'Guided Missile' Strategy for MG Shows Promise in Mice

MDA-supported researchers have used genetic engineering to target renegade cells of the immune system in mice with a disease resembling myasthenia gravis

Researchers at Johns Hopkins and elsewhere say they've developed a gene-based therapy that specifically homes in on T cells primed to attack acetylcholine receptors in mice with an MG-like disease.
Article Highlights:
  • By equipping antigen-presenting cells of the immune system with a genetically engineered "guidance system" and molecular "warhead," researchers were able to specifically target cells of the immune system that were orchestrating an attack on acetylcholine receptors (the most common underlying cause of MG).
  • The experiments successfully controlled the immune response to acetylcholine receptors in mice with an MG-like disease.
  • The strategy has potential in human MG but has not yet been tried in people with the disease.
by Margaret Wahl on October 25, 2012 - 10:47am

Researchers funded in part by MDA say a gene-based therapy designed to treat myasthenia gravis (MG) has shown promise in mice with an MG-like disease.

The research team was led by Dan Drachman, a longtime MDA research grantee at Johns Hopkins University in Baltimore, who also co-directs the MDA neuromuscular disease clinic at that institution. Drachman, a professor of neurology, has a special interest in MG, which is an autoimmune neuromuscular disease.

In autoimmune disorders, the body's immune system mistakenly attacks its own tissues. (Its usual role is to fight infection.)

Most people with MG produce antibodies (immune system proteins) against a part of the muscle fiber known as the acetylcholine receptor. Normally, signals pass from nerve fibers to muscle fibers through these receptors. In MG, however, this pathway is disrupted, leading to fluctuating weakness that can be debilitating and even life-threatening if the respiratory muscles become involved.

'Guided missiles'

The goal of Drachman and colleagues, who published their results in the Oct. 15, 2012, issue of the Journal of Neuroimmunology, has been to disrupt the specific renegade immune response to the acetylcholine receptors while leaving the rest of the immune system intact.

The researchers created what they describe as "guided missiles" aimed only at the renegade immune system cells. They equipped the guided missiles with a "warhead" designed to kill the cells at which it was aimed.

First, they removed antigen-presenting cells (cells that "present" proteins to the immune system) from mice; they then genetically modified these cells so that they presented acetylcholine receptor proteins and injected them into mice with an MG-like disorder. That action, by itself, would be expected to worsen the autoimmune, MG-like disease.

But the researchers added a secret weapon — what they called a "warhead" — to the antigen-presenting cells, again using genetic engineering. The warhead, known as Fas ligand, interacts specifically with activated immune system cells (activated T cells in this situation) and kills them. The strategy therefore targets the very cells that are activated against acetylcholine receptor proteins.

The treatment dramatically reduced the immune response to the acetylcholine receptors in the mice, without interfering with the rest of the immune system. However, the researchers say, the study was not long enough to determine whether the mice were permanently cured of their disease.

"Theoretically, a similar approach to treatment could be translated to patients with myasthenia gravis," says an Oct. 1 press release from Johns Hopkins Medicine, "but so far it has not yet been tested in humans, and it is not yet known whether repeated courses of the therapy might be needed."

Current MG treatments

Current treatments for MG include:

  • drugs — such as prednisone, azathioprine, cyclosporine mycophenolate mofetil and tacrolimus — that suppress large parts of the immune system (which can have serious side effects);
  • pyridosigmine, a medication that prolongs the signal that flows from nerve to muscle tissue;
  • a procedure called plasmapheresis, in which antibodies are physically removed from the bloodstream; and
  • removal of the thymus, an organ in the chest that's involved in the immune response.

None of these treatments is as specific as the one Drachman and colleagues hope to develop.

Various other experimental therapies also are in development for MG.

For more information

To learn more about autoimmune disease in general and MG in particular, see: 

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