Multiple sclerosis: how could gene and cell therapy help?

Over 400,000 people in Europe have multiple sclerosis (MS). It can cause blurred vision, extreme fatigue, pain, numbness, loss of movement, and balance problems. There are generally three main disease courses: relapsing-remitting MS, secondary progressive MS and primary progressive MS. MS is the most common disease-causing disability in young adults. There is currently no cure. Scientists are investigating whether stem cell and gene therapy techniques can be used to support people living with MS.

What do we know?

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system.

In MS, the immune system attacks the coating covering nerve cells (myelin sheaths). Myelin sheaths insulate and protect nerve cells. Without them, nerve cells cannot send signals around the body correctly. They also undergo nerve damage. This leads to the symptoms of MS.

MS is typically categorised as either:

relapsing-remitting MS (marked by periods of severe symptoms and inflammation, followed by periods of recovery)
Secondary progressive MS (which follows on from relapsing-remitting MS; the ‘recovery’ periods stop, and the disease gets progressively worse)
Primary progressive MS (a form of MS which gets progressively worse, without recovery periods, from the start).

There are currently no treatments to reverse nerve damage and neurodegeneration in MS.

What are researchers working on?

Some studies use chemotherapy to remove the stem cells creating an overactive immune system. Patients then receive an infusion of blood stem cells, to build a new immune system which will not attack myelin. This strategy, named haematopoietic stem cell transplantation, has had positive results in clinical trials. It now available as a treatment for patients with aggressive relapsing-remitting MS. However, its efficacy in progressive MS is limited.

Researchers are working to develop treatments and drugs which will be effective for progressive MS.

Researchers are investigating whether neural stem cells could be used to treat progressive MS. Neural stem cells could help in two ways:

Replacing myelin and repairing damaged neurons.
Releasing molecules which protect the nervous tissue from damage, and dampen the overactive immune response.

What are the challenges?

The main challenge to developing MS treatments is the wide range of patient experiences and symptoms. The trigger and the mechanisms causing the disease and the symptoms can be very different between patients. While strategies for managing relapsing-remitting MS have improved, the treatment of progressive MS still represents an unmet need. While stem cell-based therapies have shown promise in early trials, more trials are needed to determine how effective they are in larger patient groups.

Introduction to multiple sclerosis (MS)

Multiple sclerosis (MS) is a disease that affects myelinated nerve cells in the brain and spinal cord. In the healthy body, myelin forms a protective sheath around nerve cells. This sheath acts like an insulator around a wire, allowing the cell to carry signals between the brain and the rest of the body. In MS, the body’s own immune system attacks the myelin, meaning that nerve cells cannot function properly.

Depending on which nerves are damaged, patients can experience a range of symptoms. Common symptoms include issues with walking, balance, and sensation, ‘cognitive fog’, and fatigue. In the earlier stages of MS, these symptoms can appear for a time (known as a relapse) and then improve (remission). This phase of the disease is called relapsing-remitting MS. Patients may find that their symptoms improve dramatically during remission, as the body repairs damaged myelin. As a person with MS ages, full remission becomes less frequent. Over time, the nerve cells are damaged and begin to degenerate. Eventually they stop working entirely. As the disease progresses, more nerve cells are affected, causing increasing disability (secondary progressive MS). A small proportion of patients develop a progressive MS at the disease’s onset, without experiencing remission (primary progressive MS).

The MS Society (UK) has information about the different types of MS here.

Current treatments

There is currently no cure for MS. Currently available treatments are referred to as ‘disease-modifying therapies’ (DMTs). Treatments focus on managing symptoms, and taking steps to prevent relapse and inflammation

There are two strands of treatment for relapsing-remitting MS:

Managing symptoms. This can include physiotherapy and lifestyle changes.
Preventing relapses and inflammation using disease-modifying therapies, such as medication or stem cell therapies.

In treating progressive MS, several treatments can be used to slow down disease progression. Symptomatic treatments, exercise and physiotherapy aim to help patients cope with symptoms. However, there is no treatment which will repair damage to the nerves after it has occurred. Researchers hope that stem cell therapies may provide new approaches which will both prevent damage, and reverse damage which has already occurred.

How might gene and cell therapy help?

Stem cells are part of the body’s normal repair system – making new cells to replace those that get damaged or die. There are several different types of stem cells. Scientists are investigating a number of ways they might be used to develop new treatments for multiple sclerosis:

Preventing damage: It is possible to use certain types of stem cells to ‘reset’ the immune system (known as immunomodulation). The aim is to prevent the immune system from attacking the nerve cells, or reduce the amount of damage done .
Repairing damage: Stem cells may be able to help repair the damaged myelin sheath, ‘remyelinating’ the nerves and allowing them to function correctly again. This could prevent the nerves themselves from degenerating. In the distant future, researchers hope that stem cells might be used to re-grow nerves that have been lost. However, this is a much more complicated process which would take years of research.
Developing new medicines: stem cells can be used to grow nerve-like cells in the lab. These cells can be used as a ‘model’ to study how MS works, and to test potential new drugs.

The various approaches all offer different advantages, and may be useful for treating different types or stages of MS.

Current research

Blood stem cells

Blood stem cells are found in the bone marrow. They differentiate in different types of immune cells, involved in causing the damage in MS.

MS patients have been given transplants of their own blood stem cells in an attempt to ‘reset’ the immune system. Blood stem cells are collected from the patient’s bone marrow. The patient’s existing immune cells are then killed using chemotherapy (treatment with powerful medicine). The patient’s blood stem cells are then injected into the blood stream, with the aim of generating new immune cells that will not attack the myelin. This method has been shown highly effective in relapsing-remitting MS patients, but not in progressive MS patients. The treatment has improved with safety over time, with ongoing improvements in treatment-related mortality rates (from 7.3% of the earliest use of the treatment during 1995–2000; 1.3% during 2001–2007; 0.7% during 2008–2016; and down to 0.2% after 2016. Data from EBMT Registry). However, it is still a risky procedure; as it involves the suppression of the immune system, it makes infections likely. It is therefore being used for patients with highly active forms of multiple sclerosis which do not respond to the best available drug therapies.

Learn more about blood stem cells here

MSCs

Cells calls MSCs are also present in the bone marrow. They normally form bone, cartilage and fat cells. Some researchers are investigating whether MSCs may help ‘re-train’ the immune system so that it does not attack the nerve cells. They may also produce useful chemicals to help repair myelin.

Despite studies in animals have shown some promising results, a recent phase 2 clinical trial evaluating the safety and efficacy of autologous MSCs in patients with active progressive MS did not reach the efficacy primary endpoint. Thereofr, this study does not support the use of bone marrow-derived MSCs in these patients.

Learn more about MSCs here

Aiding repair

The brain contains stem cells called neural stem cells (NSCs). The brain’s own neural stem cells attempt to repair myelin after damage. However, this process is inefficient and is not enough to repair all the damage caused by MS over time. Researchers hope to find ways to encourage these neural stem cells already present in the brain to do more effective repairs, or to add new neural stem cells to improve repair. Improving repair of the myelin sheath would enable the nerve cells to transmit messages again and would reduce degeneration of the nerves.

Like other stem cells, NSCs maintain an undifferentiated state. This means that they do not differentiate to replace damage cells. Rather, they release molecules that encourage and facilitate growth, repair, and reduced inflammation.

Transplantation of foetal-derived neural stem cells in animal model of multiple sclerosis have demonstrated a range of therapeutic benefits. In both rodent and primate models, these cells restored the function to damaged nerves.

A recent ‘first-in-human' Phase I Study evaluated the safety of intrathecally transplanted foetal NSCs in patients with progressive MS. (This means the cells were transplanted into the fluid-filled space within the tissues surrounding the brain and spinal cord.) The safety primary outcome was reached, with no severe adverse reactions related to NSCs. Exploratory secondary analyses showed a lower rate of brain atrophy in patients receiving the highest dosage of NSCs; they also showed increased levels of anti-inflammatory and neuroprotective molecules in the fluid surrounding the brain and spinal cord (cerebrospinal fluid, CSF). Although preliminary, these results support the rationale for future clinical studies with NSCs in a larger cohort of patients.

Studying disease and developing drugs

Embryonic stem cells and induced pluripotent stem cells  can produce every type of cell found in the body. Researchers have developed ways to control these stem cells to make human nerve cells and myelin in the laboratory. These lab-grown nerve cells do not yet meet the strict safety and purity standards that would be needed for transplantation into patients with MS. However, they give researchers a valuable opportunity to study the problems that occur in MS. They can also be used to test the effects of potential new drugs. Carrying out studies on cells may help to speed up the progress of drug development because important information can be obtained in the early stages of a study using cells, before research on animals is required.

Learn more about disease modelling here

Next steps

Some MS patients can now be treated with blood stem cell transplantation. This is an option for patients with relapsing-remitting MS, or aggressive disease which does not respond to the best available drugs. However, this treatment strategy is not effective in patients with progressive MS.

Several other types of stem cells are being investigated for their potential use in future treatments for more MS patients: stem cells may be able to repair the myelin on nerve cells, or perhaps in the long-term may even be used to grow completely new nerve cells. Stem cells are unlikely to cure multiple sclerosis; however, in the future it may be possible to use them to slow, stop or even reverse the progress of the disease. Much more research is needed to establish whether the different sorts of stem cells can provide safe and effective treatments for MS, and how those cells should be used.

Find out more

International MS Society Public Information Booklet on Stem Cells

The European Multiple Sclerosis Platform

Multiple Sclerosis Trust

The MS Society (UK)

Multiple Sclerosis Discovery Forum - includes regular roundups of MS research findings

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