carSpinal cord injury is a devastating condition that generally results in sensory and motor paralysis below the level of the injury. More than 12,000 individuals in the United States per year suffer spinal cord injuries from motor vehicle accidents, falls, sports accidents, or other causes. The impact of lifetime of paralysis after spinal cord injury is particularly sobering because injuries primarily occur in young people between 16 and 30.

Most spinal cord injuries are in the cervical (neck) region of the spinal cord. Even very small improvements in neurological recovery in these patients could restore arm and hand mobility, significantly impacting quality of life. Despite the serious nature of spinal cord injury and potential for therapeutic benefit, there are no drugs on the market to repair neuronal damage and reduce paralysis after spinal cord injury.

Extrinsic Barriers to Regeneration

Axons in the central nervous system (CNS) can regrow after injury when treated with drugs that promote regeneration. Axon regeneration is blocked, in part, by extrinsic barriers to regeneration. BioAxone’s CEO, Dr. Lisa McKerracher (then at McGill University) led the first group to purify and identify a protein in myelin called MAG with regeneration blocking activity. Since that time, a wealth of growth inhibitory proteins that block regeneration in the CNS have been identified. Some investigators have developed compounds that block individual growth inhibitory protein or their receptors. BioAxone took a more promising strategy and developed a compound that acts on a convergent point of signaling for all growth inhibitory proteins, a signaling protein called Rho. The drug that was developed from this approach, VX-210, formerly known as BA-210 or Cethrin™, is a Rho inhibitor that could offer both a regenerative and neuroprotective activity after an acute spinal cord injury. VX-210 is an investigational first-in-class biologic drug that has been licensed to Vertex Pharmaceuticals.

BioAxone is developing Rho kinase (ROCK) inhibitors as second generation drugs to treat SCI. An orally available drug that promotes axon regeneration could be incredible powerful if used during active rehabilitation. Such a drug could enhance the natural process of axons to reorganize networks during rehabilitation.

Intrinsic Barriers to Regeneration

More recently, the intrinsic barriers to regeneration were identified as another barrier to regeneration and recovery after spinal cord injury. Intrinsic barriers to regeneration reflect mechanisms related to a diminished capacity of older axons to regenerate as part of a developmentally programmed process that occurs in aging. Perhaps the most important target to overcome the intrinsic barriers to axon regeneration is a protein called PTEN. Experimental knockdown of PTEN in preclinical models stimulates robust regenerative axon growth. However, until now, therapeutically relevant strategies to knock down PTEN expression to promote axon regeneration have not been developed. BioAxone has created a novel self-delivering RNA interference technology (sdRNA) to knock-down expression of PTEN in adult neurons.

Modulation of PTEN expression has the potential to improve recovery after CNS injury by helping neurons create new adaptive circuitry to overcome deficits caused by lost connections after injury. The scientists at BioAxone are exploring ways to target drug delivery to specific neuronal compartments where drug action is needed.

Combination Therapies for Chronic SCI

Innovative drug/therapy combinations directed at multiple and proven therapeutic targets have the potential to dramatically improve outcomes after SCI. While the drugs that BioAxone is working on will first be tested as monotherapies, they have the potential to ultimately be used in combination with other effective drugs. As for other challenging disease indications, combination therapies that target multiple signaling pathways show the most promise for future treatment of acute and chronic SCI. Ideally, the combinations will target both extrinsic and intrinsic barriers to regeneration.