Geron's looking to heal spinal injuries with human embryonic stem cell derived progenitor cells repairing damaged nerves.

Almost a year after the FDA halted the study, Geron‘s clinical trial for a human embryonic stem cell (hESC) therapy for spinal cord injury is back on track. The Silicon Valley biopharm company recently announced that it had satisfactorily addressed the FDA’s concerns about cysts formed in animal models of the treatment that had stalled the trials. While the year delay was a serious setback, Geron’s pursuit of spinal cord injury repair is still the most advanced hESC therapy being tested in humans. While it is only in phase I of clinical trials, Geron’s hESC therapy carries the promise of at least partially healing paralyzed patients. This is the kind of research that Christopher Reeves and so many others advocated for, and it is finally moving forward again.

Geron is building off of Hans Kierstead’s amazing work at UC Irvine. In animal studies, researchers were able to get rodents with induced spinal injuries walking again. Think about it, a rat with a huge lesion on its spinal cord can’t move it’s hind legs, but after embryonic stem cell therapy it regains most of its mobility. Here are two videos that showcase these incredible results. The first is an explanation by Kierstead and the second is a brief look at a rat before and after treatment. Awesome!

We won’t know how powerful the Geron hESC treatments will be until they’ve undergone clinical trials, which is why getting those trials underway is so important.  As we discussed in September of last year, the FDA had stalled Geron’s clinical trial for GRNOPC1 (the hESC spinal cord injury therapy) due to the formation of cysts in some of the rodents treated in preliminary studies. While these cysts were microscopic, seemed benign, and were quite ordinary for spinal injuries, the FDA didn’t want to take any chances. Over the past year, Geron has gone back to these animal studies and developed new techniques and approaches to minimize the formation of these cysts. According to their recent press release, Geron has developed new molecular markers and release assays and performed additional animal studies that demonstrate lower numbers of cysts. The FDA is now more satisfied with GRNOPC1 and permitted Geron to continue its groundbreaking human trials.

That phase I trial will be primarily focused on safety, and has a rather limited patient pool. Only those with severe nerve injury and likely to demonstrate grade A impairment (as defined by the American Spinal Injury Association) will be enrolled. Those treated in the trial will receive hESC as injections seven to fourteen days after injury which is a pretty short window. Geron has yet to release the names of the half dozen or so medical institutions where the trials will take place, but says that information is likely to come online soon. It looks like, however, that given the short window of possible treatment, and the strict guidelines for patient selection, that those with premeditated interest in joining Geron’s study are unlikely to be accommodated in phase I. In other words, if you already have a spinal injury you’re not going to be involved in this part of the trials. Perhaps that will change as they move from safety to efficacy (in later phases…likely years from now).

The long term potential of these trials, however, is very promising. The Geron study stands out even among other stem cell trials because of the capacity for healing nerve damage. In the trials, human embryonic stem cell derived glial progenitor cells will be injected directly into lesions along a patient’s spinal cord. Animal models indicate that the glial progenitor cells should work to promote nerve growth and repair the myelin sheaths on the nerves. This ‘remyelination’ of the nerves is a critical component of healing spinal cord injury as it allows signals to be passed along the nerve. Here’s a video animation that explains more:

Damaged myelin, however, is not unique to spinal cord injuries. It plays a crucial role in multiple sclerosis and Geron is moving towards non-human primate studies for MS using GRNOPC1 (or similar hESC therapy). Additionally, Geron has stated it is researching treatments for Alzheimer’s disease (animal models) and Canavan disease (rodent models). Although we have seen a promising MS treatment that could be ready much sooner than a hESC technology, if Geron could develop therapies for any of these conditions it would be a major breakthrough.

Despite the range of possible applications Geron seems primarily focused on treating spinal cord injury. Rightfully so. There are few uses for hESC that are as noble or as awe-inspiring as getting a paralyzed person to walk again. Of course not even Geron is claiming that their GRNOPC1 treatment will be able to produce that kind of result, but it’s probably on everyone’s mind when they hear stem cells and spinal cord injury in the same sentence. The extent to which hESC will actually be able to treat spinal injury is a great unknown. Animal tests had rodents regaining the control over hind legs after treatment, but that was under very controlled conditions (and not in humans, clearly). It will likely be years before we know the full efficacy of GRNOPC1. A lot may hinge on Geron’s eventual success – if they face too many more regulatory delays or don’t develop a marketable product it may discourage other companies from investing in hESC therapies. Even with the pressure this is a very exciting time. The world’s first human trials for embryonic stem cells are back on track. Let’s hope they produce great results soon.

[image credits: Geron]
[source: Geron site and press release]

TCA Cellular Therapy out of Louisiana has several FDA approved clinical trials for stem cells underway, including one for ALS.

Stem cell treatments continue to gain ground in the United States. Louisiana based TCA Cellular Therapy has 6 FDA clinical trials in progress, the latest of which is the first approved US trial to use stem cells to treat ALS (Lou Gherig’s Disease). TCA performs autologous transplants that use a patient’s own bone marrow to produce stem cells, culture them, and then inject them back into the body. This avoids the need for donor matching. Among the other FDA approved clinical trials TCA has underway are studies on heart disease and limb ischemia (blood vessel blockages in legs). According to the TCA website, while the limb ischemia trials are still in phase II and phase III of FDA approval, the company hopes to begin treating patients for the condition in 2012. If ultimately successful in all phases of these trials, TCA would be able to provide its treatments anywhere in the country, and franchise the practice to others. TCA’s work is another example that, although it is taking its sweet time, FDA approved stem cell therapies are coming to the US.

We recently discussed how doctors in a Colorado clinic are already providing orthopedic stem cell therapies without the need for FDA approval by keeping treatments as part of a medical practice only. What is TCA gaining by going through rigorous FDA clinical trials? Well, they can eventually take their treatment, distribute it, and market it (it’s already patented). This means they have a lot to offer investors, and TCA is actively pursuing them. It’s unclear how much funding they’re looking for, but the first three years of work (7 FDA trials in progress or completed) took less than $3 million. Below is a promotional video from TCA that seems to be aimed at both patients and investors. It’s a little heavy on the rhetoric (the narrator really needs to chill out) but it highlights most of what you need to know about TCA. There’s a clip about a patient who was successfully treated (for heart disease/damage) starting at 2:47, and if you skip to 5:20 you’ll see a step by step explanation of how the autologous stem cell therapy is performed.

Whenever I see a company providing (or in the process of providing) stem cell therapies, I like to check if they are legit. TCA has already completed three phase I FDA clinical trials, and has several more in the pipeline. That’s a good sign. There are a few papers produced by TCA about their work currently ‘in press’ with major medical publications. Impressively, Dr. Jose Minguell has papers discussing mesenchymal (multipotent) stem cells and heart conditions that have been published in the American Journal of Cardiology, and in Experimental Biology and Medicine (part of the Royal Society of Medicine). These are high caliber credentials and a great sign that TCA’s science is top notch.

As part of that science, you should take note that TCA multiplies (cultures) stem cells before injecting them back into a patient. From my discussions with doctors in the field, this step is a crucial one. There are many clinics (all over the world) that will withdraw and isolate stem cells. Yet, if these cells aren’t in a high concentration, it seems unlikely that you’ll get an effective dose. TCA spends 3 weeks or so culturing a patient’s cells until they have 30-40 million mesenchymal (multipotent) adult stem cells. This work is performed at their in-house GMP lab and stored at Life Source Cryobanks (which TCA has a controlling interest in). Again, these are signs that TCA knows what it’s doing.

Unfortunately, there aren’t a lot of hard numbers to reveal how effective each stem cell treatment has been in trial.  Judging by the titles of the papers TCA has currently ‘in press’, those numbers are likely to be forthcoming. There are a series of patient testimonials, but we’ve seen these from every other stem cell clinic in existence.

Patients are clamoring for stem cell therapies, and except for a few clinics in the US, they generally must travel outside the US to get them. While a 2012 arrival for a stem cell ischemia treatment sounds good, the estimate could be off by months or years. And while I appreciate the seriousness of ischemia, it is just one of many conditions (diabetes, AIDS, blindness) that could possibly be treated by stem cell therapies. ALS, which has few effective treatments, is just the latest in the list of illnesses whose sufferers are going to pressure the FDA for quick approval. In other words, I don’t think we’re going to see the demand for US stem cell therapies to be satisfied any time soon.

Of course, that demand isn’t a bad thing. It will hopefully encourage investors to keep TCA well funded as it continues its clinical trials. Eventually, the rigorous methodologies of the FDA should pay off and we’ll have many different effective stem cell treatments. Look at TCA. Even within just one stem cell company we see efforts to treat several different forms of cardiovascular damage and a neurological illness (ALS). That’s an encouraging sign of the variety of stem cell therapies we’ll have on hand in the next few years. In the meantime, the struggle for patients to receive the treatments they want, regardless of government approval, will continue.

[image credit: TCA]
[video credit: TCA]
[source: TCA Cellular Therapy, Clinical Trials.gov,  Experimental Biology and Medicine, Google Health]

George Hamilton helped create this new artificial artery using nanotechnology.

Researchers at London Royal Free Hospital are hoping to save limbs and lives with the creation of their new artificial artery. Unlike current artery replacements, this grafting substance was created using nanotechnology and can pulse with the natural movements of the body. That pulsing will allow the polymer tube to be used in very small grafts (<8mm), giving hope that damaged arteries which would normally lead to amputations or heart attacks can now be treated. According to a recent press release, the Wellcome Trust has given [L]$500,000 to begin clinical trials of the new artificial arteries by the end of 2010. We could see the new polymer arteries in grafts, stints, and other vascular surgeries in the next few years.

Heart and vascular disease is the number one killer in most industrialized nations, and costs countries billions in health care, and lost wages. Nanotechnology, biotechnology, robotics, and stem cells are reinvigorating the development of artificial components of the cardiovascular system. We’ve seen hearts grown from stem cells in labs, artificial mechanical hearts, companies spending millions to develop artificial blood, and now even artificial vascular tubes which act more like the real thing. Combined with upcoming advances in robotic and micro-surgery, medicine could be on the path to conquering its public enemy number one.

The new artificial artery material was developed by Professors George Hamilton (vascular surgery) and Alexander Seifalian (nanotechnology and tissue repair). The substance is a polymer which has been embedded with different types of special molecules. Some of these molecules aid circulation, others encourage stem cells to coat its walls. That coating is very important and may allow the artificial tissue to bond better with the body and promote long term health. Most importantly though, the design of the artificial vascular tissue is resistant to clotting and can pulse.

Just those two traits put the new substance way ahead of current artificial arteries which have to be large in order to avoid dangerous platelet build up. In fact, for damaged arteries smaller than 8mm (~0.31 in), surgeons generally have to rely on finding donor veins in the patient’s body. These veins are typically found in the lower limbs and surgically transplanted to where they are needed. When a patient doesn’t have a good donor vein, and has artery damage that can’t use a modern artificial graft…they can lose the limb with the damage, or are at very high risk for heart attacks (if the damage was located in the chest).

The Royal Free Hospital artificial artery then, is poised to fill a much needed gap in cardiovascular surgery devices and could save lives and limbs all over the world. Eventually, its developers hope to create an entire line of off-the-shelf grafts and stints to fit a wide-range of vascular needs. Hopefully the clinical trials in 2010 will prove very successful.

If they do, this will be another feather in the cap of nanotechnology, which has been slowly revolutionizing material sciences and will continue to do so in the upcoming years. Forget creating artificial arteries that are as good as the real thing, nanotech could make ones that are even better. Along with respirocytes (artificial blood cells), and medical nanobots, artificial vascular tissue is just one of the many ways that nanotechnology could extend the capabilities of the human body. Until we all get our new nanotech enhanced bods, we should probably keep in mind that the best way to survive heart and arterial disease is never to develop it in the first place. Stay healthy, everyone.

[photo credit: Royal Free Hospital, London]

Stop seizures with an implant that gently shocks your brain.

The medical uses of electrically shocking your brain have a dubious history and a worse portrayal in movies. One Flew Over A Cuckoo’s Nest certainly didn’t leave viewers rushing to strap electrodes to their head. Yet, the medical industry continues to explore how mild electrical stimulation could help with brain diseases the same way that pacemakers help with heart disease. Neuropace, a company based in Silicon Valley, is in clinical trials with their RNS System. The RNS is a neurostimulator implant that monitors brain activity and shocks select regions to prevent epileptic seizures. Currently in clinical trial, the device represents a new era of healing the brain through electric shock.

Epilepsy affects around 1% of the world’s population (2.5 million or so in the US alone) and can be treated with medications or even surgeries. However, some patients are not good candidates for the epilepsy surgery, and many (Neuropace estimates 40-50%) are dissatisfied with their medications due to side effects or lack of efficacy. The RNS implant could help millions worldwide control or prevent their epileptic seizures. Similar treatments with the same implant could be used for many other neural illnesses.

The concept behind the RNS implant is treating seizures through ‘responsive stimulation’, which is based on work done by Bergey et al in 2002 (Epilepsia Vol 43, Issue s7). Regions of the brain before a seizure demonstrate erratic signals that can be stopped using appropriate electrical stimulation. Most other anti-epileptic systems created up to now do not monitor the brain for activity. Instead, they simply shock the brain on a regular basis as prevention. RNS is monitoring more and shocking less.  That’s a philosophy I can get behind.

In order to provide that stimulation, the RNS implant is placed under the skull by a surgeon and electrodes are connected to the relevant portions of the brain. Programming and data acquisition is conducted wirelessly using a wand connected to a modified laptop. This seems somewhat like the BrainGate 2 implant we discussed earlier.

Neuropace’s clinical trials are very rigorous and will have taken a total of 2- 3 years to complete. Prospective patients keep seizure diaries for 3-15 months, and undergo close scrutiny before being approved. Once implanted, the patient undergoes 5 months of double blind testing. Termed ‘sham stimulation’, some patients will have their implants on for that period of time, and some will have implants turned off without their knowing. To insure a double blind study one of the monitoring doctors will also be unaware if the patient is actually receiving shocks. After the sham stimulation, all patients will have their RNS implants activated.

Neuropace's RNS implant could become as common as a pacemaker.

The trials involve more than 240 patients in 28 facilities across the US (including Yale Medical, Johns Hopkins, and Mayo Clinics) and should be finished around December 2009. It is targeting only those patients over 18 years old who show poor response to at least two epilepsy medications. The patients will stay on those meds during the trial. Preliminary studies suggest the RNS implant is effective in treating seizures.

One day, having a brain implant could be seen as no more extraordinary than having a pacemaker. Regulation of destructive brain signals (such as epileptic seizures) or controlling machines (as with Braingate) will be just some of the possible applications. The work done with these implants may pave the way for input/output devices using brain electrical signals. We could even see neural enhancement through measured stimulation. Of course, anyone thinking about tinkering with the mind via electrical shocks should first take a long hard look at Jack Nicholson.

Geron's treatment for spinal injury GRNOPC1 is based on embryonic stem cells and is stalled in its clinical trials.

As if waiting for eight years wasn’t bad enough, we could see another few months pass before the first clinical trials for embryonic stem cells get underway. Geron (Nasdaq: GERN) won FDA approval for these trials back in January. Mid-August saw announced delays, and Geron finally revealed why on August 27th: cysts. As we mentioned before, Geron is looking to create a therapy for spinal cord injuries, and their latest round of animal tests revealed a larger than expected occurrence of small cysts. The official press release points out that these cysts are microscopic, not spreading, and actually fairly common with spinal injuries. Geron is dedicated to working with the FDA to get the trials back on track as soon as possible.

Being the first embryonic stem cell research to get FDA approval for clinical trials means that all eyes are on Geron. This is what people have been dreading/hoping for: that humans will finally see the benefits of the much debated use of stem cells from frozen embryos. It’s the sort of work that Christopher Reeves advertised for and that many pressured George W. Bush to prevent.

Successful or stalling, Geron’s research has large implications for the rest of the stem cell community. If they find a successful spinal cord therapy, thousands of patients in the US and abroad may finally find a way to reverse devastating injuries. Just as importantly, however, if Geron fails before they have a chance to start, or has its FDA approval permanently placed on hold, it may discourage investors looking to fund companies utilizing stem cell therapies. Both Geron and the FDA know that, and this hold may be an overly cautious delay to make sure that no larger problems arise later in the clinical trial.

How serious is the cyst problem? Geron uses human embryonic stem cells to generate progenitor cells that regulate spinal cord nerve coverings. A cocktail of these cells, called GRNOPC1 is injected into mice that have been given a spinal lesion. As Geron point out, injuries to the spine such as this one cause much larger cysts in 50% of test subjects anyway. Furthermore, the cysts failed to develop into teratomas, alleviating concerns of uncontrolled cell growth and a repeat of that horrible scene from Total Recall.

While the FDA declines to comment on ongoing holds on clinical trials, Geron’s press release would have you believe they are about to restart at anytime. Even if Geron is permanently stalled, though there’s no reason to think that they would be, embryonic stem cell research will continue. Investor fear may slow things down, but the technology holds such amazing promise that it can’t be contained. Even adult stem cells have been shown to have great success with diabetes, corneal blindness and other diseases. Stem cell research in China is proceeding rapidly, and animal therapies in the US are becoming common. Any way you look at it, the tide of stem cells is too powerful to be stopped by microscopic cysts.