Researchers who study multiple sclerosis (MS), a debilitating autoimmune disease in which the body attacks the lining (myelin) of the brain and spinal cord, have spent years seeking a cure. There may be hope on the horizon. A British scientist, Su Metcalfe, formerly of Cambridge University, has made a crucial discovery that offers the first hope of a cure for MS.
This comes as great news to the 2.3 million people around the world who live with MS, which leads to a host of physical and mental side effects including muscle weakness and even blindness.
“Some people get progressive MS, so go straight to the severe form of the disease, but the majority have a relapsing or remitting version,” Metcalfe said.
The disease tends to show after age 30, and at best, treatments can manage symptoms, but cannot repair damage. “All you can do is suppress the immune response, but the drugs that do that have side effects, and you can’t repair the brain. The cost of those drugs is very high, and in the UK there are a lot of people who don’t get treated at all,” Metcalfe said.
Dr. Metcalfe made her discovery while working at the surgery department at Cambridge University. Now, with the new company she formed to pursue this treatment, called LIFNano, she is working toward a solution that will harness the body’s immune system combined with nano-technology, without drugs, to repair the damage to the brain and spinal cord.
What she discovered was “a small binary switch, controlled by a LIF, which regulates inside the immune cell itself. LIF is able to control the cell to ensure it doesn’t attack your own body but then releases the attack when needed.”
LIF, which stands for leukemia inhibitory factor, is a kind of protein, which plays a key role in a variety of biological processes ranging from “inflammatory responses, neuronal development, embryonic implantation, stem cell self-renewal and cancer progression.”
“I was looking to see what controls the immune response and stops it auto-attacking us,” she said. “I wanted to understand something that was so simple on one level but also so complex.”
How does it work?
Metcalfe and her colleagues’ research suggests that LIFNano’s treatment is the result of “a biological switch that allows inflammation to occur when necessary.” LIF counters the inflammatory effects of IL-6, a cytokine that can lead to chronic inflammatory conditions if the switch becomes chronically unbalanced as it does in autoimmune disease.
They believe that a targeted delivery of LIF particles to the body’s own lymphocytes, immune cells, can “restore the natural balance of the cell's binary switch with recovery of normal responsiveness to both LIF and IL-6.”
Even more crucial, when the inflammatory stimuli are reduced, certain lymphocytes will actually release LIF, promoting tissue repair.
Metcalfe has studied immune cells for many years and finds them fascinating. “The immune cell is the only single cell in the body that is its own unity, so it functions alone. It’s probably one of the most powerful cells in the body because it can kill you, and if you haven’t got it you die because you haven’t got it,” Metcalfe said.
The LIF treatment may be as close to a magic bullet as exists so far for MS. “LIF, in addition to regulating and protecting us against attack, also plays a major role in keeping the brain and spinal cord healthy. In fact it plays a major role in tissue repair generally, turning on stem cells that are naturally occurring in the body, making it a natural regenerative medicine, but also plays a big part in repairing the brain when it’s been damaged.”
Metcalfe was thrilled the more she learned about how LIF functions. “So I thought, this is fantastic. We can treat autoimmune disease, and we’ve got something to treat MS, which attacks both the brain and the spinal cord. So you have a double whammy that can stop and reverse the auto-immunity, and also repair the damage caused in the brain.”
Of course, like all good science, trial and error is often involved. She found that LIF didn’t survive outside the cells for very long—only about 20 minutes—before the body breaks it down. The answer to this snag came in the form of nanoparticles.
The nanoparticle nexus
Nanotechnology, in which microscopic particles derived from biodegradable polymers deliver therapies and medicines, is not new. In fact neuromedicine is considered by some the ultimate frontier in medicine, and, Metcalfe found, was the perfect vector to deliver the LIF to waiting cells. Metcalfe’s team used nanoparticles made from “…the same material as soluble stitches, so they’re compatible with the body and they slowly dissolve,” she said. They were developed at Yale University, credited as co-inventor with Metcalfe, but LIFNano has a worldwide license to use them.
“We load the cargo of the LIF into those particles, which become the delivery device that slowly dissolve and deliver the LIF over five days. The nanoparticle itself is a protective environment, and the enzymes that break it down can’t access it. You can also decorate the surface of the particles with antibodies, so it becomes a homing device that can target specific parts of the brain, for example. So you get the right dose, in the right place, and at the right time.”
A future without drugs?
Perhaps the most exciting part of this form of therapy is that it doesn’t use any drugs. “We’re simply switching on the body’s own systems of self-tolerance and repair. There aren’t any side effects because all we’re doing is tipping the balance.” Autoimmunity occurs when that balance she speaks of has gone off in some way. This therapy helps to reset it. “Once you’ve done that, it becomes self-sustaining and you don’t have to keep giving therapy, because the body has its balance back.”
Moreover, LIFNano removes the two key barriers to regenerative medicine where stem cells or tissue grafts are used—there is no immune rejection, or risk of biologic contamination. LIFNano essentially just restores the body's own reparative immunity, which can theoretically reduce or limit the necessity of prescription drugs.
Metcalfe has received initial investments from pharma company Merck and the government’s Innovate UK agency, and hopes to attract more investment, with the aim of starting clinical trials in 2020.
Should they be successful, they hope to branch out to treat other autoimmune diseases, as well.
“MS is our key driver at the moment, but it’s going to be leading through to other major autoimmune disease areas,” she said, adding that psoriasis is high on their list, as is type one diabetes. “Downstream there are all the dementias, because a LIF is a major health factor for the brain. So if we can get it into the brain we can start protecting against dementia."