Could She Develop a Breakthrough Treatment for Multiple Sclerosis?
WHY YOU SHOULD CARE
Because she’s fighting a disease affecting millions of people.
Neuroscientist Dr. Su Metcalfe comes off as unassuming. She speaks softly and has a reserved demeanor. But an intensity pulses below the composed surface. Metcalfe is developing nanoparticles to treat multiple sclerosis by reprogramming the body’s immune system without the side effects of costly prescription drugs. She tells OZY that study findings showing their promise are “as clear as day.”
Multiple sclerosis (MS), a neurological disease that affects an estimated 2.3 million people, occurs when the immune system attacks the myelin sheath, the protective coating that encases nerve cells, triggering symptoms such as vision problems, poor balance and muscle spasms. Current treatments typically kill all immune cells, which prevents them from ravaging myelin but also leaves the body vulnerable to infection. Metcalfe’s nanoparticles deliver a growth factor, LIF, directly and specifically to sites of nerve damage, which keeps the immune system from attacking myelin — and doesn’t kill off immune cells, allowing them to mobilize against harmful invaders when needed. What’s more, LIF can actually help repair damaged myelin.
Metcalfe launched LIFNano, a company to develop her proposed MS treatment, in 2013. She recently received a prestigious global funding award from Merck Serono and, using mouse models of MS, has proven for the first time that LIF-containing nanoparticles are potent in protecting the brain. A clinical trial is set for 2020.
Today’s MS drugs work mainly by tightening the leash on the immune system. In theory, Metcalfe’s technology would start there but would also take it a step further by stimulating the repair of damaged myelin. If it holds up in clinical trials, “that would be a really significant addition to the treatments we have,” says Bruce Bebo, executive vice president of research at the National Multiple Sclerosis Society. And unlike injections or pills that bathe the bloodstream and nervous system in medication, nanoparticles can deliver high concentrations of a drug precisely where it’s needed, so patients would need only small doses, explains Walter Royal III, director of the Maryland Center for Multiple Sclerosis Treatment and Research at the University of Maryland Medical Center. Another benefit? A more targeted approach means fewer side effects.
Using mice engineered to model MS, they showed that the nanoparticles induced the stem cells to mature into healthy myelin.
To be sure, Metcalfe, senior research associate at the University of Cambridge in England, has yet to test her technology in human clinical trials. “It’s a lot of theory at this point,” Bebo says. Royal agrees — “It’s showing a great deal of promise, but there’s a lot of work that needs to be done before it can be made available for treating patients” — and notes that it may benefit only a subset of them.
Metcalfe has a thin, serious mouth and milky blue eyes. Her father walked out when she was born, leaving her mother to raise Su and her two siblings in a dirt-floored fisherman’s cottage near a harbor in Yorkshire, England. Living close to the sea sparked Metcalfe’s curiosity about the natural world. She earned bachelor’s degrees in zoology from the University of London and pathology from Cambridge, where she later earned her Ph.D. — also in pathology – and completed a postdoc.
At Cambridge, Metcalfe discovered a crucial “master switch” in immune cells called T lymphocytes. Her team observed that LIF flips the switch to the “TOLERANCE” setting in response to the body’s own cells. This causes the T lymphocytes to mature into Treg cells, which suppress autoimmune attack. In contrast, another protein, IL-6, flips the switch to “AGGRESSION” in response to harmful foreign invaders, causing the T lymphocytes to mature into Th17 cells, which then mount an immune attack.
Normally, this dynamic balance keeps the immune system from attacking the body’s own cells in a highly specific manner but enables it to kick it into gear against foreign invaders if necessary. But with MS, that balance gets thrown off-kilter: IL-6 levels remain high and LIF levels low, enabling rogue Th17 cells that specifically target myelin to develop. The master switch fails, allowing an attack against the body’s own myelin.
Maybe LIF could restore and maintain that balance, Metcalfe thought. In fact, LIF could pack a double whammy by activating brain stem cells to mature into myelin cells that could replace the damaged myelin. Except for one problem: The body breaks down LIF after just 20 minutes in the circulating blood – not enough time for its effects to take hold.
Metcalfe had an idea: Why not protect LIF by encapsulating it in a nanoparticle? She loaded LIF into nanoparticles made from the same material as dissolvable stitches and coated with antibodies that latch onto a protein found on the surface of T lymphocytes. This way, the nanoparticles would target only the cells responsible for myelin damage, sans side effects. Sure enough, in mice, she found that they prevented IL-6 from driving T lymphocytes to become Th17 cells. These T lymphocytes instead developed into Tregs, flipping the switch to “TOLERANCE.” The same LIF/IL-6 switch has been found in MS patients, where LIF also drives T lymphocytes to become Tregs.
Later, Metcalfe and colleagues coated LIF-loaded nanoparticles with antibodies that bind to proteins located on a type of stem cell found in the brain and spinal cord. Indeed, using mice engineered to model MS, they showed that the nanoparticles induced the stem cells to mature into healthy myelin, repairing the damaged myelin.
Some see Metcalfe’s work as controversial: They question her “master switch” theory, believing that LIF and IL-6 are one and the same in their actions. Another of her challenges is starting up a biotech business — new territory for her, says Florian Kemmerich, board chair of LIFNano. But, he adds, “She is an incredibly perseverant person,” and her approach is “a mix of very soft and subtle … with an enormous strength.”
It’s a mix that could lead her on a path to cures for other autoimmune diseases, like psoriasis, and even neurodegenerative diseases including Alzheimer’s. Like her nanotechnology, sometimes inconspicuous packages can hold stunning surprises.