Flotte, Moore comment on surprising results of gene therapy trial
It’s not unusual for patients participating in gene therapy trials to exhibit an immune response to the introduction of genetic material via a viral vector—an immune response either to the vector itself, or to the genetic material the vector delivers. This adaptive immune response is being carefully studied in early stage gene therapy trials that involve introducing new genes to, for example, muscle tissue; by contrast, trials where transgenes are delivered to sites where the immune response is less robust, such as the photoreceptors in the eye, seem to avoid some of the challenge of this adaptive immunity.
What is unusual is an immune response to proteins that weren’t part of the vector or the transgene. Just such a surprising result is the subject of expert commentary in the Oct. 7 issue of the New England Journal of Medicine by Terence R. Flotte, MD, dean of the School of Medicine and professor of pediatrics and molecular genetics & microbiology, and Melissa J. Moore, PhD, Howard Hughes Medical Institute Investigator and professor of biochemistry & molecular pharmacology. In the editorial they consider a gene therapy trial for the muscle-weakening disease called Duchenne muscular dystrophy (DMD). In the trial, one patient developed a rapid immune response to proteins that were not part of the transgene or the vector, but instead were related to mutant muscle fibers that are the hallmark of the disease itself.
Flotte, a national figure in the field of gene therapy, and Moore, whose work on the very protein, dystrophin, whose deficiency leads to diseases like DMD, are intrigued by the possibility of an auto-reactive immune component to such muscle-wasting diseases–suggesting a new way of thinking about the pathology of DMD, and suggesting potential new therapy.
Duchenne muscular dystrophy is the most common form of muscular dystrophy, and is characterized by a rapid degeneration of muscle. It affects about 1 in 3500 males (although females can be carriers of the gene, they very rarely develop the disease). The disorder is caused by a mutation in a gene that contains the code for the production of the protein dystrophin, the key structural fiber in muscle tissue.
