Evaluation of a Novel T Cell-Derived Peptide for Delivery of Antisense Oligonucleotides to Treat DMD Cardiomyopathy
Abstract
Background: There is an urgent medical need for new drugs for the treatment of heart failure in patients with Duchenne muscular dystrophy (DMD). Heart failure is a leading cause of death in many forms of muscular dystrophy, including DMD. Currently, there is no cure for DMD. Their muscles and hearts are gradually damaged and weakened. While care for breathing function has improved the expected course of the disease, heart failure has emerged as a leading cause of death in many forms of muscular dystrophy, including DMD. Many of them die of heart symptoms in their 20s or 30s. Dr. Yokota’s previous study demonstrated that DNA-like molecules called antisense oligonucleotides (AOs) effectively restore dystrophin, a protein missing in DMD patients, and improve muscle function in a severe animal model, a dog model, of DMD. This study directly led to the development of an AO called viltolarsen. However, viltolarsen and other DNA-like molecules for DMD are poorly taken up by heart muscles and, as a consequence, have little effectiveness. Therefore, a new method providing effective yet safe delivery of DNA-like molecules to the heart of DMD patients is urgently needed to prevent heart-related death. Objective: We will develop a next-generation therapy for patients with heart symptoms in DMD. We will use small DNA-like molecules. DNA-like molecules act like a stitch or Band-Aid to mitigate the effects of genetic errors. As a result, these molecules restore gene function. However, currently available DNA-like molecules are not efficiently delivered to heart muscles. We have recently discovered a molecule that efficiently delivers DNA-like molecules to the heart muscle in fish and mice. We will connect the DNA-like molecules and the delivery molecules. These molecules are designed to target the gene products of their gene in both heart and body muscles and correct their erroneous products. We will test the effects and safety of these molecules in a dog model since the dog model displays severe heart symptoms as opposed to other animal models. Study Design: We will chemically synthesize the DNA-like molecules connected to the delivery molecules and test them in the DMD dog model. We will use the dog model carrying the same errors as seen in human patients in the gene that causes muscle and heart symptoms in muscular dystrophy. These molecules will be injected into dogs through the blood vessel. First, we will determine the amount of molecules needed to treat the condition. Second, we will evaluate whether the treatment leads to correction of gene products, functional recovery in heart and bodywide muscles. Lastly, to mitigate the risk of side effects, we will examine the safety of these molecules through blood tests and assessment of body tissues and cells. Innovation/Significance: This project is innovative for using a novel molecule recently discovered to deliver DNA-like molecules into the hearts of mice and fish. These molecules will be chemically synthesized and tested in animal models. This project aims to overcome the heart delivery barrier limiting current drugs and DNA-like molecules. This project is expected to have great impact by advancing studies of a safe and effective class of drugs for heart delivery, ultimately easing the burden on patients and families. This study will prolong and improve the quality of life of DMD patients. Importantly, these delivery molecules can be used to deliver other drugs and treat many other forms of heart diseases. Successful completion of this study will eventually lead to human clinical trials. If the treatment can stop heart muscle damage in dogs, that would set the stage for giving the experimental treatment for boys with DMD. Our goal is to start clinical trials within 5 years. To this end, we recently launched a new company OligomicsTx with collaborators, clinicians, and business partners. Our team is a member of The Cooperative International
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210801
Entities
People
- Toshifumi Yokota
Organizations
- United States Army
- University of Alberta