Integrins as a therapeutic tool for CNS repair

Repair of the damaged spinal cord and brain is a major unmet need in the treatment of neurological diseases, with no treatments currently licensed. After spinal injury the nerve fibres that connect the brain to the spinal cord are cut, leading to paralysis and loss of sensation in the body below the area of damage. In order for patients to regain function the nerve fibres must be made to regenerate so as to reconnect the brain to the body via the spinal cord.

Several laboratories are working to develop treatments to enhance axon regeneration after spinal cord injury and various candidates have emerged. However these first-generation treatments are only partially effective. The programme will develop a new strategy for inducing nerve fibre regeneration. Regrowing nerve fibres have to penetrate the extracellular matrix that lies between cells. In order to gain traction on this material the nerve fibres must have adhesion molecules known as integrins that adhere to molecules in the matrix. Axons in the brain and spinal cord lack the integrin that is needed to interact with the spinal cord and brain extracellular matrix. We have found an integrin that solves this problem. In order to make it possible for this integrin to stimulate nerve fibre regeneration we have to use genetic engineering to place the molecule in nerve cells, then we have to ensure that the integrins can be transported into nerve fibres. In addition, inhibitory molecules in the damaged nervous system can turn off integrins, and we will develop methods to turn them back on. Together these interventions have the promise of stimulating robust regrowth of damaged spinal cord nerve fibres.

The aims of the application are to use integrin engineering to promote axon regeneration after spinal cord injury. In order to regenerate in the damaged CNS axons must grow through the extracellular matrix, for which they need an integrin that recognises the CNS matrix glycoprotein tenascin However CNS axons lack a tenascin-binding integrin. By expressing an integrin that recognises tenascin we were able to promote exuberant growth on inhibitory environments. However this approach is only partially successful in vivo because the inhibitory molecules in the environment inactivate integrins and because integrin transport into mature CNS axons but not PNS axons is blocked at the axon initial segment. The programme will: 1) indentify the trafficking mechanism for integrins in PNS axons, 2) Investigate regulation of integrin trafficking by arf6, 3) find why transport of integrins and other molecles into axons is blocked at the axon initial segment of CNS axons and how to overcome it, 4)investigate the use of talins and kindlins to promote integrin activation in axons, 5)investigate the use of constitutively active integrins to promote axon regeneration in inhibitory environments, 6) investigate the use of integrin activating antibodies to promote regeneration. The successful strategies will be tested in a spinal injury model.