For Ami Mankodi, M.D., it was love at first sight. When she was in the fourth grade in Mumbai, India, she remembers seeing a picture of a brain in a book and knowing then that she wanted to be “a brain doctor,” not yet aware of the word “neurologist.”

"I looked at the organ, and I said, ‘Mommy, I want to become this doctor,’" said Dr. Mankodi. "Something struck, and there was no other option in my life."

Now a principal investigator at the National Institutes of Health’s (NIH) National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Maryland, Dr. Mankodi has been involved in research that has helped shape a fundamental biologic and molecular understanding of myotonic dystrophy (DM).

Dr. Mankodi has participated in important advances in understanding critical questions about myotonic dystrophy, and these advances have pointed the way toward therapeutic approaches to treating the disease. But many questions remain unanswered about DM progression and how to best measure the severity and progress of a patient’s individual condition, questions she is working to answer today.

Finding Targets

Dr. Mankodi earned her medical degree from Grant Medical College in Mumbai, India, before performing post-doctoral work in the lab of Dr. Charles Thornton at the University of Rochester. After seven years in Dr. Thornton’s lab, she then completed a neurology residency at Johns Hopkins Hospital. The research she conducted with Dr. Thornton included the creation of a mouse model for myotonic dystrophy type 1 (DM1) and provided evidence that the disease was RNA-mediated. 

The genetic mutation driving myotonic dystrophy causes expression of RNA that contains expanded repeating code in the portion of the RNA not involved in the production of protein. The repeats are associated with both skeletal muscle degeneration and the diminished ability of the brain to communicate with muscles to relax after activity. One thing that Dr. Mankodi and her colleagues discovered was that an effect of these repeats was to reduce the number of chloride channels on the muscles. These channels are needed to receive electrical impulses that instruct muscles to relax and restore to a normal state after they have been constricted for activity. In simple terms, it is why someone who has myotonic dystrophy may find it difficult to open their hands after grasping an object, relax their jaw or tongue, or experience other muscle cramping symptoms of myotonia. 

The good news, according to Dr. Mankodi, is that it points the way to a therapeutic approach because it suggests researchers may be able to restore normal function with drugs designed to bypass errors in RNA, such as so-called antisense therapies that are in development today. 

“We didn’t even know 25 years ago where the gene defect was, and that was 100 years after the first clinical description,” Dr. Mankodi said. “In the last 25 years since gene discovery, we have come a long way to understanding the disease mechanism.”

Unanswered Questions

Despite advances that Dr. Mankodi and other researchers have made in the understanding of myotonic dystrophy, much remains unknown about the disease. A component of Dr. Mankodi’s research today is aimed at understanding how the disease progresses. Because there is wide variation in the severity of symptoms, the constellation of symptoms any one patient will develop, and the rate of progression of the disease, such an understanding is critical to improving treatments and developing therapies. A better understanding of the disease will help researchers establish meaningful endpoints to assess the effectiveness of potential therapies in clinical trials, and consistent ways to measure improvement or decline in those living with the disease. 

In 2011, MDF awarded funding to establish the first-ever Myotonic Dystrophy Clinical Research Network (DMCRN), research infrastructure co-led by Drs. Charles Thornton and Richard Moxley, III of the University of Rochester. The DMCRN was originally located at five academic institutions around the U.S. and was created in part to prepare standardized trial sites for potential therapeutics working their way toward human clinical trials. NIH is one of now eight medical centers participating in the network and Dr. Mankodi serves as a primary investigator. Her work there focuses on developing tools to measure the severity and progression of the disease. 

“We need to develop more tools and more community effort,” said Dr. Mankodi. “We are, as part of the clinical research network, trying to define the disease status, the disease burden, the disease progression and trying to identify reliable outcome measures that can be applied to therapeutic trials. Efforts are being made in this direction.”

As an example, Dr. Mankodi points to a recently-concluded study at six of the DMCRN sites to see how consistent measurements are in the same patient between three-month time points and between two sites. A new 500-patient study will launch this summer that will gather disease progression and other natural history information, as well as seek to identify genetic modifiers that scientists believe partially control the disease severity patients experience.

Dr. Mankodi is also working to develop tools to measure muscle strength and muscle relaxation time in the hands. At first, she and her team tried to do this with a glove but found it wasn’t a reliable approach because of different hand sizes. In a new tool, markers are placed on the hand and read by a computer using laser trackers. She said they have already developed such a device for the ankle. Dr. Mankodi and her team are also working to develop clinical and imaging biomarkers of pulmonary function. Through the DMCRN, they collected tissue and blood samples in one study to look at biomarkers over the course of time. More than 100 patients were enrolled in that study. 

But even with the unknowns, researchers are trying to decipher, Dr. Mankodi is optimistic about the potential of developing therapies to treat myotonic dystrophy. To get there, though, she believes collaboration will be critical. 

"We are still at very early stages, but the momentum is increasing and driving interest," she said. "It’s going to involve patients and patient support organizations like MDF, the [pharmaceutical] industry, researchers, and regulators. These are the key components, and we need to bring the pieces of the puzzle together. It’s community-wide action that will be needed, and that is exactly what’s forming the basis of the Myotonic Dystrophy Clinical Research Network. The steps are being taken."

Dr. Mankodi will speak at IDMC-11 in September 2017 at the upcoming biennial global conference of approximately 400 DM researchers. The International DM Consortium meeting brings together scientists, clinicians, associations and patients to accelerate clinical and fundamental myotonic dystrophy research. IDMC-11 will occur this year in conjunction with the 2017 MDF Annual Conference. Both events will be held in San Francisco, California.