February 17, 2021 / Research

Duchenne UK and PPMD Award $350,000 to Address Immunological Challenges of Gene Therapy in Duchenne

Parent Project Muscular Dystrophy (PPMD) and Duchenne UK are excited to announce Professor Kanneboyina Nagaraju at Binghamton, the State University of New York, as the recipient of our 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 organizations in the amount of $350,000. Our joint Q&A below explains some key terms associated with this research.

These are promising times for research into Duchenne muscular dystrophy (Duchenne). 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 Duchenne 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 recognize 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 read PPMD’s recent blog 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.

We received a large number of proposals, and three were taken forward for final review from a panel of highly qualified, specialized 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 recognize 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.”

To learn more about PPMD’s innovative research agenda and our investment portfolio, click here.


What is an immune response?

An immune response is how your body recognizes and defends itself against potential harm, such as viruses.

Viruses have evolved to get inside cells by recognizing 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 recognize 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.

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 recognizing 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 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, Duchenne. The reasons why this is 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 Duchenne 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 PPMD’s Gene Therapy Initiative page.

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