BOZEMAN — A Montana State University scientist who researches a genetic disorder that leads to blindness and early death is about to take the next step toward offering a solution.
Frances Lefcort, a professor in the Department of Cell Biology and Neuroscience in the MSU College of Letters and Science, said she is now in discussions to develop a clinical trial that will test in humans a compound that has already proven itself in mice.
Lefcort was the principal investigator of a new MSU study that discovered that the compound BGP-15 prevents the death of nerve cells and even restores their function.
The findings hold particular promise for people with Familial dysautonomia (FD), a rare condition that disrupts the development of the peripheral nervous system and causes it and retinas to degenerate. The peripheral nervous system, or PNS, connects the central nervous system to limbs and organs.
Lefcort and her team recently published their findings about BGP-15 in the journal Proceedings of the National Academy of Sciences (PNAS). Lead author was Sarah Ohlen, who earned a doctorate this spring. Ohlen was a graduate student in MSU's Department of Cell Biology and Neuroscience in the College of Letters and Science.
"I'm very excited that these data are published in PNAS and for the potential now for clinical trials," Ohlen said. "Many events have come together during this project with the help of many people. It's exciting and humbling.”
"I realize how rare it is to work on a project that may directly and within a short time period translate to treatment," Ohlen continued. "That aspect kept me pushing forward with this project more than anything else. It felt important to keep going."
Co-authors on the paper were Letters and Science Distinguished Professor Lefcort; Magdalena (Maggie) Russell, an undergraduate student who in April was named a recipient of the prestigious Goldwater Scholarship; and Michael Brownstein, who worked for the National Institutes of Health and now the Dysautonomia Foundation.
"When I first started working in the lab, I had never heard of FD," said Russell, a junior in cell biology and neuroscience. "However, the more time I have spent researching this disease, the more fascinating it has become. It is particularly exciting to be able to draw similarities between FD and more common neurodegenerative diseases such as Alzheimer's, Parkinson's and ALS."
Lefcort said two of her cousins died from FD, which has been a motivating force behind her research. Because of a mutation to a single gene, her cousins had a hard time getting out of bed in the morning. They couldn't move easily from the horizontal to vertical because their bodies couldn't regulate their blood pressure and respiration rates.
The cousins also vomited often. They had trouble walking. One cousin almost severed a finger but it didn't hurt. The ability to feel pain and temperature is highly diminished in people with FD, Lefcort said. The same cousin, who lived into his 50s, eventually became blind. His sister died at age 27.
Lefcort said she learned about the compound that might have helped her cousins during a meeting of the Dysautonomia Foundation where she spoke about her previous findings. Brownstein was in the audience and heard Lefcort mention that the cells of people with FD are stressed. He later told Lefcort that BGP-15 had relieved cellular stress in people with Type 2 diabetes. He suggested she investigate its potential for FD.
Lefcort acquired the compound, which is made by N-Gene Inc. in New York. Her students -- Ohlen and Russell -- then tested it in the lab.
"Experimentally, my biggest challenge at the bench was working with a neuronal population (from our FD mouse model) that was limited in number and also sick," Ohlen said. "With few neurons to work with, every step of each experiment had to be sometimes painstakingly planned out and always carefully executed.
"There were also very long hours spent on the microscope examining behavior of these stressed neurons individually and their intracellular processes," Ohlen said.
Those long hours eventually led to the PNAS paper and current discussions about a clinical trial. Russell said her involvement and the "wonderful" mentoring she received from Lefcort and Ohlen also contributed to her winning the Goldwater Scholarship.
"Without their constant support, I would never have been able to even apply for the Goldwater Scholarship -- let alone receive it," Russell said.
She added that "The BGP-15 project was one of the first projects I was involved with when I joined the lab. I was able to learn many new techniques through this work that will prove useful as I continue my research. I am very grateful to have made contributions to this exciting project."
Lefcort said the recent study was a translational study, meaning that it was designed to bridge the gap between basic research and the clinical treatment of patients. She is now in discussions with the Dysautonomia Foundation about developing a clinical trial for BGP-15 as it relates to FD. Since she will be on sabbatical this fall at the Dysautonomia Clinic at New York University Langone Medical Center, and the Dysautonomia Foundation is located in New York City, she said it will be a convenient time and place to design the trial.
"The (Dysautonomia) Foundation is the hub for planning clinical trials for patients with the disease," Lefcort said.
Lefcort added that she doesn't know when the trials will begin, how long they will take or what the outcome will be, but they are a next step toward being able to offer a solution to people with FD.
Lefcort's study was funded by a five-year, $1.5 million grant from the National Institute of Neurological Disorders and Stroke and by a $60,000 grant from the Dysautonomia Foundation. Her recently published paper was her second in PNAS and her 38th article in a peer-reviewed scientific journal.
As for Ohlen, she said she will continue working for Lefcort this summer.
"Now that we know more about the cellular events that could potentially be targeted in these sick neurons to improve their survival, we may begin testing other compounds," Ohlen said. "As for what's next, I value and am eager about science communication and teaching, but executing experiments is an amazing process. I will be working this summer to explore my options."
Contact: Frances Lefcort, (406) 994-5656 or firstname.lastname@example.org