We seek to harness the potential of surviving tissue to restore function. To support neurological function, nerve cells must be connected electrically by long cellular fibers, termed axons. In nearly all neurological conditions, a substantial portion of brain and spinal cord is preserved. If remaining healthy tissue can be “rewired” with appropriate axonal connections, improved neurological function can result. The formation of new connections and the recovery of function after injury depend upon new axonal extension from remaining cells. Without treatment, axonal growth is extremely limited in the adult brain and spinal cord, and recovery is typically restricted. Today, no FDA-approved therapeutic promotes new connections between surviving nerve cells.
Nogo Receptor and Myelin InhibitionIt has been known for a number of years that the white matter of the CNS inhibits axon growth in the adult brain and spinal cord. A molecular characterization of inhibitors in CNS myelin led to our identification of the protein, Nogo. We also identified a receptor protein for Nogo termed Nogo-66 Receptor, or NgR1 (schematic of this pathway at left). In vitro assays of neurite outgrowth and ligand receptor binding were developed to identify and characterize this pathway. With this ligand receptor pair in hand we have developed peptide and protein inhibitors of Nogo Receptor signaling. Such molecules selectively block the inhibitory effect of myelin on axon growth in vitro.
Nogo and Nogo Receptor antagonists have been tested extensively by us and by others in animal SCI models. Molecules with Nogo/NgR1 blocking activity promote the growth of axons in the adult spinal cord and promote recovery of walking performance in injured animals without side-effects. We have demonstrated benefit in both acute and chronic spinal contusion models with NgR(310)ecto-Fc protein therapy (see below). Functional recovery of rats after stroke is also enhanced by this treatment.
We are working to optimize blockers of this system for clinical use with structural biology, mutagenesis and high-throughput screening methods. We are also working to expand knowledge of NgR1-initiated signal transduction.
Other Limits of Neural Repair
The Nogo/ NgR1 pathway plays a prominent role in vivo, but it is not the only molecular brake on neurological recovery. We are actively studying ephrins, CSPGs, SPRRs, LRRTMs, ROCK, RGMs and other pathways for synergy with the NgR pathway.
Clinical Spinal Cord InjurySpinal Cord Injury (SCI) is perhaps the clearest example of a CNS disorder in which axons are cut by trauma but most neurons survive. Axonal growth of both cut and surviving fibers is the crux of any significant recovery and therapeutic intervention. For SCI, the annual incidence in the U.S.A. is 12,000, and the prevalence is over 250,000. The most recent estimate for the U.S. prevalence of individuals with paralysis due to Spinal Cord damage is 1,250,000, according to the Christopher and Dana Reeve Foundation. After acute stabilization, the only currently available treatment modality to improve function in subacute and chronic SCI is physical therapy.
Clinical Ischemic Stroke
When brain ischemia creates cerebral infarction, a substantial amount of spontaneous functional recovery over 6 months is common and rearrangement of function can be demonstrated by fMRI. A therapeutic agent capable of enhancing neuroplasticity has the potential to greatly augment this endogenous process in the subacute to chronic post-stroke period. Agents (such as the NgR-Fc decoy receptor) that promote sprouting increase recovery after stroke in animals. For stroke, the annual incidence in the U.S.A. is 500,000, and the prevalence of stroke survivors is over 3,000,000.