The Challenges of Gene Therapy Approaches in Advanced Muscular Dystrophy
Kevin Campbell, PhD, a Howard Hughes Investigator at the University of Iowa, discussed his mouse model research into the pathophysiology of muscular dystrophy and how it relates to gene therapy approaches.
Kevin Campbell, PhD
Muscular dystrophy gene therapy will likely have its greatest impact as a preventative treatment for patients who have not yet developed symptoms or who are still in the early stages of symptom development. Although, many patients do not receive treatment until they are older, and at this point much of their condition may not be reversible by current gene therapy approaches.
As such, understanding the pathophysiology of muscular dystrophy is key to developing new therapies that can more effectively treat older patients. Kevin Campbell, PhD, a Howard Hughes Investigator at the University of Iowa, who gave a keynote speech on this topic at the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting, held May 7 to 10, 2024, spoke to CGTLive® afterwards about his work related to this topic.
CGTLive: What did you present at ASGCT?
Kevin Campbell, PhD: I presented our work on the molecular insights into the pathogenesis of muscular dystrophy and our approaches to try to treat muscular dystrophy, in particular with older animals.
Can you give an overview of the key points from the presentation?
The key aspect in terms of the molecular pathogenesis was to understand the protein dystroglycan. It's a part of a complex of proteins where if any of those proteins are mutate it leads to different forms of muscular dystrophy. Dystroglycan is kind of unique in that it's heavily glycosylated. These are sugar groups that are put on dystroglycan. Any of the enzymes that put the sugars on, if they're mutated, lead to a form of muscular dystrophy, which we call dystroglycanopathy. So I tried to explain the pathogenesis pathway, but then also look at the function of the glycans. There's one particular glycan called matriglycan that's added to dystroglycan and that binds extracellular matrix proteins with very high affinity. We showed the structure of that interaction. The structure gave us some clues in terms of the function of the glycan.
We also recently have been able to demonstrate there are 2 chains of this polysaccharide. It's a repeat of glucuronic acid and xylose. Those 2 chains probably link into multiple proteins in the extracellular matrix or the basement membrane that surrounds muscle. When these proteins are defective, you have a defect in the basement membrane, either the structure or assembly. Our work suggests that the pathogenesis of muscular dystrophy is due to the abnormal basement membrane interactions with the muscle membrane. In that case, the muscle is not protected from contraction induced injury.
We then went on to discuss the work on gene transfer. In particular, our lab has a strong connection with the families that have dystroglycanopathy. Those families ask us lots of questions. There's been a lot of excitement in the field with treatment of spinal muscular atrophy, where you can treat and really do an amazing job. But these are very young children when they're treated. What I explained to the audience is that's really prevention of disease. I showed you an example of a paper we had back in Molecular Cell in 1998, where we actually showed prevention of muscular dystrophy. We went in very early into a hamster model of muscular dystrophy. That's exciting and that's going to be used and is very good for those patients. But most of the patients that we are interacting with are children that are older, and so they and their families ask the question, is anyone working on treating older patients? I convinced a postdoc in the lab who was training as a neurologist in Japan to take on that project with our mouse model. So we treated mice at around 30 weeks of age to 35 weeks of age, where they have a pretty severe muscular dystrophy. We were quite successful in doing the gene transfer. In a number of indications it looked like it was really working. We improve lifespan, we improve the weight of the animals, the muscle physiology returns. Two things that they didn't fully recover were grip strength and respiratory function. We're not sure why. It's possible the virus wasn't targeted correctly. But those are also integrated physiology processes. I think we can repair the individual cell, but the muscle is much more complicated than 1 muscle cel. In order to get effective muscle contraction and to use your muscles there's lots of into interactions with the nervous system, neuromuscular junctions, muscle spindles... So we think there's more work to be done in order to repair the integrated physiology, which is really important.
How would you summarize the big implications of this for the healthcare community?
For this meeting, the big implication is that you can treat older animals with gene transfer and it can be effective, but there's still work to be done in terms of making it fully effective for some integrated muscle physiology functions.
Are there any areas of interest for further research that you can discuss?
I didn't show this slide, but this might help the audience understand. So if you have a car, and you have a flat tire, and you decide that you want to drive on it, you could repair the car and put a new tire on it. That's prevention of any kind of accident. But say you decide to drive with the car, and you crash, and the car is totaled, okay? There, if you put a new tire on it, it's not going to work. It's much more complicated when you try to do repair or do gene therapy in cases where there's lots of pathogenesis that has already occurred. In the car, the tire was defective, but now maybe the electrical system doesn't work. Or maybe now the gas tank has been broken. So you have to really understand the pathogenesis. I think there's more work to be done to understand what's going on in in muscular dystrophy. At the same time, it's exciting that we can get a lot of functions repaired. Muscle is a very plastic tissue and it repairs itself; you build muscle with exercise. So I think this is a lot of hope, in terms of going forward.
Is there anything else you want to share?
My talk started with a picture of Caitlin Clark. She was a really outstanding basketball player at Iowa and she's done really well. She just got into the WNBA. There is a lot of excitement about her. She's a person that has a really positive and almost infectious attitude. To do this type of research science, most of the time, things don't work. A lot of people in the public think we just do experiments and they work. Most experiments don't work. So you really have to have that positive attitude to get it to work. I mentioned a lot of things I like about her at the start of my talk. One particular thing came from my granddaughter. She said, Caitlin is nice. And I said, "Well, why is she nice?" And she said "she thanks people." And that's how I started off, by thanking people: the families that were involved and Jeff Chamberlain and Ben Davis. I think we need to do more of that. Iowa last year with Caitlin Clark was such an exciting time. With the current situation in the world, it was just nice to focus on something really positive. I think that's something that's needed for any research you do: having this positive attitude and contagious attitude that gets your students and postdocs really excited about the work.
This transcript has been edited for clarity.
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