Development of an RNA Therapeutic for the Treatment of Charcot Marie Tooth 1A
Abstract
This proposal from DTx Pharma addresses the fiscal year 2022 Peer Reviewed Medical Research Program (FY22 PRMRP) Portfolio Topic of Neuroscience, specifically the FY22 PRMRP Topic Area of Peripheral Neuropathy. The FY22 PRMRP Strategic Goal addressed in this application will be Treatment, namely, to develop and evaluate novel treatments, strategies or therapeutic targets, including research to repurpose existing drugs, for associated neurological diseases and psychological conditions and develop and test treatment strategies to manage symptoms and improve quality of life for those affected by associated neurological and psychological conditions. Charcot-Marie-Tooth disease (CMT) encompasses a heterogeneous group of inherited peripheral neuropathies affecting both motor and sensory nerves. It affects 75,000 people in the United States and leads to muscle weakness and atrophy in the legs and arms, foot deformities and loss of sensation and numbness. The disease is slowly progressive and variable, and those affected may have difficulties with everyday activities and a shorter life expectancy. While the age of disease diagnosis varies, only 12.5% of the population is expected to be diagnosed before 14 years of age. Accordingly, it is expected that military Service Members will be diagnosed as the disease progresses during their military careers. Currently, there are no curative or symptomatic therapies have been approved for CMT. Current care consists of physical therapy, occupational therapy, and use of orthopedic devices to help patients cope with disability, along with medications for neuropathic pain. The most common form of CMT is type 1A, which is an inherited disease affecting between 25%-40% of all CMT patients, and results from the duplication and overexpression of a specific gene. This gene, PMP22, plays an essential role in the formation and maintenance of the nerves and its overexpression causes degradation of the protective tissue surrounding these nerves, a process known as demyelination. These defects impair the transmission of electrical signals needed to drive muscle movement, resulting in peripheral neuropathies affecting both motor and sensory nerves. Several publications have demonstrated that suppression of the overexpressed gene can result in functional improvements in animal models of CMT1A, however, this success has not been translated into the clinic. DTx Pharma has developed the FALCON platform that modifies already effective gene-targeting therapeutics to ensure their delivery to the correct tissues and cells and their retention in these tissues and cells for a sufficient amount of time, enabling them to act on gene overexpression by binding to and silencing them. In preliminary work, DTx Pharma screened over 60 drug candidates and identified a lead compound able to both silence PMP22 overexpression found in CMT1A and also able to reach and be retained in the nerve cells a sufficient amount of time to act on the gene overexpression prior to being broken down and flushed out of the system. In preliminary studies in mice, this compound, DTx-1252, was able to reverse disease and restore nerve function for 60 days following a single administration, without causing any adverse safety effects. DTx Pharma is currently working to compile a regulatory package for DTx-1252 in order to commence clinical trials. The Aims proposed herein will help to confirm our ability to manufacture DTx-1252 for clinical use, identify appropriate dosing and schedule in animals that can later inform dosing in clinical trials, and fill in gaps in our knowledge around the duration of effect of the drug, options for alternative routes of administration, and potential consequences of over-suppressing the target gene. Critically, these data will allow us to see whether there is a clear and viable path to move DTx-1252 into clinical trials for CMT1A patients. This project will also serve as validation of the FAL
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310470
Entities
People
- Arthur Suckow
Organizations
- United States Army