications so far.
Today I received a press release which carried forward the good news. Based on the results so far with the first three, they are going ahead with a fourth with double the injections (both sides of the spine). This is great news as it is showing the procedure and product to be safe (the primary objective of this trial). It is still too early to determine any efficacy and the trial isn’t designed to measure that anyway.
With each success the barriers are pushed back a little further. The success of the Neuralstem trial will pave the way for other trials.
The ALS Therapy Development Institute is a non-profit biotech fully devoted to finding a treatment for ALS. A few years ago they undertook a genome-wide association study (GWAS) on the animal model of ALS (the G93A mouse).The results implicated the costimulatory pathway which links the innate and adaptive immune systems. In an attempt to address that pathway, TDI used a monoclonal antibody against CD40L. This decreased a specific T-Cell interaction which led to the body attacking the axons of the motor neurons. A very good description of the study can be found at the Alzheimer Research Forum (Alzheimers, Parkinsons, and ALS are selective neurodegenerative diseases so research in one can provide clues into the pathways of others).
This finding is interesting for a few reasons. For the first, it marks a shift in looking at ALS as a motor neuron disease to seeing it as some other dysfunction in which the neurons are injured. Second, while the treatment described isn’t a “cure”, it does point towards a significant pathway of disease management.
Another important point is the success reported by TDI. Since the development of the murine model of ALS numerous researchers have claimed varying degrees of success in preclinical work only to have the candidate substance fail in human trials. TDI undertook an internal study to figure out why and discovered numerous variabilities for which researchers must account when designing trials. TDI’s mouse program is now recognized as the “gold standard” for that model. The fact that they can report measurable and repeatable results is significant.
Of course mice aren’t men and this isn’t a cure, but it does give quite a bit of hope that a truly effective treatment may be within reach.
[UPDATE 04-02-2010: TDI discusses this via MP3 podcast.]
[UPDATE 04-05-2010: The study is now available free of charge in PDF format. Very good of Nature Publishing Group to make this available to PALS and CALS!