Development of Long-term Intrathecal Romidepsin: A New Drug Candidate for SCI-Induced Spasticity

The goal of our proposed Small Project is to develop an intrathecal administrative approach using Romidepsin in for the purpose of treating spasticity. This study includes efficacy and safety primary outcomes, and mechanistic exploratory outcome measures. Results from this project will allow us to determine the longer-term effectiveness of low-dose, chronic Romidepsin administration through an IT route, and general safety of this translational approach. We will carry out two objectives to address the goal of this project. In objective 1 we will establish the effectiveness of low dose, chronic IT delivery of Romidepsin on H-reflex hyperexcitability associated with post-SCI spasticity. We have previously shown that acute intraperitoneal (IP) delivery of Romidepsin is effective in altering dendritic spine dysgenesis in spinal motor neurons, and that it can effectively reduce nociceptive, sensory neuron hyperexcitability in a burn-inflammatory model. Additionally, our preliminary data show that IP delivery of Romidepsin in SCI mice reduces H-reflex hyperexcitability. Because spasticity is an ongoing, chronic disease, however, acute injectable systemic treatments have limited clinical value. As such, we now seek to understand the efficacy and safety of long-term infusion using a clinically relevant drug delivery method using the clinically established intrathecal catheter infusion method. [In objective 2 To assess Romidepsin effectiveness with the IT route, we will compare spasticity and health outcomes of SCI mice receiving IV treatment of Romidepsin—the currently established clinical delivery method for T-cell lymphoma in humans (Yang, 2011). Here, Romidepsin will be injected into the lateral tail vein in mice (i.e. IV infused). IV delivery carries the advantage of flexibility in that the drug delivery can be easily adjusted. However, IV can lead to systemic side effects and has limited ability to cross the blood-brain barrier which limits its efficacy for CNS injury and disease. Here, we will determine if IT or IV delivery of Romidepsin is equivalent (or superior) in attenuating the underlying pathology, e.g., loss of rate dependent depression (RDD) of the evoked H-reflex, of spasticity following SCI.] In summary, this project will establish a translational low dose IT delivery system of Romidepsin directly to the spinal cord following SCI (Objective 1). [It will also gather comparative data against spasticity treatment with IV-infused Romidepsin following SCI (Objective 2).]