Abstract
There is an urgent need for a therapy that reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. We show here that intramuscular delivery of neurotrophin-3 (NT3, encoded by NTF3) can induce sensorimotor recovery when treatment is initiated 24 h after stroke. Specifically, in two randomized, blinded preclinical trials, we show improved sensory and locomotor function in adult (6 months) and elderly (18 months) rats treated 24 h following cortical ischaemic stroke with human NT3 delivered using a clinically approved serotype of adeno-associated viral vector (AAV1). Importantly, AAV1-hNT3 was given in a clinically-feasible timeframe using a straightforward, targeted route (injections into disabled forelimb muscles). Magnetic resonance imaging and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, treatment caused corticospinal axons from the less affected hemisphere to sprout in the spinal cord. This treatment is the first gene therapy that reverses disability after stroke when administered intramuscularly in an elderly body. Importantly, phase I and II clinical trials by others show that repeated, peripherally administered high doses of recombinant NT3 are safe and well tolerated in humans with other conditions. This paves the way for NT3 as a therapy for stroke.
Highlights
Stroke rapidly kills brain cells and is frequently disabling
We have shown that NT3 improves recovery of function in two additional studies with no evidence for any decline of function in the control groups (Duricki et al, in preparation) so we predict that the benefits of NT3 that we describe in this current manuscript will be reproducible by others. The data from these studies showed, consistently, that adult and elderly rats recover some sensory and locomotor function after stroke when treatment using NT3 is initiated starting 24 h after stroke. These studies show that 24 h delayed intramuscular injection of an AAV1 encoding human NT3 improves sensorimotor recovery in adult and elderly rats after focal cortical stroke
MRI and histology showed that lesion volumes were similar between stroke groups, ventricular expansion was similar between stroke groups, and the extent of corticospinal loss was similar between stroke groups
Summary
Stroke rapidly kills brain cells and is frequently disabling. Globally, there are 31 million stroke survivors, with another 9 million new strokes annually (WHO). NT3 restores sensorimotor function following spinal cord injury in rats (Schnell et al, 1994; Grill et al, 1997; Zhou et al, 2003; Fortun et al, 2009) by promoting axon growth and synaptic plasticity in multiple locomotor pathways including the corticospinal tract and proprioceptive pathways. All these systems express TRK and/or p75 receptors for NT3 in rodents and primates including humans (Altar et al, 1993; Barrette et al, 2007; Brock et al, 2010). We examined the ability of NT3 to promote recovery in a model of stroke
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
