Multiple sclerosis: Novel gene immunotherapy could prevent, reverse disease

Researchers have developed a gene immunotherapy technique that has reversed MS in mice.

A strategy to prevent and reverse multiple sclerosis might finally be in sight; a team of researchers has developed a form of gene immunotherapy that has achieved such a feat in mice.

In a new study, researchers reveal how their novel technique allowed them to target and suppress destructive immune cells that play a role in the development of multiple sclerosis (MS).

The therapy prevented MS development in mice and reduced clinical symptoms of the condition in mouse models of the disease, the team reports.

What is more, when combined with a current immunosuppressive drug, the treatment led to complete remission in mice with end-stage MS.

Senior study author Brad Hoffman, of the University of Florida in Gainesville, and colleagues recently reported their results in the journal Molecular Therapy.

MS is a progressive neurological disorder that can cause numbness or tingling, muscle weakness, problems with mobility, and fatigue, among other symptoms.

It is estimated that around 2.3 million people across the globe are living with MS, and the disease is most commonly diagnosed between the ages of 20 and 50 years.

The exact causes of MS remain unclear, but studies have indicated that an immune-mediated process is involved, whereby the immune system mistakingly attacks myelin - that is, the fatty substance surrounding and protecting nerve fibers.

Immunotherapy and myelin

Hoffman and team explain that this immune-mediated process involves the activation of immune cells known as self-reactive effector T cells. These cells attack proteins in myelin, including myelin oligodendrocyte glycoprotein (MOG).

The researchers note that regulatory T cells normally curb the harmful activity of self-reactive effector T cells, but this does not happen in people with MS.

Previous studies have shown that the introduction of regulatory T cells may help to prevent the myelin damage caused by self-reactive effector T cells, as well as some of the neurological symptoms of MS. However, Hoffman and colleagues note that the effects are short-lived.

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With this in mind, the researchers set out to develop a gene immunotherapy strategy that could provide long-term protection for myelin.

Their approach involves using an adeno-associated virus (AAV) vector to deliver a gene that encodes the myelin protein MOG to the liver. This prompts the activity of regulatory T cells specific to MOG, which suppresses the destructive activity of self-reactive effector T cells.

"Traditional AAV gene therapy has been focused on delivering a transgene that produces a therapeutic protein," says Hoffman. "Here we use the platform purposely to induce specific regulatory cells in order to restore immune tolerance and reverse an autoimmune disease."

Technique reversed clinical symptoms of MS

Upon testing the gene therapy technique in mouse models at high risk of MS, the researchers found that it prevented the rodents from developing clinical symptoms of the disease over the course of 7 months.

Furthermore, they found that their gene therapy approach reversed a range of symptoms in mice that had already developed MS, including neurological deficits and hind-leg paralysis.

The researchers note that their immunotherapy strategy alone was unable to reverse late-stage MS in mouse models. But when combined with a short dose of the immunosuppressive medication rapamycin, the technique led to complete remission in almost all mice with late-stage disease.

Specifically, this combinatory approach reversed severe paralysis in the rodents and prevented any MS symptoms in the mice for around 100 days.

Hoffman and his colleagues were pleasantly surprised by their findings.

"Leading up to the project," Hoffman explained to Medical News Today, "I had spent nearly a decade studying the mechanisms of gene therapy-induced immune tolerance. Hence, I was confident that the gene immunotherapy would be effective, especially for preventing disease."

"However," he continued, "my team and I were surprised and impressed at how effective it was at reversing pre-existing disease and restoring mobility in mice that were essentially paralyzed."

A feasible therapy for humans?

It goes without saying that the safety and efficacy of the gene immunotherapy technique need to be evaluated in human trials, and there are a number of significant limitations to overcome.

"Although the gene immunotherapy was very effective in mice," Hoffman told us, "it is important to remember that the mice model of MS is less complex than the human disease."

Discussing the next steps, Hoffman told MNT, "[...] MS is not caused by an immune response, or lack of immune tolerance, to a single protein. Therefore, we are incorporating additional myelin-based protein sequences into the gene therapy in order to broaden the tolerance-inducing capability of the treatment."

Despite the potential barriers, the researchers are hopeful that their findings will pave the way for an effective strategy to prevent and reverse MS in humans.

"The viral gene therapy platform that our method is built upon has been successfully utilized in the clinic for other diseases. Thus, we are very optimistic that this method can be adopted for human use in patients with early-stage MS."

Brad Hoffman

He also told us that it is likely to be at least 5 years before their gene immunotherapy technique is made available to patients with MS.

"Although the liver-directed gene therapy platform is clinically used to treat other diseases, this particular application is complex and may require additional testing," he said