2013 Spinal Research strategy grants round
Four new strategic projects have been approved for funding by the trustees. A summary of each project is detailed below.
Promoting respiratory motor function after chronic and severe cervical spinal cord injury (STR117 – 3 years)
Dr Warren Alilain, Professor Jerry Silver and Philippa Mary, Post Doctoral Fellow (Case Western Reserve University, USA)*
A major cause of morbidity and mortality following cervical spinal cord injury (SCI) is respiratory dysfunction due to the disruption of the nerve fibres that help to stimulate the diaphragm. Unfortunately, severe and clinically-relevant injuries that affect breathing are inherently difficult to study in animal models due to the technical difficulties and ethical concerns surrounding ventilated care. The research team at Case Western Reserve University have developed a combination injury that overcomes this difficulty making it possible to study these injuries in the severe and chronic setting. In this model the group hope to demonstrate improved respiration by administering the enzyme chondroitinase to disrupt chondroitin sulphate proteoglycans (CSPGs) – a known inhibitor of nerve fibres regeneration – to promote plasticity (the ability of intact nerve endings to sprout new growths) and remodelling of spinal cord circuitry. Chondroitinase is already known to digest the scar tissue that impedes nerve regeneration and stifles changes needed for effective rehabilitation. Treatment will be combined with intermittent low oxygen training, a rehabilitative strategy demonstrated to increase respiratory drive and circuitry strength. This project addresses an important clinical issue building on previous published data and is the first study to assess respiratory function following application of a novel combination treatment strategy designed to promote plasticity and drive after chronic and severe cervical SCI.
* Recognised with the Robson Award
Understanding recovery with combinatorial strategies – mechanisms of anti-Nogo-A antibody, epidural stimulation and locomotor training (STR118 – 3 years)
Dr Ronaldo Ichiyama (University of Leeds, UK)
After experimental treatments, recovery is often reported but the mechanism is less well documented, particularly in studies looking at combinatorial treatments. Ichiyama sets out to investigate the fundamental changes in the local spinal circuitry involved in walking as well as the contribution, if any, of changes in the “command”, or so-called supraspinal, circuitry descending from above the injury. Changes in both the local and supraspinal circuits have been proposed for improvements in function that are seen and he will investigate how a combination of three potentially complementary therapeutic strategies affect outcome and define the underlying mechanism by which this recovery occurs. He is a world expert in the application and study of epidural stimulation in spinal cord injury and has teamed up with Martin Schwab who has led the pre-clinical and clinical development of anti-Nogo-A antibody, a plasticity-enhancing treatment. To this therapeutic combination he will introduce locomotor training. Using electrophysiological techniques, a picture should emerge linking the anatomical, physiological and functional changes responsible for recovery as well as crucial information on the interplay of this combination of treatments. Clinically, all three treatments are feasible (all are currently in man) but their use in combination will be strengthened by a clearer understanding of mechanism, particularly in light of findings that the timing of application of plasticity-enhancing and rehab treatments has a critical, sometimes harmful, bearing on outcome.
Recovery of forelimb behaviour and cortical activation after neural stem cell grafts induced to pyramidal neuron lineage combined with treatments to promote axon growth following cervical spinal cord injury (STR119 – 2 years)
Giles Plant (Stanford University, USA)
A compelling issue in the SCI field is whether, or to what extent, severed axons that re-grow just beyond the injury site contribute to true functional benefit in a patient. It remains unknown, for example, whether these axons re-establish meaningful electrical connections. This project will examine a three-way combinatorial treatment, using (i) a strategy that hopes to boost the growth capacity of injured neurons, (ii) a cell-based therapy to bridge the injury site and provide a suitable surface for new growth and (iii) rehabilitation to strengthen newly-formed connections. The objective is to improve recovery of forelimb function after severe cervical injury. A key element in this project is the technique being used to boost growth. Previous studies have shown that it is possible to achieve very profound regeneration in the optic nerve by genetically manipulating the optic nerve cells. Unfortunately, the technique used to create this genetic modification is not applicable to human clinical use. By contrast, the approach used in this study (using viral particles to deliver agents that knock down the activity levels of growth supressing genes) is more clinically-feasible and, if successful, would be a major advance in the field.
Combining stimulation of the intrinsic neuronal growth propensity with bridging of the spinal cord lesion site with skin progenitor derived Schwann cells and locomotor training (STR120 – 1 year)
Wolfram Tetzlaff (University of British Columbia, Canada)
This project will attempt to boost the regenerative capacity of injured neurons using small therapeutic peptides that have been modified to target spinal cord tissue. This targeting feature allows the treatment to be delivered non-invasively by simple injection to the body rather than the delicate cord. The therapeutic peptide itself interferes with signals in the neuron that normally supress growth in adults. To optimise repair the group from the University of British Columbia will transplant cells derived from skin which they have modified in a way that makes them adopt the characteristics of remyelinating cells, or Schwann cells. The researchers have previously shown these skin-derived Schwann cells integrate with host cord tissue far better than normal Schwann cells and retain the ability to remyelinate axons. Both features are potentially beneficial. The research team hypothesise that the structural repair will give rise to greater functional recovery if combined with rehabilitative locomotor training. The treatment strategy will be translatable to humans and, if successful, this project will hopefully contribute to the development of effective repair strategies for severe spinal cord injuries in the acute and chronic state.