Promoting tissue repair and functional recovery after spinal cord injury by targeting the microtubule regulatory protein Fidgetin-like 2.

Traumatic spinal cord injuries (SCI) impact hundreds of thousands of people, and there are no therapies
available which can promote regeneration and clinical meaningful improvements in sensory, motor, or
autonomic function. Fidgetin-like 2 (FL2) is a microtubule (MT) regulatory protein that modulates MT
dynamics through its putative MT-severing activity, regulating cell motility and axonal growth and
guidance. We have identified FL2 as a negative regulator of axonal growth and demonstrated that targeted
depletion of FL2 following peripheral nerve injury enhances functional nerve regeneration in rats. Our
preliminary studies show that following injury FL2 is upregulated at the injury site in several adult tissues
including the spinal cord. Based on these data, MicroCures has developed a siRNA nanoparticle-
encapsulated formulation to target FL2 after SCI, which can be applied onto the dura or injected
intrathecally. In pilot studies using rodent SCI models, we found that local depletion of FL2 from the injury
site using a nanoparticle-encapsulated FL2 siRNA improved recovery of locomotor function. Here, we will
conduct proof-of-feasibility studies to determine the efficacy of MicroCures’ nanoparticle formulation in
promoting healing using a rat contusion model. In Specific Aim 1, we will repeat our pilot study in a larger
cohort of animals, assessing efficacy through evaluating recovery of hindlimb locomotor function as well
as expanding our assessments to include bladder, sexual, and sensory function. In Aim 2, we will
characterize structural and morphological changes at the lesion with treatment through a combination of
MRI/DTI imaging and immunohistochemistry analyses. In Aim 3, we will conduct a discovery-level
toxicity study to characterize the safety profile of our therapeutic using a subset of the animals from Aim
1. Completion of these studies will provide strong evidence of whether our therapeutic formulation, called
SiFi2, is an effective and safe therapeutic for treating SCI, and whether it should be further tested and
developed in IND-enabling studies. FL2 acts through mechanisms considerably different from other
genes/proteins/factors currently being investigated as treatments for SCI; to our knowledge, these studies
would represent the first reported success of promoting healing after SCI through an siRNA-based targeting
of a microtubule regulatory protein.

Grant Number: 1R41NS137941-01A1
NIH Institute/Center: NIH
Principal Investigator: Lisa Baker