Could we be on the cusp of a cure for multiple sclerosis? If LIFNano, a Cambridge company, is successful, the prospect might be more than just wishful thinking.
The company’s technology, which relies on nanoparticles, is currently at the pre-clinical stage and has not yet been tested in humans. However, with two major funding awards in place – one from Merck and the other from the UK Government – the therapy could begin clinical trials as soon as 2020.
“Our goal is to deliver LIFNano as a precision medicine with unique curative potential at the root cause of multiple sclerosis, rather than dealing with the symptoms,” says Dr Su Metcalfe, the company’s founder. “By harnessing the body’s own power to heal the brain, we aim to meet the most urgent need in MS treatment.”
The hunt for a cure
MS is a disabling autoimmune neurological condition, commonly beginning in young adulthood. It affects around 2.5 million worldwide, with around 100,000 cases in Britain alone and a further 50 people diagnosed every week. In Scotland’s Orkney Islands, which has the highest incidence globally, the condition afflicts as many as 1 in every 170 women.
While the symptoms vary widely from person to person, they commonly include fatigue, difficulty walking, numbness or tingling, or muscle stiffness and spasms. The disease either takes the form of a progressive illness, or assumes a ‘relapsing-remitting’ course. In every instance, the disease occurs when the body mounts an autoimmune attack against the brain and spinal cord.
“Specifically the autoimmune attack is against the myelin sheath that normally insulates the electrical activity of nerve fibres,” says Metcalfe. “This underlies the cause of MS, where loss of myelin in turn leads to a wide range of symptoms as specific nerves become inflamed and lose function.”
At present, MS has no cure. While a range of therapies can prove helpful, these drugs only manage the condition – e.g. by returning function after an attack – rather than addressing its root causes. Even with careful management, the prognosis is still fairly bleak: sufferers have a reduced life expectancy and most eventually lose the ability to walk.
“Treatment aims to suppress the immune system, concomitantly suppressing the attack against myelin, using drugs,” explains Metcalfe. “These succeed in modifying the disease progression but many have unwanted side effects, in addition to leaving the patient at risk of infection.”
She adds that many patients remain untreated due to the high cost of MS treatments – especially in low economy countries. And while new experimental therapies, using stem cells, are being trialled, these are high cost, high risk, and far from simple.
“The most urgent need is for a treatment that protects the brain,” says Metcalfe.
Flipping the switch
Metcalfe’s idea for such a treatment took shape while she was working at the Cambridge University department of surgery. She had been looking to find out what controls the immune response, and stops it auto-attacking healthy people.
“We know MS is caused by an error in a small population of highly specific immune cells called T lymphocytes – these cells normally protect the brain,” she says. “When the error occurs, the cells become switched into attack mode. So, I reasoned – we need to understand what goes wrong. Why does the cell flip from a protective ‘friend’ to an aggressive ‘foe’?”
She discovered a small binary switch that operates the ‘friend’ and ‘foe’ settings. A protein called Leukaemia Inhibitory Factor (LIF) controls this switch, holding it on for ‘friend’.
“LIF is a small natural signalling protein that acts on stem and precursor cells in the body,” she explains. “It is able to activate these cells in order to replace damaged cells during tissue repair – for example repair of a torn muscle. A further key role of LIF is to sustain a healthy central nervous system, protecting nerves and maintaining myelin.”
LIF, she inferred, might be an important candidate for treating MS patients. It would provide a double whammy for treatment – resetting self-tolerance and protecting the brain.
Unfortunately, she soon ran into a problem: namely that LIF breaks down in the body within ten minutes. This doesn’t leave long enough for any therapeutic effects to take place.
The solution, she realised, was nanoparticles. Through encapsulating LIF protein inside very tiny particles, able to deliver the protein to the requisite parts of the brain, it would be possible to overcome the issues associated with its short half-life.
“The nanoparticles gradually dissolve, ending up as carbon dioxide and water,” she says. “In fact the particle material is the same as that in soluble stitches used to close surgical operations. Like stitches, they do their job – release LIF at the target site – then disappear.”
Passage to the clinic
Following Metcalfe’s discovery, the LIFNano platform technology has been engineered by teams at the University of Cambridge and Yale University. Already, the first LIFNano product has been developed, and has been proven safe and effective for animal models of MS. Its flexible design allows delivery of LIF to specific sites of disease, across the blood-brain barrier.
Since it is not a drug, it lacks the side effects associated with other MS therapies. It simply flips the switch for the body’s own repair system, switching it out of ‘foe’ mode and resetting the balance.
What is more, because the platform technology has already featured in successful Phase II trials, the product has a high chance of making it to the clinic.
“Our development of LIFNano to treat MS is greatly de-risked for eventual FDA approval,” says Metcalfe. “To move forward to the clinic as quickly as possible we have identified a team of highly skilled specialists who are able to manufacture the clinical grade LIFNano particles, bringing a world-leading technology able to tap into the body’s own ability to protect and repair itself.”
Ultimately, the team hopes to be able to deliver LIFNano as a precision medicine with unique curative potential for MS. And while the drug will most likely be beneficial in its own right, it should also prove a useful supplement to patients’ existing treatment regimens.
The approach has been lauded by the scientific community: it was named by the European Nanomedicine Community’s Translational Advisory Board as one of the most exciting technologies currently in development, and has won a number of different academic and industrial competitive awards.
The company is now hoping to attract more investment, with a view to beginning human clinical trials within the next three years. Although she concedes a 2020 start date is ambitious, Metcalfe says the area is attracting strong interest from big pharma.
“By harnessing the body’s own power to heal the brain, we aim to meet the most urgent need in treatment of MS,” she says. “The technology could profoundly improve therapeutic outcomes, reduce costs, and increase safety, as well as being scalable and universally applicable to meet the global market demand.”
Should this go according to plan, it would amount to nothing less than a step-change in medicine.