Extracellular Vesicle-Based Therapeutic Technologies for Duchenne Muscular Dystrophy
Abstract
Duchenne muscular dystrophy (DMD) is an incurable disease caused by the loss of functional dystrophin protein, which leads to degeneration of skeletal and cardiac muscle. DMD patients become wheelchair-bound between 6 and 12 years of age and usually die in their early twenties. typically due to cardiac and/or respiratory failure. New treatments are urgently needed, the most promising of which is gene therapy that can restore the production of the missing dystrophin protein in affected children. The current state-of-art gene therapy is based on adeno-associated viruses (AAVs) which prompt muscle cells to produce the missing protein. However, only a small group of patients can benefit from AAVs. Most people’s immune system recognize AAV-based drugs as invading viruses and destroys them immediately or soon after receiving the drug. Additionally, patients can receive the drug only once; all subsequent treatment attempts are blocked by the immune system, and this remains the biggest clinical challenge. Being able to use the gene therapy drugs repeatedly; however, is crucial because gene expression will be lost during the child’s skeletal and cardiac muscle development. Here we will use extracellular vesicles (EVs), natural delivery vehicles of the human body, to overcome this unresolved problem. Our innovative approach is to optimize a new delivery technology that can be utilized for dystrophin replacement in DMD, based on the use of EVs or AAVs incorporated inside EVs (EV-AAVs), thereby shielding gene therapy drugs from the immune system. Due to the endogenous nature of EVs and their innate ability to cross biological barriers, we expect that our innovative approach will result in a novel method to treat all DMD patients without exception, in a safe, efficient, and repeated way. Hence, this invention will represent a major advancement over existing delivery systems, which do not fulfil all these requisites. This project builds on more than 10 years of work in our laboratory; we are world leaders in EV therapeutics and have established state-of-the-art tools and methods for EV engineering. We have also developed several molecular therapies for neuromuscular diseases such as DMD, and therefore all the skills and resources needed to the success of this project are in place in our laboratory. Getting this funding would allow us to generate the proof-of-concept data in the next 2 years, needed to support future funding necessary for the clinical development of our strategy, so that every individual with DMD can ultimately benefit from our contribution in the next 10 years. This project is unique and crucial, as we will overcome the key limitation to the widespread use of gene therapy approaches in the clinic. Furthermore, if successful, our breakthrough technology can be easily extended beyond DMD to target several muscular dystrophies and other genetic diseases.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211067
Entities
People
- Matthew Wood
Organizations
- United States Army
- University of Oxford