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A fluorescence light micrograph of human neural stem cells. Credit: Cell Applications Inc / Science Photo Library.

Researchers in Milan showed that neural stem cells can be administered to patients with progressive multiple sclerosis with no toxicity or adverse events, a key step towards a potential new treatment intended to slow the evolution of the disease. The results of the phase 1 clinical trial appeared in Nature Medicine1.

Multiple sclerosis is an inflammatory neurodegenerative condition that affects about 3 million people in the world. It typically emerges in people between 20 and 30 years of age. Its causes are still unknown, but experts think that genetic and environmental factors can trigger the disease. The patient’s immune system is misled into attacking the brain and spinal cord, causing inflammation and disrupting the myelin sheath that surrounds nerve fibres, impairing the transmission of signals between neurons.

About 85% of multiple sclerosis patients experience autoimmune flare-ups followed by partial or total recovery, the so-called relapsing-remitting disease course. In the initial phase, symptoms come and go, but eventually inflammation causes the degeneration of the nerve fibres leading to permanent disability. In a smaller group of people, multiple sclerosis has a progressive course, with symptoms and disability gradually worsening.

Over the last 20 years a number of drugs have been developed for relapsing-remitting multiple sclerosis. They are monoclonal antibodies that act on immunity and prevent flare-ups. “However, they perform poorly on the persisting subtle inflammation of the central nervous system that is typical of the progressive condition”, says Gianvito Martino, scientific director of IRCCS Ospedale San Raffaele, the study’s senior author.

Martino and colleagues first used animal models to study the behaviour of transplanted neural stem cells, that are undifferentiated cells capable of generating different types of cells in the nervous system. When infused into the cerebrospinal fluid, they reach the damaged areas in the brain and the spinal cord, and they secrete proteins that promote self-repair of the myelin sheath and of the axons, while also reducing inflammation.

A phase 1 clinical trial then started at San Raffaele Hospital in 2017, involving 12 patients with progressive multiple sclerosis. Each of them received a single administration, via lumbar puncture, of neural stem cells derived from a human fetus, in different concentrations to test whether toxicity would appear above a certain dose. “We proved safety and tolerability of the treatment up to the highest dose”, Martino says.

Moreover, three months after the administration, the researchers analysed the cerebrospinal fluid of patients and found it enriched with neuroprotective and immunomodulating proteins. “Two years later we found that the patients treated with the highest dose had suffered a lower loss of grey and white matter, as the disease progressed, compared to the patients treated with the lowest dose”, Martino says.

To prove the efficacy of the treatment, the group is now planning a phase 2 clinical trial, that should start in a couple of years. At the same time, they are exploring the possibility of using autologous stem cells, obtained from the tissues of the patient. This way, they could spare the patient the burden of immunosuppressants necessary to prevent rejection.