There are currently between 183,000 and 230,000 survivors of spinal cord injury in the US alone. Of this cohort, 55% of individuals are in the 16 to 30 year age group, and many can expect a similar life expectancy to the general population. Providing medical support to these patients is therefore prolonged and costly. Improved treatment options would thus not only dramatically improve the quality of life of patients, but they would also considerably reduce the impact on health care budgets. Up until recently, functional recovery following spinal cord injury was believed to be restricted by limited regeneration and plasticity of injured axons in the adult central nervous system and any loss of motor and sensory functions was accepted as being irretrievable. Ground-breaking research published in the 1990's demonstrated that this is not the case since the inability of damaged nerve fibers to regenerate was an active process under the control of molecules able to inhibit and repulse growing neurites. Furthermore, blocking these molecules was shown to be able to restore mobility to animals subjected to spinal trauma. Nogo, a myelin-derived axon outgrowth inhibitor, was believed to be one such molecule. A 66-residue domain of Nogo (Nogo-66) is expressed on the surface of oligodendrocytes and can inhibit axonal outgrowth through an axonal Nogo-66 receptor. IN-1 is a monoclonal antibody that recognizes Nogo-A and promotes corticospinal tract regeneration and locomotor recovery; however, the undefined nature of the IN-1 epitope in Nogo, the limited specificity of IN-1 for Nogo, and nonspecific anti-myelin effects have prevented a firm conclusion about the role of Nogo-66 or its receptor. Yale researchers have recently addressed these issues by identifying NEP1-40, a competitive antagonist of Nogo-66 receptor derived from amino-terminal peptide fragments of Nogo-66. NEP1-40 blocks Nogo-66 or CNS myelin inhibition of axonal outgrowth in vitro, demonstrating that the receptor mediates a significant portion of axonal outgrowth inhibition by myelin. Intrathecal administration of NEP1-40 to rats with mid-thoracic spinal cord hemisection results in significant axon growth of the corticospinal tract, and improves functional recovery. Thus, Nogo-66 and its receptor have critical roles in limiting axonal regeneration after CNS injury, and NEP1-40 provides a potential therapeutic agent. Further development of NEP1-40 or non-peptide homologues is therefore eagerly awaited.

Adapted from GrandPre et al , Nature 2002 May 30;417(6888):547-51

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