SBIR-STTR Award

Roughly 17,000 people in the United States will suffer a spinal cord injury (SCI) this year. For the vast majority of them, the injury will leave them incapable of walking or, if they have suffered a cervical SCI, entirely dependent upon others for assistance in all of their activities of daily living from feeding to personal care. More importantly, chances of improvement as a result of therapeutic interventions are bleak since there are no approved therapies that enhance functional recovery. The cost to these individuals, and to society as a whole, are significant as SCI often occurs in adults in their peak earning years. Most therapeutic interventions currently being tested are developed for use in the acute period from hours to days after injury. We are developing a small molecule that has neuromodulatory activity for treating both acute and chronic SCI patients. Neuromodulation after injury has the potential to restore functional recovery, as shown by a number of different investigators. After SCI there is an electrochemical imbalance that prevents motor neurons from eliciting normal muscle actions that are critical for movement of arms and legs. This imbalance is partly caused by a decrease in the chloride transporter called KCC2. It has been shown that by restoring normal levels of this transporter in spared spinal cord neurons, paralyzed mice regain walking ability. This grant application aims to examine new compounds that have the potency and properties to be translated towards human clinical studies, by testing them in preclinical models.

Public Health Relevance Statement:
Narrative Many thousands of people in the USA suffer spinal cord injuries each year, and many more are already living with a chronic spinal cord injury. Most drugs currently under development are for treating spinal cord patients within the first few days after injury and must be administered under carefully controlled circumstances in the hospital. We are developing an orally administered drug to improve functional recovery after spinal cord injury that could be taken from days to months after injury.

Project Terms:
Activities of Daily Living; Acute; Adult; allodynia; Americas; Analgesics; analog; Anatomy; Animals; Applications Grants; arm movement; Axon; base; Biological Assay; Biological Availability; Biological Markers; Cervical spinal cord injury; Chemistry; Chest; Chlorides; Chronic; Clinical Research; Collaborations; comorbidity; Contralateral; Contusions; cost; cost efficient; design; Development; Dose; Drug Kinetics; Electric Stimulation; Enhancers; Evaluation; FDA approved; feeding; FOS gene; FOS Protein; gamma-Aminobutyric Acid; Hospitals; Hour; Human; Hyperalgesia; Hypersensitivity; improved; In Vitro; in vitro activity; in vivo; Individual; injured; Injury; Ion Channel; Ipsilateral; Lead; Leg; Lesion; Mechanics; Membrane; Metabolic; Modeling; motor deficit; motor function recovery; Motor Neurons; Mus; Muscle; nerve injury; Neuromodulator; neuronal excitability; Neurons; neuroregulation; novel; Oral; Oral Administration; Oral Examination; Pain; painful neuropathy; Paralysed; Patients; Penetration; Pharmaceutical Preparations; pharmacodynamic biomarker; Phase; Pilot Projects; Posterior Horn Cells; Pre-Clinical Model; pregabalin; prevent; Process; Prodrugs; Property; prospective; protein expression; Proxy; Pyrimidines; Quality of life; Rattus; Recovery of Function; Research Personnel; response; restoration; Rodent; Safety; Self Care; Series; severe injury; small molecule; Societies; spared nerve; spasticity; Spinal; Spinal Cord; Spinal Cord Contusions; Spinal cord injury; Spinal cord injury patients; Stains; Structure-Activity Relationship; symporter; Testing; Therapeutic Intervention; Time; Tissues; Toxic effect; Translating; United States; Universities; Walking

There are no approved therapies for treating paralysis after spinal cord injury (SCI), despite roughly 17,000 people suffering SCI per year and about 300,000 people living with chronic SCI in US. For the vast majority of patients, injury leaves them incapable of walking or, if they have suffered a cervical SCI, entirely dependent upon others for assistance in all of their activities of daily living from feeding to personal care. The cost to these individuals, and to society as a whole, are significant as SCI often occurs in adults during their peak earning years. Neuromodulation after SCI has the potential to restore functions, as shown even in chronic SCI patients using epidural electrical stimulation in clinical case studies. We are developing a non-invasive, oral neuromodulating drug that can widely treat the majority of SCI patients who have spared, but dysfunctional, spinal cord tissue. After SCI there is an excitation/inhibition imbalance in the spared spinal cord tissue that leads to paralysis, spasticity and neuropathic pain. This imbalance is caused by a decrease in the CNS- specific chloride transporter called KCC2. Indeed, restoring KCC2 by both pharmacological and genetic methods in spared spinal cord neurons leads severely paralyzed rodents to regain stepping ability. Furthermore, KCC2 enhancer drugs reduce neuropathic pain and spasticity in rodent models. In this application, we propose to carry out non-GLP and GLP IND-enabling preclinical research on drug efficacy and safety of our novel KCC2 enhancer drug, AXN-006. After completion of the proposed aims, AXONIS goal is to be ready to commission GMP drug product manufacturing, file an IND and move rapidly into a first-in-human Phase 1 clinical trial in healthy volunteers. The overarching goal is the commercialization of a first-in-class oral KCC2 enhancer drug to treat paralysis, pain and spasticity in SCI, as well as other relevant neurological disorder indications. Public Health Relevance Statement

Project narrative:
Many thousands of people in the USA suffer spinal cord injuries each year, and many more are already living with a debilitating chronic spinal cord injury. Many therapies currently under development are for protecting the tissue after spinal cord injury and must be given to patients as soon as possible after injury, which is difficult in clinical practice and not useful for chronic patients. We are developing an orally administered drug that acts to rebalance activity within the spared tissue after a spinal cord injury, in order to improve mobility and treat chronic pain and spasticity, and could be taken by patients from home from days to weeks after injury.

Project Terms:
<21+ years old>