Golden retriever dogs make a good animal model for muscular dystrophyRossana Tonlorenzi & Maurilio Sampaolesi, San Raffaele Scientific InstituteAn infusion of stem cells scraped from blood vessels has helped dogs with a form of muscular dystrophy to walk more normally, perhaps heralding a treatment for the human disease.
Muscular dystrophies are a group of widespread genetic disorders in which the muscles gradually break down. The most common form, called Duchenne muscular dystrophy, is caused by mutations in a gene called dystrophin and inevitably causes paralysis and death.
Giulio Cossu of the San Raffaele Scientific Institute in Milan, Italy, and his colleagues had previously shown that a type of stem cell called a mesoangioblast, which lives in the walls of blood vessels and can generate muscle cells, can help mice with a form of muscular dystrophy1. So they set out to study the effect of the cells in an animal model that more closely mimics the human condition: golden retriever dogs with a mutation in their dystrophin gene.
The team extracted the blood-vessel stem cells from normal dogs, grew them to large numbers in the lab, and injected tens of millions of cells into sick dogs in five monthly injections.
Afflicted dogs usually develop troubles walking by 8 months old. But many of the treated dogs did much better; one was still walking well at 13 months of age. The results are published online in Nature2.
Cossu says that the team has already identified the equivalent stem cells from humans and that clinical trials could start in a few patients by late 2007. But they will need to test more dogs first. "We're not rushing," Cossu says.
It's uncertain whether this type of treatment can repair heart muscle or the diaphragm, which also fail during muscular dystrophy. Furthermore, it is unclear whether the stem cells might lodge themselves elsewhere in the body and cause unwanted side effects.
Straight to source
Stem cells can travel through the blood, squirming their way out into muscles throughout the body.Rossana Tonlorenzi & Maurilio Sampaolesi, San Raffaele Scientific InstituteBy examining the dogs' muscles, the team found that the stem cells had travelled through the blood, squirmed their way out of capillaries and into many muscles throughout the body. There, they had fused with existing muscle fibres, manufactured the missing dystrophin protein and rejuvenated the fibres.
Researchers have been testing other types of stem cell to treat muscular dystrophy, such as ones extracted directly from muscle or bone marrow. But these cell types have either revived only a few muscle fibres or needed to be injected directly into each muscle.
The real advantage of the mesoangioblast cells is that they can be injected into the bloodstream and swim to most muscles in the body, says neurologist Thomas Rando who studies muscular dystrophy at Stanford University, California.
Stem cells have been touted as the way to regenerate numerous failing tissues — but none have yet become tried-and-tested human treatments. Rando says that muscular dystrophy is a good disease to target, because the replacement cells only have to fuse with existing muscle fibres, rather than spawning brand new cells or tissues.
Tailor-made
In terms of treating human disease, cells donated from another person are not ideal because a patient has to take lifelong immunosuppressant drugs to avoid rejection.
Cossu's team looked at one possible solution to this problem: they extracted stem cells from sick dogs and used gene therapy to insert a working copy of the dystrophin gene into these cells. They then injected the dogs with their own, 'fixed' cells.
Dogs treated this way began to manufacture dystrophin, but they did not have improved symptoms. Cossu thinks the results might be improved by using a different version of the dystrophin gene (which is notoriously difficult to handle because it is so large - in humans it is more than 2.5 million base pairs long, and by far the largest gene in the human genome).
From all angles
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Other methods to treat muscular dystrophy are nearing clinical trials. Some groups are trying to deliver a replacement dystrophin gene to all muscles using a virus. Others are working on drugs that encourage a cell to ignore the mutation in its gene and manufacture a correct form of dystrophin protein.
"I think we may be approaching a time when we'll see multiple approaches combined," says muscular-dystrophy researcher Jeffrey Chamberlain of the University of Washington, Seattle.
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