Stem cell conference part five: safety first for current human stem cell trials

One human neural stem cell line that has cleared the US Government’s regulatory hurdles is that developed by the biotechnology company Neuralstem. To date, nine patients have received implants of these cells with few complications reported. Two of the clinicians leading the study at Emory University, neurologist Jonathan Glass and neurosurgeon Nick Boulis, outlined the system that has been developed to ensure extremely accurate implantation into the spinal cord. Both clinicians stressed the importance of safety – the spinal surgery procedure was constantly tested, evaluated and refined, along with the creation of clear ‘stopping criteria’ during the three-hour period of surgery. In this trial, the central tenet of the hippocratic oath – primum non nocere (first, do no harm) – is taken very seriously indeed.

 

Daniel Offen, a representative from the Israeli company, Brainstorm, presented the strategy for their planned clinical studies using patients’ own stem cells from bone marrow (so called ‘mesenchymal’ stem cells), which have been modified to become more-‘astrocyte-like’ and have also been demonstrated to secrete neurotrophic factors.  

These cells will be administered by intrathecal or intramuscular injection. It is important to reiterate that the above preclinical and clinical studies mentioned above are not trying to create new motor neurones to ‘re-wire’ the nervous system.  Instead, the aim is to provide the surviving motor neurones with a supportive environment to try and fight off whatever is causing them to become damaged. It is also important to stress that the primary outcome of these early studies is to ensure the implants are safe.

 

Of course, implantation of mesenchymal stem cells have been tested before – albeit, not in the modified form that Brainstorm has developed. Dr Letizia Mazzini from University of Novara Italy has experience of performing such studies and has published her research in medial journals over the past few years. There have been no serious adverse events in the short or long-term related to the technique. Unfortunately, there was no strong evidence of any beneficial effect and it is not clear whether the cells actually survived long-term, once implanted. 

By 7pm, the presentations for Day 1 drew to a close, but a few glasses of wine in the next room ensured continued discussion. My brain was suffering from information overload…

 

And we still had another day to go…..

The honeymoon is over for stem cells!

We arrived in Florida yesterday evening. This morning it was a case of getting to know where everything is – I can tell that we are going to be getting our daily exercise just by walking from one end of the hotel to the other! As the day gradually warmed up I resisted the pull of soaking up some sun (having left the UK with forecasts of yet more snow… !) and attended some of the talks at the International Alliance of ALS/MND Associations “Ask the experts” session.

 The talk I was really keen to hear was Nicholas Boulis’ presentation on “Spinal cord surgery of ALS – human neural stem cell transplantation”. Dr Boulis is a neurosurgeon who has worked in the field of ALS/MND for seventeen years. He has spent this time developing techniques for spinal cord surgery. He had a fantastic, easy to understand presentation style, which made it so much easier for the audience to understand the technical details he was describing.

There are many different types of stem cells that exist – ranging from embryonic stem cells right through to endogenous stem cells. Embryonic stem cells are the stem cells that can turn into literally any cell in the body. On the other end of the scale endogenous stem cells are stem cells that exist in the adult body that are dormant.  Dr Boulis gave an eloquent description of each type, explaining that at the moment ALS research is concentrating on pluripotent cells (in the middle of the two types of stem cell described above) – cells that have decided roughly which tissue they are going to turn into, but not specific to the cell types within that tissue. Hence the title of his talk – using neural stem cells, stem cells that know that they are going to turn into neurons of one type or another.

There have been a number of studies conducted in rat models of ALS that show the potential of stem cells to treat the disease. However, Dr Boulis commented that these studies reflected the honeymoon of stem cell research into MND. “As we move from taking things that work well in the rat to humans, the honeymoon period is coming to an end and things will start to get sticky” he commented. “ It’s going to be a long haul. Right now we are trying to prove that the stem cells are not dangerous, rather than be able to show that they are beneficial”.

Dr Boulis talked about some of the pitfalls to look out for during stem cell surgery. For example, it is important to avoid applying too much pressure to the spinal cord, to be careful of the volume of fluid that is injected and the speed of the injection. These are exactly the type of things that Dr Boulis has been studying to get it right. He described a fascinating series of experiments conducted in pigs. The studies began by using microelectrodes to work out exactly where in the spinal cord the needle should be injected.  I learnt that the human spinal cord is 6mm long and 8mm wide. The area that stem cell surgery should target is 2mm square. He talked about designing the mechanical apparatus that holds the syringe, to the need for a flexible syringe. Again, more fascinating facts – did you know that the spinal cord moves when you breathe and when your heart beats? Hence the need for a flexible syringe, to move with the cord.

After perfecting the techniques in pigs, the next step was to try these techniques in humans. The Neuralstem trial investigating the safety of giving stem cells into the spinal cord is currently underway in the USA. The study was designed as a ‘risk escalation’ rather than a ‘dose escalation’ that would be the basis of a drug safety study. The first group of patients were not able to walk and received injections of stem cells in one side of the spinal cord only; the next group were not able to walk but had stem cells injected into both sides of the spinal cord. He explained that these patients had some pain, but that this was transitory and the longest period of pain was three weeks. The next group of patients are those that can walk before the surgery – this is the current status of the study. Two patients have taken part so far, having had stem cells injected into one side of the spinal cord only. Both patients have walked out of the hospital after the surgery. For those wanting to know even more technical detail, when he said ‘one side’ he meant five injections of 10 microlitres each (to give you an idea of scale, a teaspoon can hold 5,000 microlitres). He explained that the Neuralstem study would be following the participants for life. At the end of the study, the lessons learned will pave the way for many stem cell studies currently in the pipeline. They may also have a wider application for delivering more conventional drugs too.

I thoroughly enjoyed this presentation and I learnt a lot! Roll on the Symposium to feed my enthusiasm for learning more about how we are all striving towards a world free of MND.