Race horse medicine affects people, changing an invasive surgery to a simple injection.

In a very unusual breakthrough, a stem cell treatment for racehorses is ready to be tried… on you. British scientists pioneered a technique in horses where an individuals’ own stem cells are grown outside the body, then injected into the damaged tendon.  There will be a clinical trial in the UK in which 24 human patients will undergo this radical new stem cell treatment for similar tendon injuries. We’ll tell you about the proven benefits in racehorses so you’ll understand the possible benefits in people. The test subjects who join the clinical trial will be in the unique position of enjoying a medical procedure that is years behind the veterinary equivalent.  If human beings have the same barely believable 80% recovery rate, this will be a leap forward for sports medicine.The transition from ponies to people began  in 2005.  After successful early treatments on horses, veterinarian Roger Smith published “Harnessing the stem cell for the treatment of tendon injuries: heralding a new dawn?” in the Journal of British Sports Medicine, which is a human medical journal.  Roger Smith, a professor at the British Royal Veterinary College, works with VetCell Bioscience Ltd., a British company that specializes in equine tendon injuries.  Smith explained in his paper, “it is hoped that our experience with horses will pave the way for this technology to be used successfully in human tendon and ligament injuries.” After years of extensive tests (on horses) they’re ready to move their treatment on people.  You can visit the VetCell website and sign up to be one of the 24 patients in the clinical trial that’s happening this year through their sister company, MedCell.

The clinical trial will treat achilles tendinitis (they’re British, they spell it with an “i”) without surgery. For treatment, bone marrow stem cells are collected from the horse, er, person, then coaxed into becoming tendon cells.  The lab grown tendon cells are injected into the site of injury.  Injecting a cure without major surgery is a big freakin’ deal because, in humans, surgery produces “Moderate to severe pain … in 20% to 30% of patients … In addition, a wound infection can occur and the infection is very difficult to treat in this location,” according to the American Academy of Orthopaedic Surgeons.  (You can also see the above surgery image in full gore mode.) VetCell states that in the “athletic horse” tendon stem cell therapy leads to about 80% recover rates, compared to about 40% using conventional surgery, as well as having very low re-injury rates after treatment.

The process of tendon repair in the horse, from VetStem's website

VetCell’s transition into human medicine shows that innovation can come from unexpected sources. “The move from clinical veterinary to human medicine is inspiring and unusual; we normally see the translation happening the other way around.” Said sports medicine professor Nicola Maffulli, of The London Independent Hospital. (His quote’s gone a bit viral, showing up in 347 websites.) In the past,  SingularityHub has published the sad fact that animals are often getting access to innovative medical treatments before humans.  Perhaps VetCell’s bold move could pave the way for other animal bio-tech treatments to smoothly transition to humans.

The reason animals can get commercial drugs and treatments faster than people in the US and other Western countries is simple: there is enormous oversight in human medical research.  Veterinary research is comparably simple. According to the FDA, bringing a new drug to market for humans requires pre-clinical laboratory tests, animal tests, and human clinical trials.  Each one of those steps costs money, lots and lots of it. Approval for veterinary drugs is simpler, requiring a single study that proves the drug is safe and effective. Because of regulatory difference, progress on animal medical research can move very quickly compared to human research.

A gap between availability of human and animal bio-tech isn’t necessarily bad.  A growing company can find important revenue through veterinary products while developing human medicine. The Intralytix company in Maryland, USA, has two animal products that are already completed and licensed out and three human products are still under development.  Intralytix is researching phage therapy, which delivers bacteria-slaughtering viruses to infections.  While they work on human medicine, they’re making food and food animals safer for humans.

The most interesting aspect of this stem cell treatment is that it has been thoroughly investigated on animals that live as practicing athletes, putting incredible strain on their bodies.  This is probably an improvement on lab animal only testing.  In the meantime, if you’ve got a banged up achilles tendon, you can go sign up for VetCell’s clinical trial.  When you go in for your injection, be comforted knowing the treatment was developed for horses worth more than your house.

[Image credit: Ruptured tendon surgery www.podiatrytoday.com; race horse, Jeff Kubina on Flickr; hypodermic needle, Armin Kübelbeck, wikimedia commons.  Info graphic from vetcell.com]
[sources: Smith and Webbon B.J.Sports Medicine, 2005, VetCell, MedCell]

A burned eye on the left, and again 6.5 years after stem cell therapy. Amazing.

Italian researchers have demonstrated the long term effectiveness of using stem cells to cure corneal blindness. From 1998 to 2006 the team, headed by Graziella Pellegrini at the University of Modena, performed 125 stem cell procedures on 112 patients, all who had lost partial or complete vision due to chemical or thermal burns. Stem cells were taken from the limbus in the patient’s own eye, cultured, and then grafted back on the eye. As recently published in the New England Journal of Medicine, the grafts had a success rate of 76.6% – leading to restored or improved vision. Better still, the positive results have lasted – one patient has been followed for more than 10 years and still has healthy vision. That’s remarkable. This work represents a real group of people who have already had their lives radically changed through stem cell treatments. More patients all around the world may see benefits from this technique soon.

Using grafts of stem cells to treat corneal blindness isn’t a new idea. Pellegrini and collaborators like Michele De Luca, were pioneering different versions of the technique back in 1997. We’ve seen related approaches to restoring damaged corneas, most notably in New South Whales. This report in NEJM, however, has something that few (if any) have presented before: a relatively large sample set that shows positive results verified over the long-term. Ten years for a successful stem cell transplant? Outside of bone marrow grafts, almost no one has that kind of follow-up history for stem cells. It’s a great sign that what Pellegrini and colleagues are doing is a viable long term cure for corneal blindness.

These before and after pictures are astounding. The top example required no further surgery to correct vision, but the others need keratoplasty.Notice the small notations in the right picture that indicate how long after treatment the images were taken. The arrows in the last row highlight that blood vessels no longer intrude onto the cornea.

The NEJM article also describes an important development in being able to predict the success of a stem cell treatment. Many of the patients in the study had mild to severe limbal damage, limiting the amount of healthy stem cells that could be harvested and cultured. Pellegrini’s team monitored levels of p63 transcription factor in the stem cells they harvested from patients. When the number of ‘p63-bright’ cells was greater than 3%, the success rate of the eventual transplant ended up around 78%. When it was less than 3%, the outcome was successful only 11% of the time. This work demonstrates that very little of the limbus need remain healthy for the stem cell transplant to still work. Using p63 levels as a metric could allow doctors to present patients with a better idea if a corneal stem cell transplant would be successful. It also hints that p63 transcription factor could be augmented or controlled in some way to improve stem cell therapies of this kind.

Amidst all the success in this recent report, we must also face some serious limitations of the work. First, these stem cell treatments were only used for corneal blindness. Not only that, but a very specific cause of corneal blindness – burns. Chemical and thermal burns can cause a wide variety of injuries to the eye, but often leave all parts of the inner eye and optic nerve functioning. Some patients retain some form of (very limited) vision. Also, because of the nature of the causes of these injuries, more than 78% of the 112 patients were men. While thousands lose their vision to chemical accidents every year, there’s a huge number of people with vision problems related to other corneal damage, retinal damage, and nerve damage that are unlikely to benefit from this technique in stem cell transplantation.

It’s also important to note that while the study followed one patient for more than 10 years, the average follow-up was closer to three years (with large variation). That’s still pretty good, but it’s not the same as saying that all 112 patients were tracked for a decade. As always, smaller data sets mean data has to be taken with a grain of salt.

Finally, I should point out that the term ‘positive results’ covers a wide range of changes in vision. A few went from seeing nothing to having restored vision. Some patients went from only being able to see the vague outline of fingers to actually being able to read and determine fine shapes. Others saw more modest improvements, and 24% failed to benefit. These changes didn’t happen overnight; they often took many weeks or more than a year to develop. About half of patients needed keratoplasty (reshaping of the cornea) to correct their vision, though that is a relatively simple procedure these days. Bottom line, it wasn’t like these patients got an injection of their own stem cells and could miraculously see the next day. Stem cells taken directly from their eyes had to be cultured and then grafted onto the cornea, and there was a sustained period of follow-up and further medical care before doctors or patients knew how successful (if at all) the procedure would be.

Still, these results are real world examples of how stem cells are already treating a loss of vision. Pellegrini and her colleagues may be able to adapt their technique to treat other (more common) forms of corneal blindness with the same impressive outcomes. Their confirmation of the importance of p63 transcription factor could also prove helpful in the wider field of regenerative medicine. This work is another victory for stem cells and another step towards being able to regenerate or regrow every part of the human body. I’m deeply impressed.

[image credits: Rama et al NEJM 2010]
[source: Rama et al NEJM 2010]

Dr. Centeno is offering stem cell therapies for orthopedic damage with remarkable results. Is this the future of stem cells in the US?

The FDA has yet to approve stem cell therapies for general use in medicine, but that hasn’t stopped doctors in Colorado from providing them anyway. Chris Centeno and John Schultz have boldly formed Regenerative Sciences Inc. in Broomfield, Colorado. RSI provides its patients with the Regenexx procedure, an adult stem cell transplant that uses your own cells (autologous) to treat joint injuries and bone damage. There’s no surgery needed. A needle extracts bone marrow, RSI isolates the stem cells and cultures them in your own blood, and then these cells are injected into the area where they are needed. They’ve treated 348+ patients with 800+ injections and show no signs of slowing down. According to RSI’s own surveys, 89% of their knee patients showed marked improvement, as did 75% of their hip patients! Within months some patients can walk or run in ways they haven’t been able to in years. We’ve seen these kinds of results from stem cell treatments before, but only in horses and dogs. That’s because human stem cell therapies like this one aren’t approved by the FDA. How can Centeno and Schultz flaunt the lack of federal approval? They claim that Regenexx is solely used as a part of their medical practice, only within the state of Colorado, and as such is no more regulated by the FDA than it would be by the FAA or the Department of Motor Vehicles. I had a chance to talk with Dr. Centeno over the phone and learn more about Regenexx and RSI. For hundreds of patients, he and his team are providing a remarkable hope. They’ve brought lab-cultured medical stem cell therapies to the US. Finally.

Stem cells have been a focal point for hype and hope for years now. Besides healing horses and dogs, they have promising effects on diabetes, corneal blindness, even HIV. It’s pretty clear that they’re also the future of organ transplants. Just the news of a stem cell related development or patent will cause a biotech company’s stocks to soar. The FDA, which regulates all interstate drug sales and related clinical trials is not trying to keep Americans from these “miraculous” cures, it’s simply trying to make sure they are safe first. Apparently, that’s taking too long. Medical tourism agencies are starting to cater to those seeking stem cell treatments. Whether or not they are ready for widespread medical use, stem cell therapies are in high demand, not just in the US but around the world. It’s no longer a question of when we will have access to these treatments, it’s a question of how.

A severely damaged knee healed to a remarkable degree. Must be stem cells. RSI is offering adult stem cell therapies in the US. That's an important first, but what will happen without FDA approval?

Patient’s interested in the Regenexx procedure face what seems to be a fairly standard experience for autologous stem cell transplants. It takes 20-40 minutes to extract the cells from hip bone marrow with limited anesthesia, and blood is also taken. Over a month RSI’s lab will isolate mesenchymal (multipotent) adult stem cells and multiply them until they have 1 to 10 million. Typically, a patient will receive an injection into the treated area once a month for three months. Positive results are sometimes seen quickly (in 1 to 3 months) but will hopefully develop within 6 to 9 months. Importantly, there’s no down time as a result of the procedure. Patients can leave the clinic and go home after each injection.  A round of Regenexx (extraction, cultivation,  and 3 injections) costs $7000-$8500. Those who produce exceptional numbers of stem cells can use subsequent injections (even in other parts of the body) for around $3500. Most insurances will not cover the treatment.

The fact that RSI isolates and cultures (multiplies) the cells is a big difference from other clinics that offer stem cell therapies. That process allows the lab to create enough mesenchymal stem cells  to really have an effect on the area in which they are injected. Many clinics around the world will take blood, marrow, or tissue and then spin out the stem cells in a centrifuge, injecting them back in on the same day. That style  of therapy could possibly be effective, but it is far less likely than with a dose of millions of multipotent stem cells. There are several doctors around the US that will provide such ‘single-visit’ stem cell therapies, but as far as I know RSI is the only that offers the lab cultured mesenchymal therapy in the US. Dr. Centeno has confirmed that he’s the only one, that he knows of, openly using this particular procedure in the US.

In the past, I have been very skeptical of stem cell treatment centers in other countries. I’d like to turn that same critical eye to Regenexx. It’s only fair. First, let’s look at the success RSI is selling. Autologous transplants are offered in the hands, hips, knees, shoulders, back (non-spinal cord injury), ankles, and bone fractures. For each of these procedures you can find many ardent and exceptionally encouraging patient testimonials on their website, or their YouTube channel, along with a flood of supportive media. Here’s a clip from a local news Channel which is pretty indicative of the rest:

Overall, RSI is claiming around 80% patient satisfaction according to its own surveys. That’s incredible, especially when you see some of their patients walking and running again on joints that have experienced years of chronic damage. It also seems Centeno and Schultz have the documented evidence to back up the claims for Regenexx’s success. RSI provides case studies for each of its treatments as well as published scientific research. According to my conversation with Centeno, RSI is currently working on a comprehensive statistical analysis of their more popular treatments so they can publish quantitative results in a peer review journal. In other words, they’ll soon publish the hard numbers – X% of patients feel Y% better Z months after the procedure.

Importantly, RSI seems to be upfront with patients about the limits of their own technique. The website FAQ clearly states that not all results will be like the testimonials, and they even have a dedicated page explaining that stem cell therapies won’t work for everyone. Furthermore, RSI has published the largest study of risks and complications associated with stem cell treatments yet produced in the US (N=227). That paper demonstrates the very low harm associated with stem cell therapies – much lower than the alternative surgery(published in Current Stem Cell Research & Therapy). Centeno told me that if we’re really worried that autologous stem cell therapies are going to hurt someone, this paper pretty much shows they won’t.

The concerns most people have with RSI are not medical, they’re political. Many applaud Centeno and Schultz for supplying the public with the cutting edge technology they demand, but worry about the manner in which it has been accomplished. Skirting FDA approval for a technique through the arguments they use opens the gate to a host of problems. If RSI can provide Regenexx because it is a doctor’s procedure not involved in interstate commerce, does that mean someone else can do the same for another treatment? What are the limits of such procedures? How does a patient know if a doctor’s therapy is safe, or effective, if it hasn’t undergone peer review and government inspection?

During my conversation with Dr. Centeno, he pointed out that doctors and surgeons are developing new procedures all the time. Surgeons will often create new devices for their own use in surgery, doctors routinely try out new dosing regimes, or therapies on their patients. This is part of the medical profession.

Still, it’s possible that even though RSI is doing what many other doctors routinely do (develop a new therapy for use in their own practice) that the federal government could try to bring them to court. The FDA seems to have taken the stance that all stem cells (whether used autologously or not) are drugs. As such, they would need FDA approval, and would likely only be developed by large pharmaceutical companies.

According to Lee Buckler of Cell Therapy Blog, Centeno’s already received a warning letter from the FDA. Centeno clarified that this is actually an “untitled letter” which has no bearing on regulation. He pointed me to this explanation on untitled letters. RSI has faced concerns from the New York Department of Health, and went so far as to pursue a provisional license, even though they are no where near NY state. Clearly RSI is hoping to avoid bureaucratic problems or at least be very prepared for them if they do arise.  Perhaps with enough positive results they can avoid legal battles and even convince insurance companies to cover Regenexx.

Hopefully so. Just look as these results. They’re pretty damn amazing. If you accept the success rates, and the possibilities for long term healing…I know people who need this. I really want them to be able to get it.

Centeno says he is working with others to provide the framework through which many more patients could receive mesenchymal stem cell therapies. He’s on the board of the International Cell Medicine Society (ICMS) which is working to track stem cell therapy patients through a registry, as well as certify stem cell clinics for practice. Through conferences and seminars, doctors are trained in IVF to work in fertility clinics. Centeno explained to me that a similar practice could instruct and track physicians interested in providing lab cultured autologous stem cell therapies. In other words, the technique used by RSI could become a regularly seen procedure in specialty clinics across the country. That may mean more patients could have access to stem cells soon.

One way or another, I know they will. FDA approval is slow, but it’s coming. Athersys has a patent for a stem cell derived drug, other companies have therapies in clinical trials. Those treatments will be here some day. In the meantime, RSI is filling in the gap. Their work may even catch on as a trend. If largely successful, insurance companies may pay for it and the federal government may end up grandfathering Regenexx in at some point. It could happen. What’s certain is that the public demand for stem cell therapies is real, growing, and seemingly justified. When that sort of pressure for a technology exists nobody can keep it down.

**Update: It has been pointed out that we have neglected to consider the long term effects of stem cell therapies. This is an oversight on our part, but the reality is that there is no conclusive understanding of what the long term effects of stem cells treatments will be. We do not know if a stem cell treatment will be effective 5-10 years after it is administered, and we know of no large study that has conclusively reviewed patients for cancer, or any long term side effect 5-10 years after a stem cell injection. I believe that part of what ICMS is trying to do (reviewing clinics, tracking patients results over the long term) may yield a better understanding in the future.**

[image credit: Denver Business Journal, Regenerative Science Inc]
[video credit: ABC 7 News in Denver via Regenexx (copyright status unknown)]
[Sources: Regenerative Sciences Inc, ABC 7 News in Denver, Lee Buckler , RSI Blog, Current Stem Cell Research & Therapy]

C'mon girl, help me get a stem cell treatment!

What are these treatments promising? According to anecdotes, the results are amazing. Old dogs with bad hips frolic like puppies. Race horses with injuries come back to become world class winners. One such racehorse, Be A Bono, won 16 out of 24 starts, earned more than 1.3 million in prize money, and was the 2004 World Champion Quarterhorse. All after a stem cell treatment. The success stories with dogs are equally remarkable, if a little tinted by emotion; check out the video from Vet-Stem after the break.

Most animals that have been treated with stem cells suffer from joint ailments. Damage to cartilage, tendons, ligaments, or arthritic inflammation top the list. Stem cells are seen as a way to provide almost magical regenerative healing to combat these ailments. The process is actually pretty simple. Rather than embryonic stem cells, adult stem cells are used. These adult stem cells are harvested in a veterinary office from fat cells in the animal, and then sent to a lab. Processing separates out the stem cells from other cells, and a concentrated dose is sent back to the vet (The turn around time for processing is only a day). The adult cells are then injected into the animal in the area that needs regeneration.

Regulation does not necessarily stop research, but it tends to slow it down as it navigates bureaucracy. That’s where the helpful word “autologous” comes into play. An autologous transplant is one where the donor and the patient are the same organism: like a fat transplant from your buttocks to your lips, or like the horse and dog treatments we just discussed. Autologous transplants of stem cells in animals are not regulated by the federal government and this has led two competing companies, Vet-Stem and Vet-Cell, to specialize in providing veterinarians with stem cells for their equine and canine patients.

From the Horse’s Mouth

The anecdotal results may be hyperbolic, but the clinical numbers are no less noteworthy. In clinical trials by Vet-Stem, 66 horses were treated and 77% saw marked improvement and a return to racing. Vet-Cell’s trials used 82 horses and had a success rate of 78%. Critics are quick to point out that company run experiments are a far cry from double-blind clinical trials, but both companies have treated thousands of horses and are making huge strides into the small animal market (read here: dogs).

Equine results from the Vet-Cell website.

Of the 1500 veterinarians that Vet-Stem has trained to perform autologous stem cell transplants, more than 60% specialize in small animals. That means that most of the transplants have moved from equine athletes to canine companions. With a price tag less than $3000, the stem cell treatment is actually cheaper than many hip replacements surgeries for larger dogs (as much as $10k or so). As Vet-Stem and Vet-Cell promote the efficacy of the treatment, you can expect more and more dog owners to be stepping up and demanding it for their pets. Considering the attachment between pet and owner, it’s an easy sell.

The harder sell would be to convince academia to validate the clinical findings…or so you would think. But of the four U.S universities that have veterinary stem cell projects (UC Davis, Colorado State University, U Penn, and Cornell) all have expressed cautious optimism about the success of treatments on their test subjects. CSU treated 15 race horses and saw 10 return to active competition. Not quite the 78% success rate of Vet-Cell, but still impressive. The UC Davis Regenerative Medical Laboratory is expanding to accommodate more work in the area as well.

Which isn’t to say that anybody really knows how these autologous stem cell treatments actually work. There’s a large debate between scientists whether the stem cells are actively reassigning to become mature cells of different types (bone, ligament, etc) or whether their presence promotes healing by releasing cytokines (cell to cell communication chemicals). There’s even argument over which kind of adult stem cells to use. Vet-stem favors fat cells, while most of the universities favor bone marrow cells. Fat cells are more plentiful, but perhaps less potent. Marrow cells are more potent, but have to be cultured to provide enough for treatment. Definitive answers to these debates may take years to resolve, but that hasn’t stopped animals from being treated today.

It Really Gets My Goat

The first equine autologous procedure was performed around 1995 by Douglas Herthel DVM. He was reporting regular success by 2001. Be A Bono was treated and then became a champion in 2004. It’s now half way through 2009 and Vet-Stem and Vet-Cell are going strong. They train new veterinarians every year in the procedure and they can process dozens of sample each week. This is amazing technology, which still needs more testing, but right now is one of the more miraculous cures in veterinary medicine. Similar treatments for humans don’t exist yet. So your horse or dog can benefit, but you can’t.

There’s a lot of really great reasons why this is so. Human test subjects are not animal test subjects, and clinical trials for humans have to be more rigorous and take longer. Collecting and isolating adult stem cells in humans still needs more time to be perfected. This technology is largely focused on joint ailments, which are important for humans, but not life threatening as they are for horses and dogs.

There are also a lot of stupid reasons why autologous transplants are years behind in humans, mainly bureaucracy, debate, and fear. I can’t help but look at these veterinary treatments and feel disappointed and angry that similar treatments are not available for humans in the U.S. Perhaps that’s an ignorant reaction. Look at the progress being made in the animal trial stages for organ replacement, or even the madcap use of stem cells in other countries, however, and you get the feeling that caution in the United States is stifling our development.

Still, progress is being made. The British parent company of Vet-Cell is starting Med-Cell, and hopes to bring the autologous treatment to humans suffering from problems in the achilles tendon. The National Institute of Health is funding programs that will focus on bone marrow stem cell treatments for arthritis, and musculoskeletal and skin diseases. ABC news Nightline recently did a report on the veterinary treatments that raised awareness and sparked a lively debate on stem cells once again.

Most of the controversy on stem cells seemed to stem from the use of embryonic cells. George W. Bush banned such research in 2001, Barack Obama opened the research again in 2009 both with great hullabaloo. The use of embryonic stem cells, however, is just one option. Adult stem cells are also viable for treating illnesses as autologous veterinarian joint treatments show. As the success of stem cell treatments continue, I hope that the bureaucracy works to adapt (or minimize) regulation so that it can promote research while still maintaining the safety of the public. That public is clamoring for better, faster, and cheaper treatments that stem cells could provide. Throw us a frikin’ bone here.