Have embryonic stems cells had their day - already?

Yesterday's article on the Times online site gave voice to Thomas Okarma (CEO of Geron) who was making the case that embryonic stem cells are the only viable source of stem cell-based treatments. Geron, you may know, are preparing to enter clinical trials with the first human embryonic stem cell treatment in SCI. The ethical debate on the use of embryonic/fetal stem cells will probably not go away and for this and other reasons other sources of stems cells are being investigated. One of these is induced pluripotent stem cells (IPS) which is a technology that takes cells from the adult (say a skin cell) and drives these using biochemical and molecular biological techniques to become stem cell-like.

Okarma's argument is a simple one and goes; since it has taken tens of $millions to develop, produce and gain approval for the ES for their SCI trial, should it be necessary to replicated these costs for every patient-tailored treatment the costs and time would be unviable.

The article stimulates a very interesting debate. Obviously, Okarma sees medicine from a profit making angle. The current "product" they have ready to enter clinical trial in SCI will not break even financially and this hurts them and their shareholders. Nevertheless, they need to show the investment made so far was worth it and that the technology is medically viable. If they can do that they might have a chance of validating a platform which can be handle turned in other indications and recoup development costs and see a profit. The interview would have been given with more than half an eye on Geron's shareholders who probably want to be reassured new technologies such as IPS aren’t about to steal the market.

As ever the Americans (perhaps I'm being unfair) don't see beyond finance and assume there cannot be a non-profit approach that sees improving peoples’ lives as a motivation in itself. It also assumes that regulatory authorities will not change their own model of approval. The authorities are not there to impede science but to ensure the process safeguards the public. If this primary objective can be met by another model of regulatory approval that fits with "designer drugs" they will move towards that, eventually. But there will have to be justification, which can only be established by demonstrating what I call "advantages rather than features."

But let's not be naive. It will come down to what drives technology - heavily biased to financial reward at present - and what does the market want. These are often aligned, not always.

Things may shift: increasingly, the market involves government who are footing the bill for an ageing society and its associated ailments. Anything that can reduce the financial and socio-economic burden will be seen as a good thing and worth investing in. Right? The government's shareholders are the people and people don't demand a profit, just better lives. In this case, then, a profit does not have to be turned at the point of sale but later when measured in terms of well fare.

So, which is best ES or IPS? We can't know yet, but competition is a very good thing.

Unlocking the salamander's capacity to regenerate

The salamander has intrigued scientists for many years with its extraordinary capacity to regenerate after injury. Why is it and how do these animals manage to completely and faithfully regenerate large body structures such as limbs when mammals don’t?

In 2005, the respected journal, Science, declared that understanding what controls organ regeneration was in the top 25 hit parade of major questions facing scientists in the coming decades.

It seems the National Institute of Health in the US agrees and has awarded a $2.4 million package of funds to the University of Florida McKnight Brain Institute to stimulate research into this phenomenon as part of their Grand Opportunities (GO) program.

The multidisciplinary teams will embark on an examination of the salamander’s response to injury and systematically “compare and contrast” that with the human’s. Humans and other animals share many of the same genes but in the case of the salamander some of these genes may be regulated differently giving rise to useful regeneration. Using the cellular and genetic makeup of salamander to guide them they hope to understand what genes to switch on and off and ultimately unlock a far greater regenerative potential in patients.

Geron trial

Stem cells were in the news again. Geron will be hoping that the US Food & Drug Administration (FDA) will allow an expansion of the clinical trial using their human embryonic stem cell-derived oligodendrocyte precursor cells to include patients with cervical injuries. Previously, the FDA had given the go-ahead for recruitment of thoracic patients only as there was insufficient supporting data for efficacy in cervical injuries at the time. However, this week sees a paper published in the journal Stem Cells by Hans Keirstead’s group (University of California) who developed the original Geron stem cell line which might help change their mind.

Antifreeze .... anyone?

A fairly low-key story appeared in a number of media reports yesterday on the use of nanoparticles in SCI. The reports (e.g. http://abcnews.go.com/Health/wireStory?id=9028713) surfaced following the epublication of a paper in the journal Nature Nanomedicine.

The nanoparticles in question are made from a compound found in antifreeze – polyethylene glycol (PEG). PEG has been quite extensively investigated as a drug delivery vehicle as it forms tiny hollow spheres into which drugs can be captured giving the drug combo distinct and often useful distribution characteristics. However, the group behind this most recent paper have been working on PEG as a therapeutic in its own right and have been doing so for some while now. Indeed, as far back as 1999 there were reports of positive effects following administration of PEG in guinea pigs and more recently in dog patients.

One of the properties of PEG is its ability to integrate with cell membranes and it is suggested this helps to patch up damaged axons that have become leaky after an injury. This in turn reduces the amount of toxic agents entering injured axons after injury and in so doing protects them from further secondary damage.

So what's new? The latest report combines PEG with another compound called poly-lactic acid (PLA) which produces particularly small diameter spheres. The combination appears to work better than PEG alone.

By all accounts the protective effects of these polymers requires very early administration (within hours post injury) which may prove difficult to achieve clinically.

Much to be learned from rehab

A number of interventions are now in early clinical trial and more are being proposed, yet there is a growing concern that existing measures to test efficacy may be inadequate, particularly if we accept that initial improvements may be poor (though still promising). Development of objective neurophysiological as well as functional measures has become an increasingly active area of research. Spinal Research recognised this some years ago and established its “Clinical Initiative” to address this need.

As part of this initiative, research funded by us at the Scottish Centre for Innovation in Spinal Cord Injury (SCISCI) in Glasgow has been specifically focused on developing outcome measures, the aim being to objectively study recovery following SCI whether it be due to natural recovery (i.e. spontaneous) and through any proposed intervention. Assessing neurophysiology – such as being able to measure changes in nerve conduction properties – may seem a tad esoteric to those only interested in practical and functional changes that represent improvements in quality of life, but if we understand more about how the two are related we will surely be better placed to discover the mechanisms of repair and importantly how to improve or optimise future treatments. We don’t want to throw the baby out with the bathwater.

The group from SCISCI presented two posters (SfN2009 Programme #542.7 & #741.9) at the recent Society for Neuroscience meeting in Chicago. They used Lokomat-driven Body Weight Supported Treadmill Training (BWSTT) as their test “intervention” and although primarily focused on developing outcome measures, one of the interesting findings of the study was that in acute patients (less than 6 months following injury) with incomplete SCI, the functional improvements seen with Lokomat were only significant during the first 3 weeks training, not beyond that. This has huge implications clinically as most research to date on BWSTT has adopted 8+ week rehab programmes and clinically there remains controversy over the optimum timing of initiation of rehab treatment. They suggest BWSTT performed for shorter periods such as 3 weeks and given early may benefit patients with incomplete SCI. Two other posters at the Society for Neuroscience (SfN2009 Programme #176.13 & #542.24) would seem to support this. In both, the beneficial effects of exercise in animals were observed within 3-4 weeks post injury. The animal studies and the clinical study at Glasgow, suggest BWSTT or exercises during the acute phase of SCI may facilitate recovery during a relatively short 3-4 weeks. Is there an optimal recovery window for interventions in the spinal cord injury common to both animals and humans and if so, what are the implications when planning future interventions in acute incomplete SCI subjects?

[My thanks to Dr Sujay Galen from the Scottish Centre for Innovation in Spinal Cord Injury who supplied the original report on which this post is based.]

Stem cells - BBC Horizon 27-10-09

The BBC’s topical science programme, Horizon, aired last night (27-10-09) with a programme exploring the potential of stem cell technology and what the future might hold in store for those living with chronic conditions. Following three individuals with different medical conditions (amputation, chronic progressive heart disease and SCI) it was the usual intercut vignettes and interviews with scientific and medical experts. Overall, it was a pretty balanced treatment of the topic, despite a tendancy towards simplifying technical hurdles and foreshortening timelines, and was careful to provide cautionary and realistic editorial on such issues as the conflict of interest that must exist when there are offers of cash in exchange for (unproven) treatments, the need for properly controlled clinical trials and the general hype inevitably surrounding stem cells.

Of note was the meeting between the subject with SCI and someone who had paid for stem cell “treatment” in India. Having watched video testimony that suggested improvement in his function, she was disappointed to find he had, in his own words, “not felt any improvement” and that what he achieved could have been achieved through rehab. His condition remained as it was before his trip to India.

She came face-to-face with one of the few western researchers (Bruce Dobkin) to examine patients before and after such unverified treatments, who told her that there was no evidence that these treatments currently work. In his view, if they did “why would you not want to conduct a small clinical trial to prove it?”. Follow this link to see a position statement – which Spinal Research endorses – from a number of eminent clinical and basic researchers on this topic which you may find interesting.

The programme ended with her meeting Hans Keirstead who, along with Geron, have developed a human embryonic stem cell line that has gained FDA approval for clinical trial in SCI. I am not sure when the programme was recorded but my own understanding is that the trial is currently on hold pending further submission of safety data to the FDA. This in itself is not unusual and a trial is very likely.

It is important to note that the cells to be transplanted in the Geron trial are not at that point stem cells. They are the product of stem cells which have been taken down a development path in culture dish to a point of relative maturity where they will only form something called an oligodendrocyte. As explained in the Horizon programme, oligodendrocytes are the cells of the central nervous system that provide the insulating material enveloping axons. The rationale for this treatment is that paralysis is due to axons being present but not functioning properly because they have become de-myelinated. There is evidence for de-myelination on some axons after SCI, but it is fair to say it is a matter of some debate amongst scientists as to the extent and significance of this in humans and it is certainly not the only or perhaps even the major cause of parlaysis. Other mechanisms by which (precursor) oligodenrocytes could provide positive effects may and probably do exist. A point conceded by Geron themselves.

At the time of posting the BBC’s iPlayer provided access to the programme.

Are we seeing inside the black box of Glial scar inhibition?

Growing axons, whether damaged or sprouting from spared neuronal tissue, are needed to restore lost function after SCI. Unfortunately, they are inhibited by molecules found on the surface of myelin – the insulting material surrounding axons that is found everywhere within the central nervous system.

The idea goes that myelin is decorated on its surface with many molecules and when growing axons come into contact with myelin, these molecules “dock” with specific receptors on the growing axon triggering a cascade of signals within the neuron telling it to go no further or even retract. Interfering with this inhibitory interaction is fundamental to a number of experimental treatments that are at various stages of development.

Crucially, there is another known potent inhibitor of axon grow, namely CSPGs [see earlier posts] which increases in concentration at the Glial scar and elsewhere after injury. Exactly how CSPGs repulse axons is poorly understood, however, creating a bit of a black box on the mechanism and thus making it difficult to develop drugs to overcome this inhibition. That is until now, perhaps.

This week, in what may be a very significant paper published in the journal Science, neuroscientists from Harvard Medical School, Boston and Case Western Reserve University, Ohio, appear to have identified a protein on the surface of the growing axon which has all the hallmarks of a receptor for CSPGs and therefore potentially important in the cause of regenerative failure.

In the paper Shen et al., develop their case thus;
(i) a protein PTPsigma (a member of a large family of transmembrane protein tyrosine phosphatases; PTPs) was known to bind other proteoglycans important in early development so it might also bind to CSPGs which structurally similar
(ii) they found that PTPsigma did indeed bind to CSPGs
(iii) they demonstrated that binding was a genuine biological interaction because binding sites could be saturated and the interaction was high-affinity – ie. it was not a non-specific interaction
(iv) pre-treatment with chondroitinase (cleaves side chains on CSPGs) renders CSPGs inactive as inhibitors and also abolishes much of the binding with PTPsigma – indicating the side chains are important to this receptor binding as they are also in inhibition

In cell culture, they found that PTPsigma bound to cells responsible for producing the Glial scar – astrocytes.

So they had very strong evidence that PTPsigma binds to CSPGs. That in itself was not enough, so they next tested the theory that PTPsigma was functionally important to the failure of axons to grow. To do this they needed a mouse strain that did not posses a functional PTPsigma arguing that neurons cultured from such a mouse would grow better over CSPGs, which they did.

Their findings open the door on a potential new and exciting lead for drug design and treatment of SCI and other neural injury/diseases.

Notes:
CSPGs = chondroitin sulphate proteoglycans