Novel Neurotrophin-3 peptidomimetic synthetic neurotrophin promotes neurological recovery after spinal cord injury

With 500,000 people paralyzed by traumatic spinal cord injuries (SCI) each year worldwide, there is a strong need for treatments that improve mobility and overall life quality after such injuries. There are currently no FDA-approved drugs that reliably improve locomotor function after injury. This is due to the complex nature of injury and our lack of ability to regenerate damaged areas of our central nervous system. Neurotrophin-3 (NT-3) is a neuroprotective, neuritogenic, pro-synaptogenic, and pro-myelinating neurotrophic factor. By binding to and activating the Tropomyosin receptor kinase (Trk) family of receptors, it supports regeneration and plasticity of neural circuits, improving cognitive and locomotor functions. NT-3 has a poor pharmacokinetic profile mitigating its clinical development, but mimicking NT-3 with small molecules with improved bioavailability is necessary for translational applications. Here, we determined 5c(i) (also known as NC101 and NRCR101), an NT-3 peptidomimetic synthetic neurotrophin, promotes neuron survival and neurite growth in adult cortical neurons. We demonstrated that 5c(i) promotes astrocytic wound healing in a scratch assay and induces pro-regenerative phenotypes in adult astrocytes. Using a severe preclinical SCI model, we demonstrate that delayed acute treatment with 5c(i) results in improved locomotor function and long-term memory without signs of adverse events, such as fatality or weight loss. Anatomical analysis of the spinal cords uncovered possible mechanisms for these neurological improvements; 5c(i) has pro-regenerative, pro-synaptogenic, pro-myelinating, and anti-inflammatory characteristics. Together, these data suggest 5c(i) has therapeutic potential to improve neurological outcome after SCI.