Neural Repair for Chronic Incomplete Cervical Spinal Cord Injury with Nogo Receptor Blockade plus Rehabilitative Training

SUMMARY Traumatic spinal cord injury (SCI) affects approximately 300,000 individuals in the United States, leading to persistent neurological deficits due to disrupted neuronal connectivity. Currently, no proven pharmacologic intervention exists for patients with SCI. Molecular studies reveal a Nogo-66 Receptor 1 (NgR1, RTN4R) pathway inhibiting axon regeneration, sprouting, and plasticity in the adult mammalian central nervous system. Rodent and non-human primate studies demonstrate that the soluble receptor decoy NgR(310)ecto-Fc, also known as AXER-204, promotes neural repair and functional recovery in both transection and contusion spinal cord injury models. The first-in-human study of intrathecal AXER-204 in chronic cervical SCI (RESET) demonstrated safety, tolerability and cerebrospinal fluid biomarker changes of neuroplasticity. Although conducted without rehabilitative training, post-hoc analysis showed improved motor strength in patients with incomplete injury. These preliminary data also generated substantial trial experience from a robust and interdisciplinary network of investigators, positioning the field for the next phase of investigation. Building upon the encouraging results from RESET, we propose a double-blind, randomized, placebo-controlled clinical trial to examine the effect of AXER- 204 combined with rehabilitative training for incomplete chronic cervical SCI. The primary safety outcome will be the frequency of serious adverse events. The primary efficacy outcome will be upper extremity motor strength. Key secondary outcomes will include functional performance and activities of daily living. An important optimization based on the first trial is the inclusion only of incomplete cases with AIS grade B-C-D, given their greater responsiveness in RESET. The second key aspect will be to provide rehabilitative training to all participants. Coupling rehabilitation with pharmacotherapy is both patient-centered and based on preclinical and clinical data indicating that rehabilitation will synergize with AXER-204-supported neuroplasticity. This clinical trial will enroll 60 patients across 6 geographically representative sites. Centers are carefully chosen both because of their prior experience and commitment to SCI translational trials. This pioneering network will recruit the full range of SCI survivors in the US. Positive results of this trial will have a major public health impact by supporting that advancement of the first neural repair drug therapy to Phase 3 studies in this disabled patient population. Project Number: 1UG3NS142157-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: STEPHEN STRITTMATTER | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $3,306,533 | Activity Code: UG3 | Study Section: Special Emphasis Panel[ZRG1 CN-J (83)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11296386