0333 GMT January 17, 2019
The researchers showed this in a mouse model that accurately recapitulates Duchenne muscular dystrophy. One in every 5,000 boys is born with this crippling disease, which leaves patients wheelchair-bound by mid-adolescence and is typically fatal by young adulthood. It stems from a genetic defect that deprives skeletal and cardiac muscles of a working version of a protein called dystrophin, medicalxpress.com reported.
"Gene therapy is on the cusp of becoming a mainstream approach for treating single-gene disorders," said Lawrence Steinman, MD, professor of neurology and neurological sciences and of pediatrics at Stanford.
"But there's a catch: If you give a gene that's a recipe for a normal protein to someone with a faulty version of the gene, whose body never made the normal protein before, that person's immune system will mount a reaction — in some cases, a lethal one — to the normal protein, just as it would to any foreign protein. We think we've solved that problem."
Duchenne muscular dystrophy is the result of a single defective gene, making it an excellent candidate for gene therapy in which a patient's faulty gene is replaced with the correct version. One way to do this is by co-opting viruses, which are simple entities that are adept at infecting cells and then forcing every invaded cell's reproductive machinery to copy their own viral genes. For gene therapy, viruses are modified by ridding them of unwanted genes, retaining the ones necessary for infectivity and adding the therapeutic gene to be delivered to a patient.
The gene encoding dystrophin is far too big for a gene-hauling virus to take onboard. Fortunately, a mere fraction of the entire gene is enough to generate a reasonably functional version of dystrophin, called microdystrophin.
The abridged gene fits snugly into a viral delivery vehicle designed some time ago by Jeffrey Chamberlain, Ph.D., a coauthor of the study and a professor of neurology, medicine and biochemistry at the University of Washington.
But there's still that sticky autoimmunity problem. To get around it, Steinman and his colleagues spliced the gene for microdystrophin into a different kind of delivery vehicle called a plasmid.
Plasmids are tiny rings of DNA that bacteria often trade back and forth to disseminate important traits, such as drug resistance, among one another.
The particular bacterial plasmid the investigators co-opted ordinarily contains several short DNA sequences, or motifs, that the immune system recognizes as suspicious and to which it mounts a strong response.