Finding a delivery method for the whole body has been a major obstacle limiting the development of gene therapy for the muscular dystrophies, according to Dr Jeffrey Chamberlain, professor of neurology and director of the Muscular Dystrophy Cooperative Research Center at the University of Washington School of Medicine in Seattle.
The method uses a viral vector, a specific type of an adeno-associated virus (AAV), which is able to 'home-in' on muscle cells and does not trigger an immune system response. The delivery system also includes use of a growth factor, VEGF, which appears to increase penetration into muscles of the gene therapy agent.
Chamberlain said the formula was the result of about a year of trying different methods.
"Our new work identifies for the first time a method where a new dystrophin gene can be delivered, using a safe and simple method, to all of the affected muscles of a mouse with muscular dystrophy," he said.
Duchenne muscular dystrophy is an X-linked genetic disorder that strikes one of every 3,500 newborn boys. The genetic disorder eliminates production of the dystrophin protein, which is necessary for the structural support of muscle. Without this protein, muscles weaken to the point where the victim cannot survive.
"By giving one single injection of this AAV vector carrying a mini-dystrophin gene into the bloodstream, we are able to deliver therapeutic levels of dystrophin to every skeletal and cardiac muscle of an adult, dystrophic mouse," Chamberlain said. "These muscles include the heart, the muscles used during breathing, and all the limb muscles. The mice show a whole body effect, with a dramatic improvement of their dystrophy."
The findings, to be published in the August edition of Nature Medicine, hint that it may be possible someday to introduce other genes into adult muscle to address conditions besides muscular dystrophy.
The newly developed gene therapy was able to perform in all muscles in the mouse, and would not necessarily have to carry the dystrophy gene. For example, gene therapy could someday reinforce muscles weakened by cancer or normal ageing, or treat cardiac disease.
Chamberlain and colleagues in the Muscular Dystrophy Cooperative Research Center are gathering data to seek regulatory approval for a limited trial in humans to determine the safety of a very small amount of the vector in human muscle.
The vector's safety will be key to further development and it is an area that has already caused researchers to pull gene therapy projects. An inhaled adenoviral vector-delivered gene therapy has led to the death of a US patient after it caused an inflammatory response in the lungs.
And last year a number of trials were halted after French researchers reported a higher than expected number of cases of leukaemia among children being treated for the fatal 'baby-in-a-bubble' syndrome, severe combined immunodeficiency (X-SCID). After three years of successful gene therapy for X-SCID, leukaemia occurred in the two youngest patients undergoing treatment.
But according to a recent conference of Euregenethy, a Europe-funded network of scientists aiming to develop standardised gene therapy regulations and encourage discussions on related ethical issues, the first successful treatments have also been reported from clinical gene therapy studies. They also noted that the overall risk of the leukaemia gene therapy is still lower than that of the available conventional therapy.