Inhibition of Repulsive Guidance Molecule A to Promote Axonal Regeneration after Cervical Spinal Cord Injury
Funded in: 2017, 2018, 2019
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Problem: After SCI, repulsive guidance molecule (RGMa), one of the most potent inhibitory proteins, is increased in the spinal cord and inhibits axonal growth.
Target: The inhibitory effects of RGMa can be neutralized by specific antibodies injected into the bloodstream and promote regeneration and recovery.
Goal: Determine the therapeutic time window for administration of human RGMa antibodies to promote axonal regeneration after cervical SCI
Scientists now have a better understanding of the cellular and biochemical changes in the spinal cord after acute spinal cord injury (SCI). Following the initial trauma, there is a cascade of molecular and degenerative events including death of nerve cells, loss of blood supply, and tissue damage due to toxic chemicals released into the spinal cord. Also, we now know about another consequence of injury that blocks the regeneration of the injured fibers or axons which is due to the release of inhibitory chemicals and the formation of structural blocks. The combination of death of nerve cells and inhibition of axonal regeneration limit recovery.
One of the most potent inhibitory proteins after SCI is repulsive guidance molecule (RGMa) which increases in the spinal cord after SCI and inhibits axonal growth. Our laboratory has shown that RGMa is upregulated after clip impact-compression injury of the rat thoracic spinal cord, and importantly, we also showed that RGMa is similarly expressed in the injured human spinal cord. Recently, we showed that the inhibitory effects of RGMa can be neutralized by specific antibodies injected into the bloodstream immediately after rat thoracic SCI and promoted regeneration and recovery. Our goal is to translate this strategy for patients with SCI. Indeed, our commercial partner AbbVie, has developed clinically relevant human anti-RGMa antibodies. However, we do not know if these antibodies will still be effective if injection is delayed to a clinically relevant time after SCI to allow patients to be transferred to hospital and assessed. Also, it is unknown if the treatment is effective for cervical injuries which are the most common in humans.
Towards this goal, our study will use a new rat cervical SCI model developed in our laboratory of a clinically relevant impact-compression injury of the dorsal columns at C4. We will examine motor and sensory axonal regeneration after RGMa inhibition with the antibody administered 2 hours (early subacute) and 24 hours (late subacute) after SCI. We will evaluate the effects on fine motor and sensory function in both the upper and lower limbs utilizing a large range of clinical and histological outcome measures. Our goal is to determine the therapeutic time window for administration of human RGMa antibodies to promote axonal regeneration after cervical SCI. This proposal has been designed to advance this novel clinically relevant therapeutic agent for human SCI.