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Immune responses to dystrophin may limit gene therapy success in Duchenne muscular dystrophy and will need consideration in future trials.

Unwanted responses by the immune system to gene therapy for Duchenne muscular dystrophy (DMD) have been seen in a small clinical trial and may pose more of a barrier to this treatment strategy than previously thought.

Gene therapy for DMD involves the injection of genes for a functional version of the muscle protein dystrophin, the lack of which is the underlying cause of this disease.

Christopher Walker, professor of pediatrics, molecular virology, immunology and medical genetics at Nationwide Children's Hospital in Columbus, Ohio, and the immunologist on the gene therapy trial team, presented the findings April 13, 2010, at the annual meeting of the American Academy of Neurology (AAN), held in Toronto.

Jerry Mendell, director of the Center for Gene Therapy at Nationwide Children's and a longtime MDA research grantee and MDA-associated clinician, was the neurologist on this MDA-supported trial.

"I don't think this is the end of gene therapy for Duchenne dystrophy," Mendell said. "Instead, it's the beginning of a new way of thinking about it. Now that we know that the immune response can be a problem, we can start dealing with it."

About the DMD gene therapy trial

The DMD gene therapy trial, supported by MDA through grants to Asklepios BioPharmaceutical of Chapel Hill, N.C., opened in March 2006. (See Safety Study of Mini-Dystrophin Gene to Treat Duchenne Muscular Dys....)

The trial, conducted at Nationwide Children's, included six boys with DMD who were 5 to 12 years old. Each received an injection into one biceps muscle of miniaturized dystrophin genes encased in adeno-associated viral (AAV) delivery vehicles, and a placebo (fake) injection into the other biceps.

The combined gene and AAV delivery vehicle are called Biostrophin, a patented product developed by Asklepios. Three boys received a low dose of Biostrophin, and another three received a higher dose.

In January 2008, the investigators announced that the gene transfer procedure was safe and said they were considering proceeding to a third and higher dosage level of Biostrophin.(See Dystrophin Gene Transfer Appears Safe in DMD Boys.) They have not, at this time, proceeded to the higher dosage level.

About the new findings

At the AAN meeting, Walker described how extensive analyses of trial data revealed unwanted immune responses to the newly synthesized dystrophin protein in four out of the six trial participants. (The immune responses were not anything that patients or doctors could perceive with the naked eye. They were seen with complex analyses of blood samples that were exposed to different parts of the dystrophin molecule in the laboratory and through examination of biopsy slides.)

In addition, Walker reported, analyses have now shown that, in some cases, the production of a small amount of dystrophin protein from some muscle fibers in boys with DMD — a phenomenon called "revertant fibers" — actually primed the immune system to react to the new dystrophin created by gene therapy.

Investigators had previously believed that pre-existing, low-level dystrophin production might make patients tolerant of new dystrophin from gene therapy, because the dystrophin would be familiar to the immune system and so wouldn’t be attacked as an invader. However, an important and unanticipated finding was that an immune response to dystrophin was detected both prior to gene delivery and after gene delivery in some patients.

This result is somewhat confusing, as is another unexpected finding. Investigators noted a partial "disconnect" between what was seen in blood tests of the immune response to dystrophin and what was actually seen in some of the muscle biopsy samples, said Scott McPhee, director of research & development at Asklepios BioPharmaceutical.

McPhee cautioned that a blood-cell immune response does not necessarily mean that the immune system will actually attack muscle tissue. He noted that there were no clinical adverse events or muscle damage related to the gene delivery observed in the trial. "There are a lot of steps that must occur for a blood immune cell that recognizes a specific protein to actually infiltrate the tissue to target the cell expressing the [protein]," McPhee said.

Meaning for families with DMD

The researchers have concluded that there is the potential for an immune response to dystrophin gene therapy in at least some children and young adults with DMD, and that this type of immune response may limit the effectiveness of the therapy. More work, however, is needed to determine exactly what limitations it may pose.

They also say an immune response could occur to dystrophin with other experimental treatments that seek to raise levels of this protein, and that the immune response needs to be considered and monitored as the field moves forward with dystrophin-enhancing therapies, such as so-called stop codon read-through medications or exon-skipping constructs.

"The study was the first to carefully assess dystrophin immunity in a clinical trial," McPhee said, "and it will help us design the ongoing and future trials of different classes of DMD therapies to be sure that we continue to learn more about the nature and clinical implications of any immune response. It will also help us identify and enroll patients most likely to benefit and most unlikely to have an adverse clinical response."

Christopher Walker noted that blood tests prior to treatment can help predict the likely response of the immune system. And, in those patients in whom an immune response is predicted to occur or does occur, immunosuppressive drugs and a procedure called plasmapheresis, in which unwanted immune system proteins are sifted from the blood, are possible ways to overcome the problem.