The promise of gene therapy continues to build momentum, in Duchenne and also in other conditions. Much has been learned about the immunological and delivery challenges of the approach since gene therapy’s early attempts in the 1990s.
In Duchenne, some of the early work in gene therapy ended with immune system reactions to the new dystrophin that was expressed by the transfected gene. But this was not the only hurdle the technology faced in Duchenne; we had to develop a viral vector that did not elicit an immune response, we had to solve the problem of how to fit the dystrophin into the vector, we had to devise a way to deliver vector to all the muscles, and we had to ensure that there was supply capacity to make enough vector.
All big hurdles, but luckily many researchers and developers in Duchenne and other disease areas, have been diligently working on these and it seems we are closer to having solutions to these problems.
In fact, two gene therapy treatments have been approved for human use in the last two years; Glybera was approved in 2014 for the treatment of LPLD (lipoprotein lipase deficiency) and Strimvelis in 2016, for the treatment of adenosine deaminase deficiency, a form of severe combined immunodeficiency. A third, Spark Therapeutics’ SPK-RPE65, is expected to reach the U.S. market by 2017. SPK-RPE65 is a gene therapy for the rare retinal diseases Leber congenital amaurosis and retinitis pigmentosa type 20.
Both Glybera and the Spark therapy use an AAV delivery system, which is the platform that most research in Duchenne is based on. These three examples are proof that gene therapy is here!
To complement these efforts, PPMD is proud to support Dr. Guy Odom, from the University of Washington, who is addressing the problem of the immune system recognizing the newly expressed dystrophin as foreign with novel methodology. See the press release here.
We are hopeful that his work will help make gene therapy in Duchenne more effective and long lasting.
Read PPMD's Press Release to learn more:
Hackensack, NJ – June 9, 2016 – Parent Project Muscular Dystrophy (PPMD), a nonprofit organization leading the fight to end Duchenne muscular dystrophy (Duchenne), announced today plans to award Dr. Guy Odom, a research assistant professor of neurology at the University of Washington (UW), a $49,000 grant for his work in gene therapy. With a long history of funding early stage research in Duchenne, PPMD believes that the technology being developed by Dr. Odom and his UW Medicine team will help optimize the promise of gene therapy as a treatment for this rare disease.
Duchenne muscular dystrophy is the most common fatal genetic disorder diagnosed in childhood, affecting approximately one in every 5,000 live male births.
Gene therapy relies on the principle that a shortened but highly functional micro-dystrophin can be introduced via a viral vector. A significant hurdle, however, is the possibility of an immune response against micro-dystrophin as the newly expressed micro-dystrophin has never been encountered before in people with Duchenne. This immune response could interfere with the expression of micro-dystrophin, as well as muscle growth and repair.
Abby Bronson, Senior Vice President of Research Strategy for PPMD, explains the strategy this way: “The adaptive arm of the immune response works by the T-cells recognizing a small part (the epitope) of the antigen (the micro-dystrophin in this case) and binding to it, leading to neutralization and elimination from the muscle. Using computer modelling and previous human epitope data (immunoinformatics), Dr. Odom seeks to ultimately design a micro-dystrophin that avoids being recognized by the immune system, potentially enabling safer and longer-term effective treatments for people with Duchenne.”
“As a key pre-clinical step forward, this funding will allow us to demonstrate whether multiple epitopes within dystrophin can be redesigned while maintaining function with greatly reduced immunogenicity,” Dr. Odom said.
As a proof-of-principle, the redesigned micro-dystrophin candidates will be initially screened for stability in mdx skeletal muscle cell cultures followed by testing the “best’ candidates in mdx mice for function and stability. Because heart muscle is so important in Duchenne, these micro-dystrophins will also be tested in cardiac cells in the mdx mice for function. The ‘best” micro-dystrophins will be further tested for immune reactivity by using T-cells previously derived from Duchenne patients, shown to be responsive to the original epitopes.
According to Bronson, “Our community, for many years now, has been interested in the potential of gene therapy as a treatment for Duchenne. Dr. Odom, in anticipating potential barriers in the functionality of gene therapy, is addressing a possible immune response head on. It is this kind of forward-looking, out-of-the-box thinking that PPMD is proud to support and nurture.”
To learn more about PPMD’s extensive research portfolio, please visit ParentProjectMD.org.