Exosomes as Therapeutic Vehicles for Duchenne Muscular Dystrophy
Abstract
Scientific Objective and Rationale: Duchenne muscular dystrophy results from a change in the DNA of a gene called DMD. (The gene name DMD is the same as the abbreviation for Duchenne muscular dystrophy – DMD). Symptoms of muscle weakness result from loss of a protein called dystrophin that is required for normal muscle function. One approach for treatment of Duchenne muscular dystrophy is called gene therapy, which uses a tool called an adeno-associated viral (AAV) vector to deliver, or carry, a therapeutic DMD gene to muscle and heart so that dystrophin protein can be produced. Sometimes a person’s immune system can make gene therapy difficult by attacking the AAV vector, thereby reducing the delivery of the therapeutic gene. The high dose of AAV vector that is required for delivery of AAV vectors to muscle and heart tissue can activate the immune system to such a degree that it will prevent the ability to give a second dose. A gene therapy method that enhances delivery of AAV to muscle tissue and that is resistant to the immune system is needed. This project will use a novel method to increase the efficiency of AAV gene therapy in muscle tissue of DMD mice by the use of small vesicles or “bubble-like” structures that contain the AAV and serve to protect the AAV and its DMD gene cargo from the immune system. These AAV-containing vesicles have shown superior delivery of genes in muscle tissue of healthy mice compared to the standard method of AAV gene therapy without vesicles. Development of AAV-containing vesicles that carry therapeutic DMD genes for the treatment of Duchenne muscular dystrophy will be a new venture. Ultimate applicability of the research: Our approach has the potential to benefit all DMD patients, including those currently excluded from participation in AAV clinical trials because their immune system is activated against AAV. This would widen the opportunity for DMD patients to participate in clinical trials. In addition, the greater efficiency of gene delivery that the vesicles provide may enable lower doses to be given to patients that, in turn, may reduce side effects that may accompany gene therapy using standard AAV vectors. (The ongoing clinical trials will provide an indication of the kinds of side effects to expect). Projected time anticipated to achieve a clinically relevant outcome: Upon completion of this proposed 2-year study in mice, we anticipate that the next step would involve the testing of our approach in a dog model of DMD in a subsequent 2- or 3-year study. During this period, with appropriate guidance from the US Food and Drug Administration, subsequent clinical trials of our approach in DMD patients could be planned and, perhaps, conducted in parallel with trials of standard AAV gene therapy that are already underway. Likely contributions of the study to advancing the field of DMD research: If successful, our approach could advance the field of DMD research by facilitating the study of a different kind of gene therapy that enables corrective changes in the DNA of genes that can have therapeutic benefit. One of these approaches is called CRISPR/Cas9 and has shown promise for treatment of DMD using mouse and dog models, potentially enabling life-long correction that may reduce the need for second doses of gene therapy. In addition, our approach could be extended to the study of other muscular dystrophies or inherited conditions that would benefit from gene therapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010492
Entities
People
- Thurman Wheeler
Organizations
- Massachusetts General Hospital
- United States Army