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Improving arm and hand function after stroke with clinically-relevant delivery of neurotrophin-3 to elderly disabled muscles: from rats to humans

Final Report Summary - STROKETHERAPY (Improving arm and hand function after stroke with clinically-relevant delivery of neurotrophin-3 to elderly disabled muscles: from rats to humans)

Stroke is caused by clots or bleeds in the brain, particularly in the elderly. It disables millions worldwide and costs the EU €38 billion each year. In this project, funded by the ERC, we have identified a new therapy for brain injury that improves grasping and walking in adult and elderly rats. Importantly, this clinically-feasible therapy reverses disability in rats when given in a medically-achievable time frame (e.g. 24 hours after stroke). Specifically, we have shown that the human growth factor Neurotrophin 3 (NT3) promotes locomotor recovery and reverses sensory neglect in adult rats when infused into disabled arm muscles or subcutaneously, starting 24 hours after stroke. NT3 improves recovery after small cortical strokes but also large cortical strokes in elderly rats.

Importantly, Phase II clinical trials have shown that systemic, repeated high doses of neurotrophin-3 are safe and well-tolerated in humans with other conditions. This paves the way for a Phase II trial in humans after stroke.

We used brain imaging to show that NT3 does not neuroprotect, consistent with the delayed time frame of intervention. Rather, it appears to induce functional neuroplasticity in proprioceptive spinal circuits and in connections from the brain to the spinal cord. We showed that NT3 protein is trafficked to sensory neuron cell bodies in the dorsal root ganglia (DRG). Using RNA sequencing we have identified genes in DRG that are dysregulated by brain injury and normalised by NT3 treatment. This enables us to begin understanding how NT3 modifies proprioceptive reflexes and corticospinal neuroplasticity.

My team also developed and tested a “RatBots” which automate the training, assessment and rehabilitation of grasping by rats which will enable higher-throughput testing of therapies for stroke but also for other diseases and injuries that affect hand and arm movements.

This funding from the ERC enabled me to consolidate my research team at a critical point in my career; I was able to retain a fully-trained and productive PhD student as a postdoctoral researcher; another postdoctoral researcher enabled us to perform MRI and another team member assisted with neurophysiological assessments. I was able to recruit two new PhD students including a biologist and an engineer. I also employed a new research technician. We have been able to publish several important papers arising from our work; we have filed an international patent on an invention and we have formed a start-up company to commercialise this invention. I secured follow-on funding for this research from a number of sources including the European Research Council (Proof of Concept grant), the Rosetrees Trust, the International Spinal Research Trust and the Brain Research Trust.

We will continue moving this candidate therapy forward towards a first-in-human trial for stroke or spinal cord injury.