Memorandum submitted by the
Scottish Centre for Innovation in Spinal Cord Injury (Bio 28)
Translation of Stem Cell Therapy for Spinal Cord Injury within the UK.
Submission by Prof Bernard A Conway, Mr David Allan & Prof Sue Barnett on behalf of the
Scottish Centre for Innovation in Spinal Cord Injury, Queen Elizabeth National Spinal Injuries Unit,
Southern General Hospital, Govan Road, Glasgow
1.0 Background
This submission is presented from the Scottish Centre for Innovation in Spinal Cord Injury
(SCISCI). SCISCI is a multidisciplinary alliance of scientists, clinicians and bioengineers carrying
out fundamental and applied clinical research in all disciplines relevant to the treatment and quality
of life of people with spinal cord injury (Fig 1)
Fig.1 Scottish Centre for Innovation in Spinal Cord Injury
Our translational and clinical research activities are focused on the Queen Elizabeth National Spinal
Injuries Unit (QENSIU) which provides acute care, primary rehabilitation and lifelong follow-up
for all people with spinal cord injury in Scotland. The QENSIU is proactive in translating
innovative treatments for patients based on sound evidence of effect and functional outcome in the
relief of the symptoms and complications of spinal cord injury. Our fundamental research activities
are supported by the research environments of the SCISCI partner organizations which currently
include 5 Scottish Universities (Glasgow, Glasgow Caledonian, Napier, Stirling & Strathclyde) and
international collaborations with centres including Zurich, Copenhagen, Philadelphia and
Edmonton. Scientific expertise specific to this submission exists in the areas of Stem Cell Biology,
Rehabilitation Engineering, Bioengineering and the Neurosciences.
SCISCI has established research facilities that are embedded within QENSIU providing a unique
research environment within the UK for supporting translational research in treatment of spinal cord
injury and its complications.
2.0 Spinal Cord Injury and Central Nervous System (CNS) Repair
The sensory, motor and autonomic consequences of spinal cord injury are well known and
collectively produce a devastating effect on a person’s health and functional capabilities for the
remainder of their lifetime.
Spinal cord injury, traumatic brain injury, stroke and many forms of neurodegenerative disease
(multiple sclerosis, motor neurone disease, Parkinson’s Disease, etc) are at the present time
incurable. These conditions are also common. Trauma or diseases that affect the CNS are
characterized by pathology associated with significant neuronal cell death and damage to the axons
(severance or demyelination) that provide communication between CNS regions. The body’s own
systems cannot reverse or repair these insults nor can any current medical intervention.
The disabilities rendered by CNS trauma or disease are correlated with the locality, extent, time
course and progressive effects of loss of neurones and the disruption to communication pathways.
For these reasons cell replacement therapies have attracted much interest and considerable research
has been undertaken in animal models to explore the regenerative potential of cell transplantation
treatments.
Strategies are being devised to bridge the gap created after CNS injury by cellular and physical
approaches based on cell seeded biodegradable scaffolds that provide guidance and a permissive
environment for regenerating axons. Within the SCISCI network (University of Glasgow)
collaborative research is ongoing between cell engineers and neurobiologists to devise such
scaffolds. Other cellular approaches include neuronal cell replacement, where transplanted neurones
are provided in the hope of providing functional integration that compensates for the dying or lost
neurones. However, strategies for restoring neuronal function do not rely solely on transplantation
of neural stem cells but also on a form of CNS support cell (glia) that provides the myelin coating
of the outer membrane of axons and which is critical for the normal conduction of nerve impulses
from one site to another. Much of this research has focused on models of spinal cord injury where
the desire to re-connect CNS areas isolated from one another following trauma is a fundamental
requirement for functional recovery.
Successful translation of treatments for recovery from spinal cord injury will also serve as avenues
for successful intervention in other disorders where loss of axonal communication between CNS
sites contributes to the patient’s symptoms (stroke, multiple sclerosis and its variants, optic neuritis,
etc.). Accordingly, the drive to improve treatment and rehabilitation of patients through novel
means of promoting recovery in the CNS remains a high priority for patients, their medical and
social carers and the research community.
Over the past 10 years there have been numerous reports from preclinical studies in animals where
regenerative interventions are claimed to have resulted in functional recovery. Significantly, few of
these studies have gone on to demonstrate that the claimed recovery is associated with a mechanism
demonstrably linked to the proposed intervention strategy. The initial optimism surrounding claims
of regeneration within the CNS are fading and a more cautious approach to translation is being
adopted by the scientific and clinically informed communities. To repair the injured human spinal
cord remains one of the most difficult challenges in regenerative medicine and one in which the
scientific and clinical communities are now realising is far from being solved. Two recent reviews
on stem cell treatments for general CNS repair (Zietlow et al., 2008) and for SCI repair (Bradbury
& McMahon, 2006) serve as timely reminders that many questions relating to stem cell treatments
for neurodegenerative conditions and CNS trauma remain to be answered.
The scientific community recognizes that stem cell therapies and their use in treatments associated
with CNS disorders should not be translated without evidence obtained from careful (and
independently reproducible) experimental studies using appropriate disease models in which the
mechanism of action associated with an improved functional outcome can be demonstrated to be the
result of the intervention modifying physiological processes. It is clear that stem cells may exert
their effect not only as replacing lost cells but also as immuomodulators of CNS tissue and
stimulating the repair process indirectly.
At present there is no scientific justification for a single treatment strategy based on stem cell
transplantation that can be considered to offer an outcome benefit to patients with spinal cord injury
or any other CNS disorder. At present, there is no evidence that centres offering such treatments can
demonstrate any functional improvement in patient health and wellbeing as a consequence of
treatment. In all cases where independent neurological assessment has been provided there has been
no evidence of cell based treatment alone inducing a lasting recovery. Vulnerable people can easily
be exploited by what appear to be credible medical centres.
3.0 The move to combinational treatments.
The CNS is a dynamic system that has potential to adapt and partially reconfigure neuronal systems.
Maladaptation following CNS disorders leads to secondary consequences that may include
spasticity and pain syndromes. Positive adaptation can facilitate functional recovery and these
compensatory and plastic mechanisms are believed to form the tenet behind both the natural
recovery process and successful rehabilitation.
In the majority of spinal cord injured cases and traumatic brain injuries there is a time window
where some degree of improved function develops post injury. It is now recognized that much of
the functional benefits claimed to be due to regenerative interventions are predominately related to
compensatory and plastic mechanisms that take effect during this period. This is also the period
where intensive rehabilitation facilitates recovery rate. However, the functional gains associated
with intensive rehabilitation are relatively modest for the majority of patients and our understanding
of the recovery processes is only just beginning. Nevertheless, rehabilitation success highlights that
a time window for treatment post injury exists in which CNS plasticity can be influenced.
What prevents more striking functional recovery remains the limited capacity of the mammalian
CNS to compensate to a deficit by the systems spared by disease or trauma or to support
functionally significant regeneration and repair of the damaged structures themselves.
What stops regeneration happening, is therefore a key part of the problem that needs to be solved.
Current research in this area is focusing on understanding the molecular events and interactions at
the site of CNS lesion that act to inhibit the regeneration of damaged neurones. The UK and Europe
is strong in these areas. Here research is identifying a number of key molecules and receptor
systems that can be manipulated to promote plasticity and regeneration in animal models of CNS
trauma (see Bradbury & McMahon, 2006, Rhodes & Fawcett, 2004). This approach has led to a
number of biologics and pharmaceuticals being promoted as candidates for clinical translation.
Cell based therapies will play an important role in restoring communication between CNS sites and
in bridging the site of lesion as described previously.
Glial cell transplantation leading to remyelination and trophic support of damaged axonal pathways
is widely considered to be one of the most promising therapeutic strategies (Reier, 2004), and
several differentiated glial cell types have been proposed as candidates. The list of candidate cell
types include non-neural cells such as mesenchymal stem cells, fibroblasts modified to express
trophic factors (Blesch et al., 2002) and olfactory ensheathing cells (Barnett and Riddell, 2007).
Cells from the olfactory system under study in Glasgow have particular potential for use in
transplant mediated repair because they continually participate in regenerative processes throughout
life (Graziadei and Monti-Graziadei, 1979, Barnett et al., 1993; Doucette, 1990). Nevertheless, the
mechanism by which transplantation of these various cell types can lead to an enhanced functional
recovery and structural reorganization needs to be better understood (Kim and de Vellis, 2009). Cell
harvesting, sorting and production into suitable constructs for transplantation into human subjects
are also challenging questions that are currently being addressed in Glasgow and elsewhere.
In animal models of spinal cord injury, olfactory ensheathing cell transplantation has produced
variable results and a consensus on the full extent of their efficacy and mode of action has yet to be
reached. Since the exact nature of the transplanted cells from olfactory tissue in for use in clinical
applications has not been determined it will be extremely important to identify and characterise in
animal studies which of the putative cells are potent in axonal regeneration.
Cell based therapies offer significant potential to improve the regenerative capacity of the injured
CNS. Spinal cord injury provides a very suitable target and is an area where there is concerted
scientific effort. However, recovery must be directed toward improved functional outcomes.
Accordingly, intensive rehabilitation performed in conjunction with novel regenerative treatments is
seen as an important adjunct as it can provide the behavioural context for shaping regenerative
outcome toward functional benefits. Regenerative medicine must therefore progress together with
supportive rehabilitation programmes to maximize functional gains.
4.0 Clinical Translation
As stated previously there are many challenges that need to be met before a safe and effective
protocol for the translation of cell based treatments for conditions like spinal cord injury can be
offered with confidence of effect. Fundamental scientific questions still remain to be answered as
do clinical issues relating to delivery, dosage, timing of intervention and rehabilitation support.
It is now clear that combining a range of therapies that promote neuroplasticity (drugs, cells,
rehabilitation) offer the most potential for patients. However, our knowledge on optimizing each of
these forms of intervention remains rudimentary and largely unexplored in terms of basic science
and its application.
There is still a considerable need for directed research to be performed at both the laboratory level
and at the clinical interface to ensure that treatments can be properly developed based on knowledge
of mechanism and knowledge that progression of treatment outcome can be adequately measured
against mechanism of action (see Fig 2). This is not happening at present. Current clinical trials may
therefore be at best considered premature and certainly will not be able to convincingly demonstrate
efficacy that can be positively correlated with the presumed mode of action of the agents under test.
Fig 2. From CNS injury to recovery a multidisciplinary approach to successful outcome .
In Glasgow we have established the infrastructure through SCISCI and the QENSIU that will allow
a concerted translational programme in spinal cord regenerative medicine to be explored. Central to
this is integration of academic researchers with clinical teams and the engagement of acute and
chronic patients in relevant pre-trial studies on assessment protocols and outcome measures,
intensive rehabilitation and assistive technologies. A programme of research on cell harvesting,
amplification and characterization is also underway.
Our centre (SCISCI) combines world class fundamental research into the following;
biology of regeneration and cell transplantation
bioengineering expertise in tissue and material engineering for scaffold development
spinal cord neurophysiology (animal and human studies)
rehabilitation engineering, physiological and functional assessment
This expertise in science and engineering is integrated into the national clinical centre (QENSIU)
dealing exclusively with spinal cord injury in Scotland and providing
A single national resource of patients supported by a highly trained specialist medical
and nursing staff.
The clinical infrastructure for complex trials.
Cell harvesting and tissue handling expertise
Local linkages to relevant support services (imaging, neurophysiology, etc.)
Good governance with patient care and wellbeing as the primary aim.
It is our view that effective strategies for successful use of cell transplantation within complex
problems such as spinal cord injury require a multidisciplinary approach that is centred on
achieving the best outcome for patients and is based on well founded scientific and clinical
evidence. The provision of this form of infrastructure will also serve to provide international
creditability for UK participation in multicentre trials and help us maintain and grow our
internationally competitive position. We believe that the structures we have put in place in Glasgow
can serve as a model for effective translational medicine for CNS injury repair.
5.0 Declaration of Interests
The authors have no conflicts of interest to declare.
6.0 References
Barnett SC, Hutchins A-M, Noble M (1993) Purification of olfactory nerve ensheathing cells from
the olfactory bulb. Dev Biol 55:337-350.
Barnett SC, Riddell JS. (2007). Cell transplantation strategies for spinal cord repair: What can be
achieved? Nat Clin Pract Neurol 3:152-161.
Blesch A, Lu P, Tuszynski MH. (2002) Neurotrophic factors, gene therapy, and neural stem cells
for spinal cord repair. Brain Res Bul 57: 833–888
Bradury EJ & McMahon SB (2006) Spinal cord repair strategies: why do they work. Nature
Reviews Neuroscience 7: 644-653.
Doucette R. (1995). Olfactory ensheathing cells: potential for glial cell transplantation into areas of
CNS injury. Histol Histopathol 10:503–507.
Graziadei PPC, Monti-Graziadei GA. (1979). Neurogenesis and neuron regeneration in the
olfactory system of mammals. I. Morphological aspects of differentiation and structural
organisation of the olfactory sensory neurons. J Neurocytol 8:1-18.
Kim SU, de Vellis J. (2009) Stem cell-based cell therapy in neurological diseases: a review. .J
Neurosci Res. 87:2183-200
Reier PJ. (2004). Cellular transplantation strategies for spinal cord injury and translational
neurobiology. NeuroRx 1: 424–451.
Rodes KE & Fawcett JW (2004) Chondroitin sulphate proteoglycans: preventing plasticity or
protecting the CNS? J Anat 204: 33-48
Zietlow R et al (2008) Human stem cells for CNS repair. Cell Tissue Res, 331:301-322
Scottish Centre for Innovation in Spinal Cord Injury
December 2009