Sumner is starting a new Center of Neurogenetic Therapeutics at Johns Hopkins to facilitate development and implementation of genetic therapies for neurological diseases.

Charlotte Sumner, M.D. cares for patients with genetically mediated neuromuscular diseases. Her practice is notable for its focus on individuals with inherited neuromuscular disorders of peripheral nerves and motor neurons, including spinal muscular atrophy (SMA) and Charcot-Marie-Tooth (CMT) disease. She co-directs the Johns Hopkins Muscular Dystrophy Association Care Center, the Spinal Muscular Atrophy (SMA), and the Charcot-Marie-Tooth (CMT) clinics, which deliver multidisciplinary clinical care, engage in international natural history studies, and provide cutting edge therapeutics. 

What brought you to Johns Hopkins University?

I first came to Hopkins in 2000 to do a clinical neuromuscular fellowship. I made the move across the country from University of California San Francisco, where I had completed residency, to Hopkins because I saw it as the leader in clinical care and research of neuromuscular diseases. It also didn’t hurt that Hopkins is close to the NIH (National Institutes of Health). I had spent time as a medical student at the National Institutes of Health as an Howard Hughes Medical Institution/NIH medical research scholar. Following the year of clinical neuromuscular fellowship at Hopkins, I pursued a research neurogenetics fellowship at NIH for five years. I returned to Johns Hopkins in 2006 for my first faculty position and have been here ever since.

I’ve been asked a number of times to look at positions elsewhere, but as a clinician-scientist focused on therapeutics development, I haven’t identified another institution where translational science is better carried out. The relationships between basic neuroscientists and clinicians are particularly strong. It has really been a fantastic place for me to do both clinical care and translational research.

What are you currently working on?

I work on monogenetic neuromuscular diseases. This includes genetic peripheral nerve diseases often referred to as Charcot-Marie-Tooth disease, or CMT, named after two French neurologists and one British neurologist. CMT is the most common inherited neurological disorder and is genetically heterogenous. It causes progressive degeneration of the peripheral nerves and results in progressive weakness of the extremities, making it difficult to walk and to do such things as write, type and grasp. Currently, there is no disease modifying therapy for any form of CMT.

The other major disease I have focused on is a genetic motor neuron disease called spinal muscular atrophy (SMA), traditionally the leading inherited cause of infant mortality. SMA is caused by recessive mutations of the survival motor neuron 1 gene (SMN1). Our laboratory work contributed to the scientific rationale underlying SMN augmentation for SMA. Taking advantage of progress in gene targeting therapeutic strategies, the field now has three FDA (Food and Drug Administration) approved treatments for SMA patients: the antisense oligonucleotide nusinersen, the small molecule risdiplam and the gene therapy onasemnogene abeparvovec.  This is a huge step forward and represents a paradigm-shifting example of how one can treat a genetic neurological disease. At Hopkins, Thomas Crawford and I co-direct an SMA focused clinic, where we provide expert care and provide these novel therapeutics to our patients. Tom sees most of the children, and I see adults. What we’re observing is if we give these treatments very early in life, there are substantial benefits, but when given later, effects are much more modest. There is much work to do to try to understand why the treatment effects are not better in older patients. Is SMN drug distribution and SMN induction ideal? What are the relative contributions of neurodevelopmental and degenerative events? Can drugs be combined? These ongoing questions highlight the need for ongoing “reverse translational” research in SMA.

Peripheral neuropathies are incredibly frequent, but relatively understudied. The percentage of the NIH budget that goes to peripheral neuropathy research is tiny relative to the burden of disease. Peripheral neuropathies can be acquired or genetic in origin. The most common acquired neuropathy in the world is the neuropathy associated with diabetes. Patients with diabetic neuropathy experience sensory loss in the distal limbs and, later, weakness. CMTs are genetic disorders, they affect one in 2,500 people, and they tend to affect motor nerves more than sensory nerves.

We have a large group of clinical and research experts here at Johns Hopkins who focus on peripheral neuropathy. It is a disease area that has been a historical strength of Johns Hopkins and part of what brought me here in the first place. We care for patients in our neuromuscular clinics, where we also engage in multicenter natural history studies and pursue clinical trials in different forms of neuropathy. In addition, several laboratories are focused on understanding the basic mechanisms that drive peripheral nerve degeneration as well as mechanisms that might enable peripheral nerve regeneration. Augustus Waller taught us in 1850 that peripheral nerves have some intrinsic capacity to regenerate, yet we still lack any therapeutic strategies that can promote this process. A colleague, Akhmet Hoke, in our division, does a lot of work on nerve regeneration, trying to enable nerves to grow back after an injury.

As someone interested particularly in genetic neuropathies, my hope is to develop therapies that target the most proximal genetic cause of the disease. My laboratory is particularly focused on a form of genetic peripheral nerve diseases caused by mutations of a cell surface expressed cation channel called TRPV4 (transient receptor potential vanilloid 4). Patients with this form of neuropathy experience limb weakness, but also have particular weakness and impaired opening of the vocal fold muscles. This can cause difficulty speaking, stridor and at times inability to breath. We discovered that dominant missense mutations of this channel cause CMT2C and distal SMA back in 2010. In laboratory-based work, we demonstrated that the mutations cause the channel to be overactive, and this results in increased calcium influx into the cell. Importantly, this excessive activity can be blocked with a small molecule TRPV4 (transient receptor potential cation channel subfamily V member 4) antagonist. In both fly and mouse models of disease, we have shown that a TRPV4 antagonist can significantly improve disease features. Previously, a TRPV4 antagonist was shown to be safe in clinical trials for other disease indications. Our hope is that TRPV4 antagonists could improve disease symptoms in patients harboring TRPV4 mutations.

How and why did you choose this subject matter?

First, my dad was an academic neurologist and a neuromuscular specialist in particular, so I was influenced from an early age. The reason I’ve always been interested in neurology and in particular neuromuscular disease is that I always wanted to work on diseases in which a treatment breakthrough could represent a substantial lessening of disability for patients.

I was always compelled by diseases that were severe, and I want to help those who suffer with them. I also felt that neuromuscular diseases might be more therapeutically tractable, and that’s turned out to be true — so far. Genetic therapies are exploding for neuromuscular diseases. The neuromuscular system is a little bit more accessible, and thus easier to evaluate.

In terms of genetic disease, I was also very interested in how an abnormality of a single molecule translates to disease manifestations in a whole person. Furthermore, genetics provides a definitive answer to how the disease started as well as the opportunity to tackle this most proximal cause. This tractability was exciting.

How has Johns Hopkins Technology Ventures helped you with your work and translation?

JHTV has been enormously helpful in two principal ways. One, they have helped us with intellectual property for the research tools that we’ve created. Second, they have facilitated research partnerships that we have had with companies interested in TRPV4 antagonists. We were initially working with GSK (Glaxo Smith Kline), who had previously developed a TRPV4 antagonist, but we are now partnering with a new biotechnology company called Actio Biosciences, who has developed a novel TRPV4 antagonist, which they aim to take to clinical trial in CMT patients.

With JHTV’s help, we have ongoing sponsored research agreements with Actio and worked very closely with them to perform preclinical studies of their compound in our mutant mice. In addition, with funding support from Actio and the nonprofit foundation the Muscular Dystrophy Association, we are performing dedicated natural history studies of patients with TRPV4 mutations in order to better define the clinical features of the disease and determine optimal clinical outcome measures that might be used during a clinical trial. We hope to be in clinical trial within the next few years, and outcome measures will likely include motor functional outcome measures that focus on limb strength, but also speech and vocal fold outcome measures, which are particularly relevant to this disease population.

How has being a woman in your field created challenges or opened unexpected doors? Were there other women who helped you along the way?

As I’ve become more senior, I do notice the scarcity of female physician-scientists more than I did. Within my own department, until recently, I was the only woman running a basic research laboratory and actively caring for patients. However, I have found remarkable women in multiple other departments, who are pursuing similar careers. It’s been gratifying to find a community that shares the experiences and perspective of being a woman physician-scientist.

I am concerned that we are losing physician-scientists. There may be a perception among trainees that it’s too hard a path and it’s not a lifestyle that that they want to pursue. To me, that’s really worrisome, particularly for translational medicine. We are in a remarkable era right now with cell and gene therapeutics. There is going to be an explosion of new medicines, but these are complicated new medicines, and we desperately need physicians who understand the science of these new treatments. I believe that we have to keep encouraging others to take this path, and in particular, encourage women to take this path. Most of my own mentors along the way have been men, but their guidance and support were critical. Mentorship remains the key to developing this career path. I take this responsibility very seriously and take joy in mentoring men and women at many levels of training.