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.

Growth Potential

Two new studies came out that I found rather interesting. The ability to transfer into humans is years off but the progress is still impressive. First up, a team at the University of Toronto developed a new technique to expand stem cells at industrial capacity. Second, Children's Hospital of Philadelphia generated a new human stem cell type called an "endodermal precursor". If the new stem cell technique can also be used to generate ectodermal precursors, it could be a major advancement in regenerative therapy for ALS. Many additional steps would still be necessary but mass-production of teratoma-free cells would be an important contribution.

Headlines

First off, there is some wonderful news: Diaphragm pacing system receives FDA approval for use with ALS patients. This is a device which extends time until vent by electrically stimulating the diaphragm. Note that this will not replace a vent as the diaphragm muscle needs neurons to release acetylcholine to the muscle fibers in order for them to contract. However, I urge all PALS reading this to immediately begin talking with your neurologist about whether this would be right for you. Here is some good information regarding the DPS.

Next up is the recent news regarding the Neuralstem trial involving stem cells implanted in the spines of PALS. Readers can see a poster-style synopsis of current trial data here. The initial results are encouraging, and one patient has even shown improvement. The next step in the trial is cervical implantation where the cells will have the chance to impact the phrenic nerve (the "money" nerve that serves the diaphragm and breathing). There is still much to learn about this technique before it is available to but a few. Remember that this is still a safety trial. I would urge readers to consider the words of Neuralstem's CEO.

Brainstorm Coming

Some more very good news for PALS in the USA: Brainstorm is bringing it's stem cell clinical trial to the US! This technology, named NurOwn, uses a patient's own mesenchymal stem cells to produce little factories for neurotrophic factors (proteins that nourish and strengthen neurons). This would provide a constant and lifetime production of support for the neighboring neurons, a much more effective approach than drugs which are only present for a short time or may be reduced or blocked by the Blood-Brain-Barrier. Note that this is not a replacement therapy, but rather one to help feed and protect existing neurons. You can read about the trial protocol here. For recently diagnosed patients they will inject into muscles to try to take advantage of axonal uptake in the hope that this will preserve the axon and its attachment to the muscle (neuromuscular junction). Patients in later stages of disease will have an injection into the spine to treat the neurons' cell bodies directly.

Cell Mates

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.

Be Yourself

"I'm nobody! Who are you?" The concept of "self" is critically important in the immune system. Each of our cells present a unique set of molecules on their outer walls which signal to our wandering immunity police that they belong ("your papers, please"). Any other cells not presenting the same combination are considered foreign invaders and are attacked ("your papers are not in order!"). This works great for resisting infection but is a major impediment to transplant surgery. Even "tissue matching" is inexact, requiring recipients to have their immune system forever after repressed in order to maintain the graft. Finding a way to allow for a graft of desirable foreign tissue but also maintain a robust immune system is a therefore a major goal. A stem cell research grant by theCalifornia Institute of Regenerative Medicine has a quite novel approach: regenerating the thymus, the "police academy" where the immunity cells learn to recognize the body's own cells from foreign invaders. The thymus atrophies in adulthood, so regenerating it from stem cells from an appropriate HLA line might trick the immune system into accepting the graft with the same HLA type. Quite a clever approach, and yet another reason that I am glad to have voted in favor of forming CIRM (ironically shortly before I was diagnosed with ALS).

More Baby Steps

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.

Medical Tourism

It's been over a month since my last post. A couple of interesting things have come over the transom but nothing really compelling for me to write about. Also I have been busy in other areas. Something compelling did show up today. An article on Nature Magazine's website concerning the controversy around stem cell medical tourism and the difficulty in regulation. While stem cells offer tremendous potential, the science necessary to fully and safely exploit that potential is still in its infancy. However, because of the potential, the desperation of people afflicted with horrible disease, and the ability to conjure and proliferate medical buzzwords over the Internet, the unwary and uninformed are preyed upon by the immoral and unscrupulous. As can be demonstrated by reading my previous entries, I am a firm believer in stem cell technology. I am anxious to participate in one or more procedures in the hope of regaining function. But the science needs a little more time to develop. Anyone offering or advocating a stem cell "therapy" is either lying or deluded. Several clinical trials are underway or will soon commence (some of which I have previously discussed). But for now, I urge the reader to save your money and preserve your health by not succumbing to the siren song of an exotic "miracle cure".

Stem Cell Update

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.

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.

Insane in the Membrane

I really love the Public Library of Science because they encourage and publish research articles in the Public domain. This gives a dilettante like myself access to current peer-reviewed medical research without emptying my bank account. A couple of fascinating (if not immediately applicable) studies recently showed up in my search results. First was a study which researched how embryonic stem cells (ESCs) are not necessarily all created equal (good summary here). I rubbed that against this study which tracked how cells convert from Inner Cell Mass to ESCs. This is just basic research, so what? Well add this study from Stanford (mentioned in an earlier post) and that basic research gets more exciting. There is one company already developing methods to use placental stem cells for pharmaceutical purposes. Knowing how these cells change themselves, thereby facilitating in vitro manipulation, would be crucial. The second study demonstrated making functional neurons out of astrocytes without first reverting them to a pluripotent state (as is done with skin cells to create induced pluripotent stem cells). Sounds great, except harvesting the astrocytes can be a bit tricky. While I consider that there are multitudes from whom whole lobes could be removed with no appreciable cognitive or behavioral impact, poking holes in the brain for experimental raw material probably isn't a good idea. And the study used retrovirus to deliver the genetic information, which for in vivo application could cause problems. (apologies for the inaccurate humor stretch) While these studies don't appear to be immediately applicable to human disease (and regenerative medicine), they demonstrate how far knowledge has advanced at an extremely rapid pace. This continues to give me hope for an effective treatment very soon. While the word "soon" has been used for decades (resulting in much cynicism among PALS), the techniques explored above are extreme changes in paradigm. And as human trials with stem cell technology are already underway, the time from basic research to effective therapies is now being greatly compressed.

Stem Cell Update

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.

Stem Cells for Dummies

Stem Cells for Dummies is authored by Lawrence S.B. Goldstein, PhD. Dr. Goldstein also co-authored the legislation which created CIRM. The book does, IMHO, a rather good job of presenting complex science in terms which laypeople can easily digest. It starts with a primer on biology as it applies to stem cells and a brief history of their discovery and initial uses. The differences between adult and embryonic cells is explored with frank discussion of the attributes and limitations. The role of these cells in the research and treatment of various diseases is discussed along with a review of the current state of the art (my previous post on stem cells deals with some cutting-edge techniques). There is a detailed section on the ethical and moral controversies surrounding this sensitive topic, and a section on common myths and misconceptions. Stem Cells for Dummies is written from the scientist's viewpoint but takes effort to present in a neutral tone. It is written for anyone who wants to understand stem cell technology without requiring a PhD. Rather than spend weeks cuddling with Google and sifting through the inevitable dreck, drop $10 and receive a great resource from a recognized expert in either dead-tree or electronic form. [disclaimer: I linked to Amazon for convenience and because I use their Kindle for PC application. If you can, support your local bookstores.]

Stem Cells

There has been a bit of action recently in terms of stem cells, with one human trial in MND which commenced this month and another which hopes to commence soon. There are a two ways for stem cells to be of benefit: Trophic support where the grafted cells support existing neurons by secreting nourishing (trophic) proteins such as GDNF and BDNF and regenerative where new replacement neurons are grown. Each approach has advantages and technical (biological) hurdles. As I said, trophic is secretion of neurotrophic ("nerve-feeding") factors. It can also occur from the implanted cells just being a close friend to the diseased neurons. A benefit of trophic therapy is that the graft cells do not need to differentiate or grow. Cells modified to become GDNF "mini-pumps" have been shown to fully protect motor neurons in animal models of ALS. Unfortunately, however, in that study the protection did not extend to the axon. While the cell body was healthy, it made no contact with muscle which is functionally the same thing as the whole cell dying. In the trial underway in the United States, Neuralstem is using fetal stem cells. While they claim their product will differentiate into neurons and glials, they only claim to be pursuing a trophic therapy. In at least one animal trial, the implanted cells extended the life of the model (it is worth noting that due to variability in the model, the ten extra days could just be statistical noise). The cells were found to fully integrate into the host central nervous system. Another group, TCA Cellular Therapy is using autologous cells taken from the bone marrow. Both of these trials involve spinal implantation. A planned trial in Israel will also use autologous cells but will do the implantation in muscle to try axonal uptake. Regenerative therapy has its own set of issues. While the ability for stem cells to become neurons has long been demonstrated, the new neurons still need to make proper axonal connections to muscle (spine -> muscle) and within the brain to other neurons (motor cortex -> spine). In 2006, a study by Johns-Hopkins achieved that in test animals. The process required not only implantation of prepared cells but also significant treatment on the muscular side of the connection (sharp readers may notice similarities to procedures discussed above). A much more recent study from Stanford showed that proper preparation of the stem cells is critical for proper behavior of the cells after implantation. The cells prepared with retinoic acid (as in the Johns-Hopkins study) failed to create proper connections whereas cells prepared by co-culture with stromal cells grew robustly and made proper connections from the motor cortex to the spinal cord, bypassing neurons from other cortexes (visual, etc.). Caveates of the Stanford study is that the work was done on very young animals (about a week old) so fully adult animals may present a different environment, and that requirements for cortex -> cord connections may be different from spine -> muscle. On most of the studies above, the links are to press releases. This is done to indicate existence and to give limited information. Copyright prevents me from republishing any studies (except for the PLOS link which is intentionally placed in the Public Domain. The reader should also note that my technical training is in hardware and software, not wetware.