Spinal 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 (36.5%), falls (28.5%), violence (14.3%), unknown causes (11.5%), or sports accidents (9.2%). The traumatic impact of a spinal cord injury is particularly sobering in light of the fact that injuries primarily occur in young people: more than 50% of spinal cord injuries occur in individuals between 16 and 30.
Seventy-five percent of spinal cord injuries are in the cervical (neck) region of the spinal cord, where even very small improvements in neurological recovery can reduce upper body paralysis in a manner that significantly improves 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. Spinal cord injury is thus a serious unmet medical need.
Extrinsic Barriers to Regeneration
Axons in the central nervous system (CNS) have the capacity for regrowth after injury if given the proper environment. 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 with regeneration blocking activity, myelin-associated glycoprotein, work that was published in Neuron in 1994. 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, such as ATI355 in development by Novartis, or Lingo in development by Biogen. BioAxone took a different 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 effect after an acute spinal cord injury. Blocking the Rho pathway works by allowing growth cones to form and extend, a process that is critical to axon regeneration. VX-210 is an investigational first-in-class biologic drug that has been licensed to Vertex Pharmaceuticals.
The Glial Scar
Drugs that target growth inhibitory signaling in the CNS are considered to address the problem of the extrinsic barriers to regeneration. Another important class of growth inhibitory proteins are the chondroitin sulfate proteoglycans that are synthesized by glial cells after neurotrauma and form a barrier to regeneration at the injury scar. Many scientific groups have documented that digestion of the scar or removal of the inhibitory glycans promotes axon regeneration and plasticity. One reason that this strategy has been so successful in preclinical experiments is that neurons in the spinal cord are surrounded in a cage of proteoglycans, called the perineuronal net. Loosening this net promotes plasticity and repair.
BioAxone has received funding from NIH/SBIR to investigate new drugs that may be promising to promote repair by removing inhibitory glial scar proteoglycans.
Intrinsic Barriers to Regeneration
More recently, the intrinsic barriers to regeneration were identified by Dr. Zhigang He and others as important targets for neural repair. The intrinsic barriers reflect mechanisms related to the diminished regenerative capacity of neurons that is developmentally programmed and occurs as neurons age.
BioAxone is collaborating with Dr. Zhigang He of Boston Children’s Hospital and Harvard University to develop drugs to overcome the intrinsic barriers to regeneration. Dr. He identified PTEN as an important intrinsic target that regulates protein synthesis and ultimately the capacity for axon regeneration. In collaboration with Dr. He, BioAxone has received funding from the NINDS and NIH/SBIR to develop novel RNAi technology that will be clinically feasible to knock-down PTEN expression. 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.
BioAxone has a second project funded by the NIH to explore the potential of newly discovered intrinsic targets, and to develop clinically relevant delivery mechanisms. 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. There is general agreement in the field that combination therapies will be needed for treatment of chronic SCI. Chronic SCI has challenges that include a well-formed scar, remaining myelin debris at the site of injury that inhibits regeneration, chronic inflammation, cell death and intrinsic neuronal changes. Any early attempt of the injured axons to regenerate has long passed, and drug combinations that act on both extrinsic and extrinsic barriers to regeneration are most likely to be successful.