A gene therapy delivered to the liver delayed progression and reversed symptoms of early-stage multiple sclerosis in mice. With improvements, the approach could be a potential treatment for the autoimmune disease, which has no cure.

In MS, the immune system attacks myelin, the fatty substance that coats and protects nerve fibers in the brain and spinal cord. Its cause is still unknown, but researchers think it stems from self-reactive effector T cells that target myelin.

Current treatments for MS focus on reducing the number of relapses—where symptoms worsen, or new symptoms appear—a patient experiences. Other approaches suppress the immune system so it does not target myelin, but this can lead to harmful side effects.

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Delivering regulatory T cells, or Tregs, to patients is an attractive way to rein in the self-destructive nature of the effector T cells, but this method is not particularly long-lasting. To solve this problem, University of Florida-led researchers seized on the liver's ability to control immune tolerance. They used an adeno-associated virus to transfer the protein myelin oligodendrocyte glycoprotein to the liver in mouse models of MS.

This treatment stimulated Tregs to curb self-reactive effector T cells, thereby protecting myelin and preventing mice from developing MS symptoms for seven months. It also reversed mild and moderate neurological symptoms, and restored mobility in mice with hind-leg paralysis. The findings are published in Molecular Therapy.

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"Using a clinically tested gene therapy platform, we are able to induce very specific regulatory cells that target the self-reactive cells that are responsible for causing disease," said senior author Brad Hoffman, an associate professor in the Division of Cellular Therapy in the University of Florida's Department of Pediatrics.

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

The therapy did not totally reverse end-stage MS. But the team administered it alongside the approved immunosuppressant rapamycin and found the combo caused complete remission in the majority of mice with late-stage disease.

"We have demonstrated that stable immune tolerance can be re-established and that active disease can be stopped and clinical symptoms reversed using our gene immunotherapy, especially during early onset of disease," Hoffman said. "Even though these studies were performed in a less complex mouse model, the data suggest this may be a potential therapy in humans with additional optimization."

The team is working on viral vectors to deliver other proteins implicated in MS, and are exploring other autoimmune disease targets for this approach. Eli Lilly recently forked over $150 million to Nektar Therapeutics to codevelop a drug that increases the number and activity of Tregs in up to 10 disease areas. Meanwhile, scientists at Cincinnati Children's Hospital Medical Center are looking to rebuild myelin in MS patients by using short pieces of RNA known as microRNAs.