‘Ringo the dog’ Helps Find Potential New Therapy for Muscular Dystrophy

Ringo, a golden retriever, has made an important contribution to science by helping researchers discover a gene that inhibits the consequences of dystrophin loss in Duchenne muscular dystrophy (DMD). Even though Ringo carried the classic DMD mutation, he and one of his male offsprings had a variant in the Jagged1 gene that allowed them to walk and run freely, seemingly unaffected by the disease. The findings are from scientists at Boston Children’s Hospital, the Broad Institute of MIT and Harvard and the University of São Paulo in Brazil and were published online last November 12^th 2015 in journal Cell.

According to Lou Kunkel, PhD, from The Boston Children’s Lab, these findings now allow scientists to screen for drugs with the same protective effect as the genetic variant. Study author Natássia Vieira, PhD, had been doing research with a group of golden retrievers that carry the classic DMD mutation causing loss or dysfunction of the dystrophin protein. The dogs affected by the disease tend to be very weak and with a very low life span (of about 2 years), however Ringo and one of his offsprings were able to walk and run. Importantly, Ringo lived to be 11 years of age. Together with Vieira, scientists wanted to find out why this happened and how could Ringo have fully functional muscles, even without dystrophin. “We decided to do genome-wide association studies (GWAS) to see where in the genome there might be a gene that modifies disease severity,” Kunkel said in a news release.

After sequencing the dogs’ DNA, the team found a section that functions as a promoter of the Jagged1 gene, turning it on at twice the rate found in other affected dogs. To make sure that Jagged1 was the cause of this major difference in disease severity, Vieira and Kunkel started a trial on zebrafish, engineered to carry the DMD mutation. This type of fish has muscles that can be clearly observed and were visible weaker with the mutation. “They’re basically immobile; if you touch them, they only move a little,” explained Kunkel. “It’s completely compromised muscle.”

Researchers found that when Jagged1 expression was genetically engineered in these fish, even though they were dystrophin-deficient, muscles appeared normal and the fish could swim without any visible problems. According to Kunkel, these findings are exciting and make Jagged1 a new potential target for therapies designed to improve muscle function. “We’re trying to mimic the effect of the promoter and trying to upregulate Jagged1 in fish and mice, using small molecules,” he says. “Zebrafish are permeable to small molecules and have a muscle phenotype that you can score.”

Kunkel first identified dystrophin in 1987,  explaining that other therapies for DMD are in the clinical arena. One treatment tricks the cellular machinery into making dystrophin, ameliorating DMD’s symptoms, while an alternative option increases the levels of utrophin, a dystrophin-like protein that may compensate for its non-existence. A third approach seeks to treat the problems caused by loss of dystrophin in the organism, such as reversing damaged production of nitric oxide to enhance blood flow. “Jagged1 upregulation is just another avenue for therapy that needs to be pursued,” Kunkel claims. “The different approaches work on different systems and are going to be complementary. This is the ‘decade of therapy.'”