John Flanagan, Department of Cell Biology, Program in Neuroscience, Harvard Medical School, Boston, USA

Overcoming inhibitors of spinal cord axon repair

Funded in: 2015, 2016, 2017, 2018


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Problem: After spinal cord injury, axon growth is prevented by inhibitors present in the scar that forms at the injury site.

Target: After identification of the molecular mechanisms by which these inhibitors bind to axons and prevent their growth, the design of therapeutic compounds to block the inhibitors can be initiated, now.

Goal: Blocking the effect of the inhibitors should allow axon growth, and restoration of lost function.

 

The spinal cord plays an essential role in transmitting information between the brain and the body, including incoming information from the senses, as well as outgoing control of movement. Within the spinal cord, this information is transmitted by long thin nerve fibers called axons. When these axonal connections are broken due to injury, the information flow is lost. Although axons in many other parts of the body can regrow and resume function, sponanteous recovery of lost connections following injury to the spinal cord is minimal.

A major reason that axons in the spinal cord fail to recover spontaneously is the formation of a scar at the injury site, which contains molecules that actively inhibit axon growth. Therefore, if ways can be found to block the effect of these inhibitory molecules, that would allow the axons to regrow. By allowing axon regrowth, nerve connections lost following injury could thus be restored, producing a lasting recovery of function.

Although the importance of scar-associated inhibitors has been known for more than two decades, it was long unclear how they affect axons. In recent years, they have now identified molecular mechanisms by which these inhibitors latch onto axons and send growth-inhibiting signals into the axon. Having identified these molecular mechanisms, they are now in a position to rationally design therapeutic compounds that interfere with the inhibitory mechanisms, and thus to promote axon growth. In this project, specific candidate therapeutics have been identified, and will be further tested in assays of cultured cells and in rodent models of spinal cord injury. Such compounds should be strong candidates for clinical use in humans, to restore function lost after spinal cord injury.