Preclinical evaluation of efficacy and safety of a new iron chelator therapy in chronic spinal cord injury

Cervical spinal cord injury (C-SCI) is a common and frequently devastating battlefield injury that can result
in a broad range of life-long locomotor and spasticity disabilities. With advances in early evacuation and
aggressive medical therapy, there are still no effective therapeutics that salvage spinal cord (SC) neurons
/reduce progressive secondary damage. Acceleration/deceleration and contusion SCI cause micro-vessel
shear injury, blood spinal cord barrier (BSCB) dysfunction, and hemorrhage. Iron deposited by diffuse
micro-hemorrhage fuels oxidative stress and inflammation through reactive oxygen species (ROS), which
further induce progressive disabilities. There is an urgent need to address both specific disabilities and risk
factors for long-term progressive disabilities, and to develop effective therapies that have excellent potential
for translation. The proposal will test the preclinical evaluation of the safety and efficacy of a new iron
chelator, SP420, with or without a programmed locomotor therapy in a rodent model of contusion CSCI.
The combination of two complementary therapies is aimed to amplify robustness necessary to significantly
improve function in a chronic setting of SCI. This novel patented iron chelator will remove bleed-induced
free toxic iron, a powerful catalyst of oxidative stress/inflammation, and with locomotor therapy it will
upregulate neural and vascular trophic agents to protect and heal injured neural and vascular tissues. The
long-term goal of these studies is to develop an effective SCI therapeutic, and to obtain sufficient preclinical
evidence to support a Food and Drug Administration (FDA) Investigational New Drug (IND) application for
human SCI clinical trials. Accordingly, Three Specific Aims will be tested in a clinically relevant rodent
model of C-SCI. Currently, the drug has an IND for iron storage disease (e.g. Thalassemia). We have
reported enduring motor (spasticity and gait) disabilities in this model. Specific Aim 1 (SA-1): Safety,
efficacy and optimization of treatment duration. SP420 will be administered SQ at one fixed dose (80
mg/kg; represents the human phase II dose) in three different durations and tested against saline
placebo controls. Treatment will be initiated at two post-injury chronic time points (post-injury week-4 and
week-12), each using a separate cohort of animals. Quantitative physiological measures of spasticity, gait,
and the integrity of axonal conduction of descending locomotor pathways functions are the primary
outcomes along with clinically relevant T1/T2W, SWI/QSM, and DTI MRIs. A comprehensive list of safety
outcomes will be assessed as well during the treatment. Specific Aim 2: To determine the efficacy of
combined SP420 and locomotor exercise therapy in mitigating spasticity and gait disabilities. All outcome
measures as stated in SA-1 will be applied. The functional/imaging/safety outcomes will be compared
among the three treatment durations and two post-injury periods. Specific Aim 3 (SA-3): To determine
SCI and treatment impacts on the temporal profile of iron toxicity/inflammation, cellular damage, BSCB
integrity, and neuroplasticity (trophic factors). A cause-effect relationship between iron deposition, tissue
damage and treatment effects of iron chelator will be studied using a combination of histological, track
tracing, and immunohistochemical assays to evaluate bleed iron, oxidative stress, inflammation, markers
for BSCB integrity, and neural, and vascular protective factors. We hypothesize that free bleed iron fuels
oxidative stress and neuroinflammation through ROS which drives the progression of neurological damage
and motor disabilities, in part. We predict that the proposed SP-420 therapy will reverse the iron-mediated
neurological damage and delayed neurological sequelae. The combination of two complementary
therapies will amplify robustness necessary to significantly improve function in a chronic setting of SCI.
Achievement of these goals will provide innovative, non-invasive, and patient-centered technologies and
treatments that will greatly facilitate treatment of veterans and civilian SCI.

Grant Number: 5I01RX003986-03
NIH Institute/Center: VA
Principal Investigator: PRODIP BOSE