The Middletown Press (Middletown, CT)
Seeking a cure for MS
Yale, Cambridge scientists hopeful about process they discovered
NEW HAVEN » Scientists from Yale University and the University of Cambridge in England have teamed up to develop a potential cure for multiple sclerosis.
It’s the first treatment that addresses the disease by disarming the immune cells that have turned against the body’s nerve cells, rather than simply suppressing them. An autoimmune disease, MS begins when parts of the body’s immune system, rather than fighting off disease, begin to attack healthy cells.
Su Metcalfe, senior research associate in the University of Cambridge Clinical School, discovered the molecular process that stops the attack on the protective myelin sheath around nerves in the brain and central nervous system. It’s that destruction of myelin that causes MS.
Tarek Fahmy, associate professor of biomedical engineering and of immunobiology in the Yale School of Engineering and Applied Science,
created the delivery system that brings Metcalfe’s treatment to the site of the disease.
Multiple sclerosis is a devastating disease that can attack people as young as 30, slowly reducing their brain volume, Metcalfe said. “They’re looking forward to 40 years of slowly getting worse,” she said. “It’s a horrible disease and it costs the global economy $100 billion a year.”
According to the National Multiple Sclerosis Society, there are more than 2.3 million cases worldwide, but the society doesn’t provide an estimate of U.S. cases because doctors are not required to report new cases. There are a wide variety of symptoms, including fatigue, numbness and tingling muscles, slurred speech, walking difficulties and muscle spasms.
Among the cells in the immune system are T lymphocytes, or T cells. One of their functions is to produce molecules called cytokines, which “specialize in alerting immune system cells to infection, cancer or any foreign intrusion in the body,” Fahmy said. The immune cells then rush to the site to fight the disease, he said.
However, T cells can go awry and turn from fighting disease to attacking the body’s own cells. “In these disease states the T cells make an error whose root cause is still an enigma to scientists and clinicians,” Fahmy said. “If this happens, then these malfunctioned T cells will produce cytokines that bring in more T cells to the site and the illness cascade of events begins.”
He said the same process also is involved in other autoimmune diseases, such as type 1 diabetes and lupus.
Metcalfe said that in 2005 she discovered that another cytokine, called leukemia inhibitory factor, or LIF, “regulates the immune response to stop autoimmune attack.” The molecule controls a switch that turns the T cells from destroyers to protectors. The way LIF acts on T cells “was a critical discovery,” she said.
“That was a world first, and we discovered that there’s a binary switch in the cell so the cell can either become tolerant or aggressive and that switch is operated by LIF,” Metcalfe said.
“LIF comes in and cuts off the signal that calls in more T cells,” Fahmy said.
The challenge to getting LIF to the diseased site was that it is a short-lived molecule. “It breaks down within 20 minutes,” Metcalfe said. So a way had to be found to deliver it to the T cells. That’s where Fahmy’s engineering expertise came in.
Fahmy confronted two issues in addition to LIF’s delicate nature. One is to avoid having LIF turn off the immune properties of cells throughout the body, the way chemotherapy attacks both healthy and cancerous cells. “It has to be targeted to those areas and it has to be a long-lasting signal as well,” Fahmy said.
“A third factor is we need a high concentration of LIF in that area,” he said. “The question then becomes, how do you get a high amount of nullifying molecules to the area that’s affected and to have those LIF molecules sustained over a long period of time.”
Fahmy’s solution was to create a nanoparticle, one ten-thousandth the width of a human hair follicle (100 to 200 nanometers), which carries the LIF molecules to the T cell like a truck carrying cargo. He used the same material used in soluble stitches and coated it with a protein that “only binds to those immune cells that are attacking” the rogue T cells. Then, the nanoparticle was loaded with LIF molecules and freeze-dried.
“When they’re exposed to water again, they start degrading and as they degrade they release the … LIF,” Fahmy said. “So it’s like a new drug, except it’s using older materials, combining them together. … I’m very hopeful that this is going to work like how natural processes in the body work.”
Fahmy said the nanoparticle delivery method is important because, “given alone by itself, this drug LIF is a very toxic drug if administered to people without a delivery apparatus.” Using the nanoparticle, the amount of LIF that needs to be delivered is “10,000-fold lower” than if it were given directly.
Metcalfe and Fahmy have formed a company called LIFNano, which will bring their treatment to clinical trials by 2020. “I’m committed,” Metcalfe said. “I’ve given my whole career, switched it over to treat patients.
“I’ve just received 1 million pounds from the U.K. government to do pre-clinical, pre-regulatory work. Part of that million pounds is going to Yale. So Yale remains very closely involved alongside and we’re continuing this synergistic value in taking this nanomedicine approach to treat patients,” she said.
Metcalfe and Fahmy hope their therapy, treating the cells with a naturally occurring molecule, will eventually replace the standard treatment of giving immune-suppressant drugs, which carry their own risks.
“This really is a whole new field of study that we call immune-engineering, and it promises to change how therapy will happen for cancer and autoimmune diseases,” Fahmy said.
“There’s nothing specific controlling the root cause of disease, which is what we’re doing, and in addition we’re repairing the myelin and protecting the nerves and there’s nothing out there today that protects the nerves,” Metcalfe said.
She said she has been at Cambridge her whole career “and working to understand what controls lymphocytes and I found LIF. It’s been a long journey.”
“There’s nothing specific controlling the root cause of disease, which is what we’re doing, and in addition we’re repairing the myelin and protecting the nerves and there’s nothing out there today that protects the nerves.” — Su Metcalfe