IND-Enabling Toxicology and Safety Pharmacology Studies for a First-in-Class CPG-Activating Drug Treatment (SPINALON) Against Chronic Spinal Cord Injury

Spinal cord injury can cause complete loss of motor control and loss of feeling in both the legs and the arms. Such an injury is permanent and has no cure. About 5,000 spinal cord injuries occur each year in the United States. The extent of the impairment depends on where on the spinal cord the injury occurs and its severity. The health effects can far exceed the lack of mobility. In the worst cases, a person may need complete care and have no voluntary bodily function from the neck down. Inactivity can lead to respiratory infections and heart disease, among other complications. These researchers are developing a medical treatment for spinal cord injury that allows a patient to make stepping motions for 45 to 60 minutes at a time. Such activity a few times each week could help reverse some of the physical deterioration that accompanies inactivity. The treatment works by temporarily activating the spinal locomotor network but does not heal the spinal cord lesion itself.

Scientific Synopsis

Spinal cord injury (SCI) is an irreversible condition for which no curative treatment is currently available. The consequences are complex and not limited to paralysis per se. Indeed, with time, the state of paralysis and chronic immobility lead to severe health problems such as cardiovascular problems, osteoporosis, muscle atrophy, immune system deficiency and life-threatening infections. Consequently, in 2002, we launched a research program supported by several not-for-profit foundations and agencies (e.g., Christopher & Dana Reeve Foundation) aimed at further understanding spinal locomotor network-activating mechanisms and, hence, at developing a palliative treatment against paralysis-/immobility-related health problems. In 2004–2005, after three years of drug screening, we discovered a drug combination (Spinalon) essentially composed of small molecules belonging to the families of monoamine receptor agonists, noradrenaline/dopamine precursors and decarboxylase inhibitors. Upon systemic delivery (s.c., i.p., or p.o.), Spinalon was found to potently activate the spinal locomotor network (often referred to as central pattern generator or CPG) localized mainly in the lumbar segments and, thus, sustained involuntary stepping movements during 45–60 min in the lower limbs of chronic and complete paraplegic mice (completely low-thoracic-transected). These exciting proof-of-concept data also included comparable observations in turtles, suggesting a phylogenetically well-conserved mechanism of action throughout vertebrates. Optimization, clinical utility and first-in-man (a case report) experiments were also conducted.

According to independent experts in the field of drug development, Spinalon is now ready to undertake final preclinical testing. Consequently, the present proposal seeks full support to perform preclinical tests in animals, including (1) safety pharmacology in dogs and rats, (2) pharmacokinetics in rats, (3) single-dose and 14-toxicity in rats, and (4) development of analytical/bioanalytical assays. We also seek support for Investigational New Drug (IND) planning and preparation as well as to explore stability of one or two final formulations (i.e., oral and/or sublingual). Upon completion of the proposed work by NIH, NeuroSpina, a biotech company based in Quebec City, has been designated to proceed and to undertake, in collaboration with partners and CROs, the first clinical trials with Spinalon (PI/IIa). In summary, this innovative therapeutic approach may allow SCI patients (i.e., specifically, motor-complete ASIA A or B patients who may benefit the most) to become physically active (treadmill training) a few times weekly. Evidence from animals and humans suggests that such an approach may lead to a safe first-in-class palliative treatment designed to prevent and even reverse health degradation and life-threatening problems associated with chronic immobility due to SCI.

Lead Collaborator

Université Laval, Quebec City, Canada
Pierre A. Guertin, Ph.D.

Public Health Impact

A drug combination called Spinalon was found to temporarily induce, with no other forms of assistance, locomotor movements in motor-complete spinal cord–injured animals. This innovative therapeutic may thus become a first-in-class treatment as well as a simple and affordable approach against the many severe health problems typically associated with paralysis and chronic immobility.


Work on this project is complete. The investigator successfully filed a Clinical Trial Application with Health Canada using BrIDGs data and initiated clinical testing.

Project Details

  • Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies