As one of only a couple of UK lawyers who are members of the American Congress of Rehabilitation Medicine, I am often asked about stem cell research and the current state of knowledge. The publicity around stem cell therapy and the proliferation of so-called ‘stem cell tourism’ has given many persons who have sustained a devastating spinal cord injury (SCI) the hope of achieving partial or full recovery. Schedules of loss claiming private stem cell therapy from locations such as India, Thailand and Panama are not uncommon.
It goes without saying that if a ‘cure’ could be developed it may have a huge impact both in relation to the health of many individuals and, by implication, the cost of these claims to the insurance industry but just how close is that?
This is not intended as a technical article but, rather, an overview of some of the myriad of different problems that exist in this extremely complicated area. Stem cell therapy has great potential but is it something that we should be planning for at any point in the near future?
Primary and Secondary Damage
Some brief understanding of the mechanism of injury is required in order to understand the initial difficulties.
Following the primary injury, which causes immediate structural damage to the spinal cord, a series of secondary damage occurs including haemorrhage, edema, demyelination and axonal and neuronal necrosis. A fibrous glial scar is then formed by infiltrated inflammatory cells across the lesion. In layman’s terms think of it as swelling, scarring and death of the surrounding tissue which all makes treatment that much more difficult.
Strategies targeting those unique mechanisms fall in to the neuroprotective domain, with the basic idea being to maintain the initial area of lesion in as receptive [to treatment] state as possible. Neuroprotective therapy works by limiting secondary damage, while neuro regenerative strategies are aimed at replacing the damaged cells, axons and circuits in the spinal cord.
Sadly, there are few neuroprotective therapies, that directly exert beneficial effects, currently available.
Period of Time Post Injury
The pathological period of SCI is divided into three phases: acute-phase (less than 48 hours) sub-acute phase (48 hours to 14 days) and chronic phase (more than 6 months).
Unfortunately, but for obvious reasons, most trials focus on patients in the chronic phase whereas initial research suggests that the sub-acute phase is the one during which patients are most receptive to treatment. There lies an important logistical issue of how to get sufficient patients, with similar lesions, so soon after the initial injury.
Different Types of Stem Cell
All stems cells are not made equal. Stem cell is a generic term with, as always, the devil being in the detail and each different type of stem cell carrying its own risks and complications.
Neural Stem Cells (NSC) are stem cells located in the lateral ventricles of the brain and the central canal of the spinal cord. Several clinical trials are ongoing. Studies published to date have shown that NSC transplantation for SCI is relatively safe, but whether it effectively improves the patient’s function after transplantation remains controversial.
Mesenchymal Stem Cells (MSC) have become the favourite seed cells in the preclinical and clinical practice of regenerative medicine due to their ready availability, wide biological effects, lack of ethical problems and low immunogenicity. A large number of MSC’s have been obtained from tissues such as bone marrow, umbilical cord, amnion, placenta and adipose tissue but each of those MSC’s from different sources have different characteristics.
Embryonic Stem Cells (ESC) are highly undifferentiated, pluripotent cells that are able to differentiate into the cells of various tissues in adult animals. Because of their high degree of differentiation, the cells have been used as an in vitro cell differentiation and regulation model. Although the clinical application of ESC’s is promising, the future clinical application faces enormous challenges due to ethical issues.
Adult Endogenous Stem Cells (AESC) are located in the adult nervous system. Normally the cells are dormant. Once the spinal cord is damaged, these cells are rapidly activated and proliferate to produce a wide number of glial cells. Some of these cells also form glial scars. There is, however, research aimed at exploring whether these endogenous cells are able to be directly activated to provide neuro-regenerative benefits thus obviating the need for any traumatic cell transplantation.
Spermatogenial Stem Cells (SSC) possess self replication and self renewal abilities and are the only type of stem cell that is able to pass the genetic material to the offspring. SSC’s have the advantage of being produced throughout life and the lack any of the ethical problems associated with ESC’s. Currently few studies have investigated SSC transplantation for SCI and most have focused on neurodegenerative diseases.
Induced Pluripotent Stem Cells (iPSC) are considered an effective alternative cell source for ESC’s that can be obtained from cell reprogramming after introducing transcription factors into somatic cells. Since somatic cells are typically isolated from the patient’s own cells this auto adjust method can prevent the occurrence of immune rejection. A common drawback is, however, the possibility of tumor formation mainly due to their potency, which is no longer controlled after transplantation.
Earlier this year, when the world was a different place, I travelled to the ISCORE conference in Barcelona where I was fortunate enough to hear a presentation by Hideyuki Okano who had just received approval from the Japanese authorities to begin the first human trials of iPSC cell transplant intervention for sub-acute SCI.
The Kyoto University Centre for iPS Cell Research and Application have prepared clinical grade, integration-free human iPSC stock. The treatment will not, therefore, use iPSC’s derived from the individual patients because of the amount of pre-clinical testing required prior to treatment (at least 6 – 9 months for autologous iPSC). Note the obvious conflict with the optimum period of treatment being in the sub-acute (48 hours to 14 days) phase.
Stem cell therapy undoubtedly has great potential in the treatment of the injured spinal cord but not any time soon: there are far too many problems that remain to be resolved before we can contemplate the clinical application of this therapy.
Even if (and when) we do get to that point, some consideration needs to be given as to whether there is likely to be a full recovery or, more likely, a partial recovery which perhaps improves sensation and some function below the level of the lesion? Every individual will be different but each of those scenarios carry their own implications including increased life expectancy, equipment needs and interaction with support workers.
Ian Slater is a Catastrophic Injury Partner at global legal business DWF. Ian specialises in claims of the utmost severity, including brain and spinal injuries. He leads DWF’s Bodily Injury Research Garage, which aims to provide horizon scanning of scientific and technological advances which may affect indemnity spend at some point in the future.