Carpe Fragments

In the developing embryo, motor neurons develop and nearly half preferentially die prior to birth (Henderson, et al., 1997, "Hepatocyte growth factor (HGF/SF) is a muscle-derived survival factor for a subpopulation of embryonic motoneurons"). As shown in Forger, et al., 2001 ("Blockade of Endogenous Neurotrophic Factors Prevents the Androgenic Rescue of Rat Spinal Motoneurons"), loss of muscular targets also leads to post-natal motor neuron degeneration. Post-natal mice engineered to have degenerated muscle spindles exhibit ataxia and resting tremors, indicating a decrease in proprioception due to loss of sensory-motor synapses (Frank, et al., 2002, "Muscle Spindle-Derived Neurotrophin 3 Regulates Synaptic Connectivity between Muscle Sensory and Motor Neurons").

One interesting factor seems to suggest a link with testosterone in preserving motor neurons, which could be a possible explanation for the statistically higher numbers of men affected in middle-age or above, and that of women in post-menopause, when hormone levels experience radical shift. Indeed, Cilliary Neurotrophic Factor, a potent motor neuron trophic factor, is regulated by gonadal hormones (Forger, et al., 1998, "Ciliary Neurotrophic Factor Receptor in Spinal Motoneurons is Regulated by Gonadal Hormones").

Leaving aside the question of hormone levels, there is much evidence that muscle-derived neurotrophic factors are necessary for the health and survival of the motor neurons. One in particular, Motoneuronotrophic Factor 1 (MNTF1), appears essential to this critical process. Experiments in Wobbler mice show that motor neuron disease increases as MNTF1 levels decrease (http://www.ncbi.nlm.nih.gov/pubmed/10453487). MNTF1 was first described in the early 90s, and the human form was successfully cloned as an artificial protein. Various fragments were extracted and shown to have neurotrophic effect.

Two overlapping domains of a 33 amino acid fragment of MNTF1, dubbed the WMLSAFS and FSRYAR domains, are sufficient to stimulate motor neuroprotection in a manner similar to the whole 33 amino acid MNTF1 fragment. The FSRYAR domain is sufficient to direct selective reinnervation of muscle targets by motor neurons in vivo in a manner similar to the 33 amino acid MNTF1 fragment. A recombinant protein containing the FSRYAR domain maintained motoneuron viability, increased neurite outgrowth, reduced motoneuron cell death/apoptosis and supported the growth and spreading of motoneurons into giant, active neurons with extended growth cone-containing axons.

For those curious about the amino acids in each domain, please refer to the image below:

Genervon has patented these fragments and is using them in a Phase 2-A clinical trial in ALS. From the above it is quite possible that at least some forms of ALS are caused by a sort of a muscular dystrophy (not to be confused with the distinct condition by that name). It therefore stands to reason that there is reason for hope that some will benefit. The standard caveat of basic and preclinical research often not translating to human trials obviously applies. However, we are entering an exciting time where extremely potent shots are being taken at more fundamental aspects of ALS. One or a combination seem likely to have the effect we have been waiting for.

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Precision Stem Cell

The following should not be taken as a recommendation (or warning) regarding Precision Stem Cell. However, that facility was recently rendered an injustice which requires correction.

On March 19, 2013, ALS Worldwide (ALSWW) published a report on the procedure carried out by Dr. Jason Williams at Precision Stem Cell in Gulf Shores, Alabama (PSC). The report was particularly scathing. However, it was replete with inaccuracies. I would like to contrast points from the ALSWW report with facts reported to me from a number of independent sources which include Dr. Williams, persons who have visited his clinic, and patients treated by Dr. Williams in the subject stem cell procedure. To begin with, I will briefly explain the theoretical underpinnings of the procedure Dr. Williams performed, as well as his motivation for doing something outside of his original medical training.

Dr. Williams explains his history, procedure, rationale, and plans for development in a recently-released video. He had been doing mesenchymal stem cell (MSC) extraction and delivery into joints for a time, a somewhat routine procedure done in many clinics as a sports rehabilitation therapy. A friend, Frank Orgel, approached him about trying the procedure to treat his own ALS. Dr. Williams was initially skeptical but after online literature research learned of studies done using this technique in laboratory settings. Note that the link here is not necessarily the one used by Dr. Williams. The reader can search PubMed using the terms "autologous stem cells amyotrophic mesenchymal" and be presented with results which are representative of the applicable published studies.

Selegiline (Anipryl, L-deprenyl, Eldepryl, Emsam, Zelapar) is a drug used for the treatment of early-stage Parkinson's disease, depression and senile dementia. Dr. Williams found published studies suggesting that selegiline treatment of MSCs was sufficient to trans-differentiate them toward a neural lineage. Dr. Williams extracts the MSCs via machines made exactly for the purpose of extraction of adipose (fat) tissue and real-time separation of MSCs from the adipose tissue. The extraction and separation process is all done in a sterile closed system. The MSCs are then bathed in selegiline solution created by from powder mixed with sterile saline using a professional compounding protocol. After treatment, the cells are then injected into the spine via lumbar puncture The idea is that the treated cells are a mixture of MSCs and neural-lineage cells which then quell the inflammatory aspect of ALS and provide neurotrophic factors. The extent and duration of benefit is presumed based on severity of progression (ie patients with a slower, less aggressive, progression would experience more benefit and of a longer duration).

TCA Cellular of Louisiana had been previously conducting a clinical trial using intrathecal delivery of MSCs to treat ALS until they were shut down for improperly administering the procedure outside of trial (including allogenic products delivered to some patients). Currently, The Mayo Clinic is conducting a similar trial. Clearly there is scientific rationale for investigating this procedure as a treatment for ALS. While Dr. Williams started with the cart before the horse, if you will, he has matured his operation into a true investigative research program. He is partnering with accredited researchers and is forming a company specifically to handle the research program. Together they are working on a genetic modification of the MSCs to more abundantly deliver anti-inflammatory and neurotrophic factors as well as concurrent delivery of the treatment vehicle to the patient cells to help the host cells defend themselves from disease process. This can be likened to the Brainstorm product which nearly everyone is excited about.

1. Precision Stem Cell is conducting a trial
As discussed above, Dr. Williams never claimed that his procedure was a clinical trial. He expanded his current practice of treating joint damage to ALS by request of a friend seeking the possibility of relief via MSC injection. Labeling the procedure as a "trial" and then remarking that there is no rigorous data collection is disingenuous at best. Further, discussion of pricing in the report appears deliberately worded to taint Dr. Williams as a con artist of the sort endemic in the world of life-threatening diseases. Dr. Williams is indeed now planning a trial, in preparation for which he has ceased treating patients, but none of the previous treatments were ever represented as a trial. Dr. Williams had been planning to transition to a trial many months prior to the ALSWW visit.

2. Dr. Williams has no credentials as a neurologist/plastic surgeon
This is true. However, neither of these qualifications are necessary to perform the subject procedure. Mechanically it is almost no different from the joint therapy he has been performing for years. Injection into the spine does carry extra risk. However, nurses without neurology credentials routinely administer spinal taps and injection of spinal block anesthesia daily around the United States, and without benefit of the imaging equipment employed by Dr. Williams. Insofar as the liposuction, Dr. Williams is certified in the use of that equipment since 2010 and can produce a copy of such certificate upon demand.

3. Positive effects lasted only 1-4 days
While the positive effects noted by some patients could indeed merely be placebo effect (impossible to determine either way absent double-blind trial), how Mr. Byer makes this claim is a puzzle. He never contacted any of the patients referred to him by Dr. Williams. The "days" time estimate Mr. Byer repeated in the ALSWW report appears to have come from a public post from a person on the ALSTDI forum. That person denies having been contacted by Mr. Byer.

4. The clinic is a poorly-equipped "stem cell facility"
Leaving aside a discussion of exactly what a "stem cell facility" is, PSC is a radiological facility. No surgical procedures are performed. The equipment used to extract, manipulate, and reintroduce the MSCs are all routine equipment useful in many procedures involving filtering and extraction of select fluids/tissue. The protocol for harvesting MSCs has been well-documented for decades. The liposuction and extraction are done with machines built exactly for those tasks in a closed system which guarantees sterility. The mention of the equipment not being FDA-approved for extracting MSCs is a total red herring apparently intended to taint the reader's opinion of PSC.

5. Sterile procedures are not followed - infection risk
Sterile procedures are indeed not followed. The reason for this is that they are unnecessary. The entire movement of cells is done via hypodermics, transferring from the patient from one sealed sterile container to another throughout the entire process and back to the patient. Alcohol swab wipe on external surfaces prior to injection is all that is necessary. There is no open surgery requiring a sterile environment. Despite the claim in the ALSWW report, surgical drapes are indeed used during liposuction. Talking about the radiology suite as an "OR" is another disingenuous attempt to discredit PSC. The table talked about is a standard flouroscopy table so Dr. Williams can use imaging guidance for his procedure. Photographs reveal the table to be very clean and in fine shape. Since patients are not under general anesthesia or sedation, the risk of "easily falling off" is a function of zero.

6. Patients have retracted statements of benefit
This claim is a mystery because the patients to whom Dr. Williams referred Mr. Byer deny having been contacted. The patient Mr. Byer apparently used in this example denies having been contacted by Mr. Byer. Further, he maintains his original statement.

7. Williams uses a 0.8 micron filter making MSC harvest impossible
Dr. Williams uses an 80 micron filter. It is possible that Mr. Byer was observing another filter type or misread the label. Dr. Williams admits the possibility of having handed Mr. Byer a 0.8 micron filter by accident. Nevertheless, this question could have been resolved by email or phone call prior to publication.

8. The selegiline mixture is unsanitary
The selegiline is not, as claimed in the ALSWW report, ground in a mortar and pestle at PSC. The selegiline solution used for bathing the MSCs is made with sterile saline (not distilled water) under the guidance and protocol of David Rothbardt, a registered compounding pharmacist. According to Dr. Williams, neither Mr. Byer nor his medical adviser Dr. Hematti ever observed compounding of selegiline at PSC. Further, the selegiline is removed via rinse after bathing period and prior to reintroduction to the patient.

9. The PSC facility has no vapor lock system
Perhaps Mr. Byer has confused PSC with a biohazard facility? This allegation makes no sense and appears another in a long string of comments included to confuse the uninformed and unwary.

As demonstrated above, the report by ALSWW is full of inaccuracies, misrepresentations, and diversions from truth. The motivations for Mr. Byer to publish that report are beyond the scope of this blog post. The facts are that PSC is a clinic offering a treatment used by many clinics for joint rehabilitation. The equipment and techniques are common and well-documented. The facility is clean and the procedure is carried out under appropriately-sterile conditions. The applicability of this treatment to ALS is unknown, although the study data available is compelling enough for The Mayo Clinic to run a clinical trial.

There are some questions regarding the treatment provided by Dr. Williams. The dosages administered are estimates based on instrument capacity rather than actual flow cytometry count. The data regarding selegiline needs further independent verification. Without evaluation, it's impossible to know how complete is the presumed process of trans-differentiation of MSCs to neural lineage. The efficacy of either straight or selegiline-treated MSC intrathecal injection is still an open question.

However, one thing is clear: PSC did not deserve such a baseless derogatory review from ALSWW.

Outta Tsai't!

I would like to give a little blog-love to my [Facebook] friend and a fantastic artist Francis Tsai. I came to know him through the ALS community and very soon became a fan of his art. When I learned he was selling prints online to help finance his care, I purchased a couple.

The first one I purchased was one he did prior to onset called "Trixie":

This was a gift to a friend who collects pin-ups. My next purchase was a much more recent one called "Horned", which sports Francis' motto "Adapt - Survive - Prevail":

The thing I really enjoy about "Horned" is that it completely (and very literally) illustrates Francis' motto. Not content with just fading away, he got a computer and some software and created it using only his eyes!

Francis truly exemplifies the willpower of PALS and the clever use of technology to overcome the physical limitations which come with advanced ALS. A person is the result of his/her mind, NOT the physical body. With a little willpower and some appropriate technology, PALS retain purpose and personal productivity and quality of life remains high.

Surf on over to Francis' DeviantArt and StorEnvy sites (linked in the images above) and check out his art. While you're there, purchase a couple of prints. The money goes to a worthy cause and they make great gifts!

PSAwesome

On Monday of last week, this excellent PSA was released by Team Gleason. It was shown on the big screens inside the Superdome but needs to be shown repeatedly on major network television (ie ABC/CBS/NBC). Please watch, share with friends, and send to your local network television stations. This is the kind of message that needs to get in front of the eyeballs of America. This is the celebrity action we have been asking for. Now let's do our part in getting it out there.

Sugar Smack

Sugar, Sugar (The Archies - 1969)

I am not a real "food crusader". I eat a lot of meat and drink my share of alcohol, and didn't mind tossing down the occasional fast-food burger or pizza. But since the late 20th Century a shift began toward the use of fructose as a cheap sweetener. Instead of cane sugar, manufacturers started using high fructose corn syrup (HFCS) to sweeten things like beverages (ever notice how Coca-Cola tastes better in other countries? It ain't just the glass bottle, son...). Not only is this highly-subsidized sweetener cheaper for manufacturers, it reacts hormonally different in the body from regular glucose sugar.Fructose does not provide the same feeling of satiety nor does it calm the pleasure centers of the brain responsible for food and reward seeking.

HFCS is now found not only in candies and other common sugary foods, but it is being added to EVERYTHING. You can find it in nearly every snack food such as chips, to condiments, to even sliced loaf bread! It's not very difficult to draw a correlation between the new ubiquity of HFCS in food and the growing obesity/diabetes issue in America. And don't think the food conglomerates aren't aware of the power of this addictive ingredient.

So why am I bringing this up on a blog about ALS and related issues? Eventually PALS will require a PEG tube for adequate nutrition. The formula given for use in the PEG is loaded with HFCS. In fact, it's in the first 3 ingredients. HFCS is the way the manufacturers boost the calorie density of the formula. My own personal experience with PEG formula is that it ended up crashing my pancreas. I was in such a diabetic shock that the doctors actually said that I might not survive the night (hogwash, I say!).

I struggled for a few weeks with my new diabetic condition. Finally I said enough to the drugs and insulin injections and started having real food pureed with fortifications such as milk products, avocados, and other vitamin supplements. Getting off that formula was the best health decision since getting my vent. I urge all PALS to eschew formula and use real pureed food. Getting a healthy diet isn't hard at all.

The ALSETF

As my readers may know, my posts this year have been a little farther and further between. I have been working on some projects. Hopefully one or more can make a real difference for PALS. It's time to talk about one of these projects: The ALS Emergency Treatment Fund.

The ALSETF is about bringing treatments in late development (post-Phase 2) to ALS patients. Right now there is no hope for the majority of living patients because over 50% do not qualify for clinical trials. For a newly diagnosed patient, the odds of living to see a drug approved which is starting trials at the same time is about 10% (actually much less considering the historical approval rate of ALS treatments). However, with recent advances into the nature of ALS, certain drugs have been developed which show real promise for treating at least a subset of PALS. More are planned to enter trials in the United States very soon. We at ALSETF mean to get that hope ASAP to PALS who are currently living.

ALSETF is a 501C3 non-profit organization with the mission to partner with government and industry agencies to enable Expanded Access Programs. Expanded Access Programs (EAPs) are FDA authorized programs that permit the use of yet-unapproved drugs under medical supervision, in specific cases where those drugs are in late stages of development and have shown preliminary evidence of safety and efficacy. EAPs are only for immediately life threatening conditions for which no effective approved therapies exist. We have open communication with the FDA's Office of Neurology products for guidance on EAPs involving investigational drugs for ALS. We also maintain open discussion with clinical leaders on the best practices for EAPs, as well as with certain pharmaceutical companies with drugs in trial and in the pipeline.

Our focus right now is to raise up to $5M to help fund certain costs of an EAP such as upgrading manufacturing to clinical-grade, production quantity necessary for fulfilling EAP demand, etc. These are all issues which can currently prevent a pharmaceutical company (especially the small start-ups likely to take a chance on ALS) from accommodating a large EAP. We believe the financial issues can be solved and that the drugs being talked about with excitement in the ALS community can be brought to those who don't qualify for trials now, while they are still living.