News Duchenne UK and Parent Project Muscular Dystrophy award $350,000 (£260,000) to address immunological challenges of gene therapy in Duchenne Muscular Dystrophy 18 February 2021 Duchenne UK and Parent Project Muscular Dystrophy (PPMD) are pleased to announce Professor Kanneboyina Nagaraju at Binghamton, the State University of New York, as the recipient of their Joint Research Grant Call of 2020. The full title of the research project is “Targeting the innate immune system to block acute inflammatory and chronic immune response to transgene and AAV vector in DMD”. Professor Nagaraju’s research will receive funding from the organisations in the amount of $350,000 (£260,000). Our Q&A below explains some key terms associated with this research. These are promising times for research into Duchenne Muscular Dystrophy (DMD). Several companies are now testing an approach that uses a shortened dystrophin gene to replace the faulty dystrophin gene in Duchenne. This is known as gene transfer using micro-dystrophin, or more commonly, gene therapy. The companies are using viruses known as AAVs (adeno-associated viruses) to deliver the therapy. However, challenges exist in getting this treatment to the entire DMD population. This is mainly because of immune responses: some patients have pre-existing antibodies to the AAVs. This means they will not, currently, be able to have the treatment because their bodies will recognise the virus and stop it from delivering the micro-dystrophin to the cells. In addition, as gene therapy is a new treatment, it is not yet clear if another dose will be required at a later stage, and it is not currently possible to re-dose with the same AAV. For more information on immune responses, see our Q&A below, or watch our film about the challenges of gene therapy delivery. This is why Duchenne UK & PPMD launched a call for projects last year that would specifically address this challenge. The organisations received a large number of proposals, and three were taken forward for final review from a panel of highly qualified, specialised scientists. They looked at a wide variety of factors, including significance to the Duchenne community, and the ability to translate the research into treatments for patients. Professor Nagaraju’s research is looking at blocking the mechanism by which the body is able to recognise an AAV virus and mount an immune response to it. Importantly, he is using medicines that are already in use in humans, in an approach known as repurposing. If this approach were successful, it would allow more micro-dystrophin to get to the cells, potentially requiring a lower dose of the AAV than is currently being administered in the trials. It may also allow patients who have already been dosed with gene therapy to receive further doses. Further to this, by using repurposed drugs, this treatment should be more easily transferable to patients. Professor Nagaraju believes that “targeting initial immune recognition pathways is one way to improve efficacy and safety profiles of AAV mediated gene therapy”. PPMD's Founding President & CEO, Pat Furlong, and Duchenne UK's CEO, Emily Crossley explained in a joint statement: “Supporting patients and accelerating innovative research is at the heart of what we do at Duchenne UK and PPMD. We are pleased to partner with each other and award this grant. Gene therapy is offering great promise, but there are challenges associated with the immune response which are limiting the rate of progress and a barrier to ensuring all patients can have access to these potentially transformative therapies. We would like to thank all those who participated and supported our Joint Grant Call and are very much looking forward to working with Professor Nagaraju on this vitally important project for the Duchenne community.” We would like to thank our charity partner, Joining Jack, and the following family funds for contributing to this project: Lifting Louis, Hope for Gabriel, William's Fund, Mission Jensen, Team Oscar, Archie's March, Chasing Connor's Cure, Team Felix, Smile with Shiv, Muscles for Mitchell, Project GO, Action for Arvin, Following Felix, Ralphy's Fund, Cure4George, Joe's Journey, Backing Jack, Defending William Against Duchenne, Ben vs Duchenne, Strength for Stanley, Standing with Jack, Jack's Mission, and Jacobi's Wish. Q&A What is an immune response? An immune response is how your body recognises and defends itself against potential harm, such as viruses. Viruses have evolved to get inside cells by recognising specific proteins on the surface. This allows them to pass through the cell membrane, delivering their genetic material and forcing cells to make copies of the virus. This is why they are so useful in gene therapy as it allows the micro-dystrophin to enter the cell and be copied throughout the body. As a virus spreads through the body, our body mounts a response and attacks it. We then develop antibodies to fight the virus there and then, and the next time the virus enters the body, we are able to recognise it and stop it before it has a chance to multiply. Why do immune responses cause a problem for gene therapy? As gene therapy is delivered through a benign (harmless) virus, if an individual has come into contact with the virus before, they will have already developed antibodies which will detect and attack the virus as soon as it enters the body. This means that the micro-dystrophin genetic material cannot reach the cells. This is the case for a significant percentage of patients. This is not just a problem when gene therapy is first administered. We may need to give second or even third doses of the gene therapy after the patient has received his first dose. The difficulty here is that even if the patient doesn’t have antibodies the first time round, the body will develop them during the first dosing as they are exposed to the virus. These antibodies will now be ready to attack and destroy the virus as soon as a second dose is given. Are other researchers looking at this problem? Yes, they are, and both PPMD and DUK are involved in supporting other work like this. One of the approaches being taken by DUK is to use drugs which temporarily suppress the body’s immune system. During this time, the virus can be given, deliver its genetic cargo, and then be removed when the drugs are stopped. This has great potential but requires very careful choice of drug. Of course, patients need to be protected during their time with a reduced immune system. In very early days, and in other disease states, some researchers tried plasmapheresis – a process where immune cells are removed from a patient’s blood. This is rather extreme, and we want a safer approach. So, what is different about Professor Nagaraju’s work? Prof Nagaraju is taking two approaches. Firstly, he is looking to make sure enough virus and genetic material reaches the muscles in the first place and then secondly, he will try to stop the body recognising the virus a second time round. This double approach, if successful, will help boys with pre-existing antibodies take part in gene therapy trials, and eventually receive the treatment, as well as being a useful tool to help facilitate subsequent administrations. What does ‘repurposing’ mean and why is it important here? Repurposing is a key research target for Duchenne UK and refers to studying drugs that are already approved for the treatment of one disease to see if they are effective at treating other diseases – in our case, DMD. The reasons why this is so important are speed and cost. Drugs that have already been approved have, by definition, been shown to have an acceptable safety profile, both pre-clinically and in early clinical studies. These studies take time and are expensive. If we can repurpose a drug, we could get it to our patients quicker and cheaper, despite the fact we may have to demonstrate safety in young DMD patients. If it works, when can we start using in patients? This is always a difficult question to answer with certainty. This work is designed to test medicines in animals and will take 2 years. If the data is promising, we would then need to test those medicines in humans, and set up a clinical trial to do so. It’s important to remember that we will be using drugs which already have safety data in humans so we would hope to move swiftly in trials which look at how effective they are, rather than test first for safety. For more information on gene therapy and the challenges involved, visit our gene therapy information page. NOTES FOR EDITORS About Duchenne UK Who are Duchenne UK? Duchenne Muscular Dystrophy (DMD) is a devastating muscle-wasting disease. It is the most common and severe form of Muscular Dystrophy. Diagnosed in childhood, it mainly affects boys. There is currently no cure. Started by families affected by the disease, Duchenne UK has one clear aim – to end Duchenne. Duchenne UK are funding research that’s focused on getting treatments to those affected now – as well as pushing for an effective treatment in the future. Duchenne UK connects leading researchers with industry, the NHS and patients to challenge every stage of drug development, from research to clinical trials to drug approval. They connect families with each other to create a network of mutual support and to pool resources, knowledge and experience. About Parent Project Muscular Dystrophy Duchenne is a fatal genetic disorder that slowly robs people of their muscle strength. Parent Project Muscular Dystrophy (PPMD) fights every single battle necessary to end Duchenne. We demand optimal care standards and ensure every family has access to expert healthcare providers, cutting edge treatments, and a community of support. We invest deeply in treatments for this generation of Duchenne patients and in research that will benefit future generations. Our advocacy efforts have secured hundreds of millions of dollars in funding and won four FDA approvals. Everything we do—and everything we have done since our founding in 1994—helps those with Duchenne live longer, stronger lives. We will not rest until we end Duchenne for every single person affected by the disease. Join our fight against Duchenne at EndDuchenne.org. Follow PPMD on Facebook, Twitter, Instagram, and YouTube.