More Progress in Gene Therapy for DMD: Slipping Full-Length Dystrophin Past the Immune System

The immune system is one of the biggest obstacles to gene therapy for Duchenne muscular dystrophy (DMD), but researchers have devised a new gene therapy method that can largely evade the body's immune defenses.

Because of their natural ability to infect a cell and co-opt its genetic machinery, viruses are considered the best vessels (vectors) for delivering therapeutic genes. In particular, the adenovirus -- which normally causes a cold-like illness -- has long occupied the center stage of gene therapy research because it's large compared to other viruses, and therefore has the capacity to carry large genes. In fact, adenovirus is one of the few vectors capable of carrying a complete copy of dystrophin -- the massive gene that's defective in DMD.

To provide a safe gene therapy vector that's still able to deliver the complete dystrophin gene, MDA grantee Jeffrey Chamberlain and his group at the University of Washington in Seattle have been trying to design an adenovirus that avoids detection by the immune system. To do so, they've removed most of the adenovirus' own genes -- the source of viral proteins that send the immune system into attack mode. These modified adenoviruses are sometimes called "gutted" adenoviruses.

But Chamberlain and his group weren't sure that the gutted adenoviruses would be able to slip past the immune system, and they were equally concerned that stripping the adenovirus of its own genes might ruin its ability to infect muscle. Also, the immune system of someone with DMD wouldn't normally "see" much dystrophin, so there's concern that the replacement dystrophin itself might become the target of an immune attack.

Using a mouse model of DMD, Chamberlain's group has now shown that gutted adenovirus carrying a mouse dystrophin gene seems to provoke very little immune response. Also, the dystrophin is effectively delivered to muscles, and in force measurement tests, treated muscles showed a lasting improvement in endurance compared to untreated muscles.

The group is planning a more fine-grained analysis to see if they can detect even a slight immune response to gutted adenovirus or dystrophin. But so far, their results support the idea of using gutted adenoviruses for safe and effective delivery of full-length dystrophin.

Read more highlights from the American Society of Gene Therapy meeting:

• Researchers Put Dystrophin Minigenes to Ultimate Test
• Making the Jump to Gene Therapy for Pompe's Disease