Meet the Expert

Learn more about Dr. Elmallah’s research on the control of breathing and pulmonary mechanics

Dr. Mai ElMallah is an Associate Professor of Pediatrics at Duke University School of Medicine. The ElMallah lab studies the control of breathing and pulmonary mechanisms of various rare genetic diseases in mouse models. Currently, the lab is focused on ALS and Pompe disease mouse models. They research the impact of gene therapy on respiratory insufficiency. Dr. ElMallah is at the forefront of preclinical rare disease research, and we were able to get her thoughts on the field and learn more about her work!



Q: What led you to pursue research neuromuscular disorders such as Pompe disease and ALS and also what interests you the most about the research?

Both of those diseases result in respiratory insufficiency and that’s what drew me to them. I started off with Pompe disease when I started my pulmonary fellowship and I was interested in the control of breathing in neuromuscular disorders. I worked at the University of Florida in the lab of two of my mentors, David Fuller a respiratory physiologist and Barry Byrne a gene therapy and Pompe expert. During my fellowship is when I got interested in the control of breathing of Pompe disease. At that time, I focused more on gene therapy and trying to get the vectors and the therapy into the respiratory control centers as well as target the respiratory muscles.

When I moved to the University of Massachusetts, we saw a lot of Pompe patients in clinic too. Whenever the patients had a tracheostomy and were put on ventilators, they had tracheomegaly, the trachea was expanded from the increased pressure. At the same time, there were some publications that were coming out showing that there was tracheomalacia and bronchomalacia in these patients that were on the FDA approved therapy of enzyme replacement therapy. That’s when I started to pursue the smooth muscle dysfunction in the airways. The flexiVent was perfect for that because you could look at the impact of the disease on the central airway resistance and peripheral airway resistance. We could use bronchoconstrictors and bronchodilators and see how the smooth muscle responded. With some ex vivo studies, we were to see that there was significant smooth muscle dysfunction in Pompe disease. That’s how I started with Pompe disease.

With ALS I got into that research when I went to the University of Massachusetts; Robert Brown a world-renowned authority and they were doing on adenovirus (AV) gene therapy to knock down superoxide dismutase 1 (SOD1) in ALS and the focus during that time involving gene therapy was on limb movements and fertility in mice. As you know ALS patients end up dying of respiratory failure, and so I wanted to see the impact of this novel therapy, first of all to kind of see if we can reproduce what others have shown in the ALS model and then try to find the effect of gene therapy on respiratory function in mice.

Q: Before your postdoctoral fellowship with Dr. Fuller and their group, what brought you into control or breathing research?

Part of a pediatric fellowship here in the United States is one month of clinical work and two months of research. Prior to finding a research project, I didn’t know whether I was going to do clinical or basic science research. I had never done basic science research before. I started this lab rotation in different labs that looked more at asthma, COPD and another with alpha 1 antitrypsin (AAT) research before I did a gene therapy lab rotation. My last lab rotation was with Dr. David Fuller doing gene therapy and I realized that is exactly what I enjoyed and loved doing. They are a great group and not many people do it.

Q: What is the current landscape Pompe disease for research? What are the current questions that are being asked and what are groups studying or trying to investigate right now for Pompe disease? 

As a homogenetic disease, the way to cure this disease is with Gene therapy. The biggest struggle has been trying to deliver the transgene using adenovirus (AV) gene therapy to all the affected areas: skeletal muscle, cardiac muscle, smooth muscle and CNS with all the motor neurons. So how do we target all of the muscle and motor neurons, that’s what we are going to be trying to figure out in the next 5 years. AV gene therapy is already in clinical trials for adults with Pompe disease. Because it’s in clinical trials, that means it will be translated pretty quickly if we find a good vector for children. There haven’t really been any systemic AV injections for children in Pompe disease. The big success in adeno-associated virus (AAV) gene therapy has been in spinal muscular atrophy (SMA), about a year ago became FDA approved. If these kids are caught before 6 months of life and are injected with AAV9-SMN, they are able to stay off a ventilator, are walking and talking at 2-3 years old. These are patients that would be ventilator dependent. I think that’s where a lot of the focus is on Pompe disease is in trying to find a cure with gene therapy.

Q: Is the challenge currently the ability to target the specific areas with the gene therapy?

I think it’s more just trying to target them all. In the animal models when we are able to get the transgene in, we see reversal of motor neuron pathology and skeletal muscle pathology so we just need to be able to get it there. Enzyme replacement therapy is something these kids get right now and they get it every two weeks, they have to have an infusion every two weeks. Because of this, they have to be immunosuppressed. It has helped a lot of the patients to stay off the ventilators, it would be great to have only a 1-time therapy.

Q: What are  the real world implications of your work, and how was the ongoing clinical trial with Duke enabled you to push your work from the benchside into the clinical study clinical study?

What was so attractive to coming to Duke is that it has a world-renowned center for Pompe disease. Dr. Priya Kishnani is a world authority on Pompe disease, and she’s managed to build up the center for Pompe. She has an annual meeting for late-onset and infantile Pompe disease where a lot of people come here to learn about Pompe disease and are followed in clinic. Collaborating with her has really helped to figure out where the deficits are in the clinic and try to push that forward with therapy.

Q: How long have you been using the flexiVent? Were there any times the data from the flexiVent caused you to look a little more into your data or changed the course of your research?

I would say, yeah 6 years.

For sure, the flexiVent studies on the Pompe mouse model that showed that the smooth muscle, that the airways were hyperresponsive. The therapy reinforced targeting the smooth muscle in the airway. That was the basis for the R1 grant I just got. Without the flexiVent data, we wouldn’t be heading down this path. For ALS it was an interesting way to look at the restrictions that occurred with the progressive neural disease. That isn’t something we continued to pursue as we did with Pompe. The other disease model I’m working on now is Duchenne muscular dystrophy (DMD) and that’s one I’m very interested in looking at airway resistances because I think the smooth muscle in Duchenne is affected and is not something we really look at.

Q: I’m guessing mice probably don’t spontaneously develop Pompe disease or an equivalent to it, so what was the basis of picking your mouse model, and what were some of the challenges that went into creating this model?

The mouse model was originally created by Dr. Nina Raben in 1998 at the NIH, that was a 129X1/SvJ * C57BL/6 background. At the University of Florida, Dr. Barry Byrne had backcrossed it to 129 to get a pure background. It has respiratory pathology, but the mice tend to be a little bit healthier. At the University of Massachusetts, we went back to the original C57BL/6 model. It’s an acid alpha-glucosidase (GAA) deficient model where they knockout the GAA gene. GAA hydrolyzes lysosomal glycogen into glucose, when that is missing glycogen accumulates in the lysosomes and leads to cellular disruption. It’s a great model histologically. But mice, given the severity of glycogen in their lysosomes, they compensate really well compared to humans.

Q: What are the next steps and questions for your lab in the upcoming years?

We are trying to find the ideal vector. We looked at the novel AAV vector and compared it to the AAV9, which is used in SMA right now. And despite that, we still found we had significant smooth muscle pathology. We used the flexiVent to assess their respiratory airway resistance and found that there was no difference despite AV gene therapy. We are collaborating with an AV gene therapy expert Dr. Aravind Asokan, and he’s looking at a novel captive modification to find a pathway to target the smooth muscle and smooth muscle progenitor cells to be able to use a one-time treatment for the smooth muscles, skeletal muscles, cardiac muscles and CNS. We will be using the flexiVent to assess that.

Duchenne muscular dystrophy research doesn’t typically look at breathing outcomes. Adding airway resistance and breathing outcomes in novel therapies is what we are planning once we are back.

Q: What advice would you give to someone starting a new lab looking at control of breathing and respiratory outcomes??

Collaborations are very important. Collaborate with experts on specific neuromuscular disorders. Finding people with clinical models, that in the clinic result in respiratory issues but respiratory outcomes are not being looked at in the lab. The clinical population is what informs our research in the lab. The goal is the go back from the lab to the clinic. That’s what makes me passionate about the research, that it may impact patient care in the future. It helps keep the goal in mind.

Given that a lot of people overlook the respiratory outcomes in neuromuscular disorders. I would say get the respiratory function equipment, which is a great way to see if the mice have a respiratory phenotype.

Thank you Dr. ElMallah for taking the time to participate in our interview series! To learn more about Dr. ElMallah’s research, check out the lab website.
Dr. ElMallah recent publications:

Cross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing. (2022). Nature Communications, 13: 5947

Intralingual and Intrapleural AAV Gene Therapy Prolongs Survival in a SOD1 ALS Mouse Model. Keeler, A.M., et al. (2020). Molecular Therapy Methods & Clinical Development. 17: 246-257

Systemic Delivery of AAVB1-GAA Clears Glycogen and Prolongs Survival in a Mouse Model of Pompe Disease. Keeler, A.M., et al. (2019). Human Gene Therapy, 30(1)

Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema. Borel, F., et al. (2017). Biological Sciences, 115(11): 2788-2793

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