Reaction to 2024 MDA Legacy Award: Jeff Chamberlain, PhD

Jeffrey Chamberlain, PhD

The 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-6, in Orlando, Florida, kicks off Monday with the opening remarks, followed by a presentation on the MDA Legacy Award. The award, considered the highest honor by the organization, is an annual recognition for outstanding accomplishments in neuromuscular disease research. This year’s recipient is Jeffrey Chamberlain, PhD, a professor of neurology, biochemistry, and medicine/medical genetics at the Institute for Stem Cell & Regenerative Medicine at the University of Washington.

The Chamberlain lab studies mechanisms leading to muscular dystrophies, the structure and function of dystrophin, and approaches to therapy. Those in the lab, including Chamberlain, have developed miniaturized dystrophin genes, otherwise known as “micro-dystrophin” and were the first to show that adeno-associated vectors could be used for systemic gene delivery to muscle. In addition, Chamberlain has written over 100 publications, covering topics related to muscular dystrophy, adeno-associated viral vectors, promising gene therapy strategies, and more. Prior to the start of the meeting, Chamberlain provided commentary on his response to the award, as well as other areas of focus in the DMD field.

Describe your initial reaction to receiving this award; what does it mean to you?

I was surprised and excited to hear that MDA was conferring this award.It is gratifying to have one’s work acknowledged in such a way.However, it was especially meaningful to me because it came from MDA, which I have always felt is the most important funding and advocacy organization worldwide for the muscular dystrophies.MDA helped launch my career by awarding me my first grant, and they have been supporting my efforts to develop gene therapy since those early days.Hopefully this means they feel their efforts were worthwhile, they have been for me.

How impressed have you been by the progress in the Duchenne field and the ways we’re able to treat patients?

I’ve been both impressed and disappointed.It is impressive to see more and more drugs hit the market that are benefiting boys with DMD, along with significant increases in patient care options that have increased longevity. However, it is disappointing that we are not there yet, and that major progress is still needed. Predicting how long it will take to develop the next breakthrough is never a productive exercise.In my lab I always tell folks that you need to take it one day at a time.If you look too far ahead it can be discouraging, but if you don’t look ahead you’ll never be driven to succeed.I’m excited by the progress so far, in some ways it has come faster than I thought possible.Still, it is not enough, and for now we need to focus on the next breakthroughs and not focus too much on the past.

What are going to be some of the major emerging concepts/research in DMD over the coming years?

Next generation gene therapies represent the key, in my opinion, but these will continue to be augmented by additional treatment pathways.Current gene therapies are exciting and have come a long way; however they are not good enough and they need to be much better.I believe three areas of study will get us there: 1) We need better genes to deliver to kids. The micro-dystrophins that I developed starting more than 25 years ago are showing promise to slow loss of muscles and the onset of weakness, but they seem too small to increase strength significantly, especially in older boys.

My group is now focused on delivery much larger and more potent dystrophin genes. A related and important area is to find out ways to increase the function and potency of muscle stem cells. 2) We need better delivery vehicles to get these large genes into muscles all over the body. There has been exciting work by several labs recently showing a major improvement in delivery efficiency, which is critically important to reduce immunological reactions against high dose vector infusions. A related breakthrough that has been slow in coming is the development of non-viral delivery systems, such as nanoparticles, which could prove to be a critical stem for effective gene therapy. 3) We need to better way to target all the muscles in the body, and this may would benefit from improved gene on/off switches (promoters and enhancers0 that will allow uniform production of dystrophin in every muscle type in the body.

What are some of the biggest questions with the use of available gene therapy for DMD and future gene therapies down the road?

The current biggest questions are how well the current vectors will work in the long term.We are seeing only a partial restoration of dystrophin, and the effectiveness of partial micro-dystrophin production is unclear.How durable will it prove to be?Can it work in older boys?Perhaps the biggest unknown is whether it will help in the heart or perhaps make things work.There are concerns about some current promoters being used and whether they even are active in the heart.There are so many variables that it is hard to know exactly where we stand, but the data in emerging quickly.

Ahead of the conference, what research areas outside of DMD excite you?

I’m interested in gene therapy as a whole, for many other disorders, including cancer and heart disease.As president of the American Society for Gene and Cell Therapy I’m able to follow progress in many different areas and disease targets.The field as a whole is progressing rapidly.DMD has in many ways led the way, but impressive breakthroughs are happing all around, and what we learn from one disease often teaches us important at lessons about other, seemingly unrelated disorders. I’m also interested in funding mechanism, we need more money to accelerate research breakthroughs, but this seems to have dropped as national priority.