Caution: Immune Response Seen in DMD Gene Therapy

Unwanted responses by the immune system to dystrophin have been seen in a small, MDA-supported clinical trial of gene therapy for Duchenne muscular dystrophy (DMD)— an unexpected finding, investigators say.

Rather than a setback, the finding is “the beginning of a new way of thinking” about gene therapy, said Jerry Mendell, director of the Center for Gene Therapy at Nationwide Children's and a long-time MDA research grantee and MDA-associated clinician. Mendell was the neurologist on this trial.

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

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.

Extensive analyses of trial data revealed unwanted immune responses to the newly synthesized dystrophin protein in four out of the six trial participants.

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 trial results April 13, at the 2010 meeting of the American Academy of Neurology (AAN), held in Toronto.

About the DMD gene therapy trial

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

The trial, conducted at Nationwide Children's, included six boys with DMD who were 5-12 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 AskBio. 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

The immune responses seen in four of the six trial participants were not anything that patients or doctors could perceive with the naked eye and did not affect the well-being of the patients. The responses 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 actually primed the immune system to react to the new dystrophin created by gene therapy. (These few dystrophin-producing muscle fibers seen in some boys with DMD are called "revertant" fibers.)

Investigators had previously believed that these revertant fibers, with their 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. This was not the case.

On the other hand, there was 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 and development at AskBio.

McPhee cautioned that a blood-cell immune response does not necessarily mean that the immune system will actually attack muscle tissue. "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.

He called the study outcomes "exciting and informative," adding, "Using gene delivery, we have uncovered a clinically relevant biological process in a subpopulation of DMD patients, related to the unexpected ability of the immune system to recognize naturally occurring revertant muscle fibers. It remains to be determined what exact role this immune recognition plays. There were no clinical adverse events related to the gene delivery in any of the patients, but it will be another marker for clinical researchers to measure and evaluate when carrying out any form of dystrophin gene or protein modification."

McPhee also noted that no patient in the trial showed an immune response to the delivery vehicle for the dystrophin gene, which he termed "AskBio's core gene delivery technology."

Based on these results, McPhee said, AskBio plans to advance to the next phase of DMD clinical studies, involving whole-limb delivery of Biostrophin, within the next 1.5 to two years. The investigators, he said, will prescreen the trial participants to assess their immune status before enrollment.

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.

Meanwhile, AskBio emphasized that it plans to continue to develop gene therapy for DMD, albeit with additional prescreening for an immune response to dystrophin.

"This study was the first to carefully assess dystrophin immunity in a clinical trial," said McPhee, "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."

Editor's note 8/30/10: In August 2010, Nationwide Children's Hospital in Columbus, Ohio, received a $7 million federal grant to pursue solutions to the immunologic obstacles to gene transfer. See Nationwide Children's Hospital Named MD Research Center.

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