Adapted from a Boston Children's Hospital press release. 

Two golden retrievers that had the genetic mutation for Duchenne muscular dystrophy (DMD), yet remained healthy, have offered up yet another lead for treating this muscle-wasting disorder.

For several years, Natássia Vieira, PhD, of the University of São Paolo, also a fellow in the Boston Children’s Hospital lab of HSCI Principal Faculty Louis Kunkel, PhD, has been studying a Brazilian colony of golden retrievers. All have the classic DMD mutation and, as expected, most of these dogs are very weak and typically die by 2 years of age. That’s analogous to children with DMD, who typically lose the ability to walk by adolescence and die from cardiorespiratory failure by young adulthood.

But two dogs appeared unaffected. Both ran around normally. The elder dog, Ringo, lived a full lifespan, and his son Suflair is still alive and well at age 11.

Duchenne escape artists

In 2015, Vieira, Kunkel and colleagues showed that both “escaper” dogs had something extra. Compared with severely affected dogs in the colony, they had increased expression of Jagged1, a gene known to be involved in muscle regeneration. That report was published in Cell.

This week in PNAS, Kunkel, Vieira and Janelle Spinazzola, PhD, show another natural advantage. Both Ringo and Suflair had decreased expression of the gene PITPNA, which encodes a protein called phosphatidylinositol transfer protein-α. This, too, seemed to counter the effects of the DMD mutation.

The researchers’ next step was to silence PITPNA artificially, through either genetic knockdown or injection of an antisense drug (a morpholino oligonucleotide). They saw the following benefits:

• Dogs and zebrafish with DMD had improved muscle structure.
• Zebrafish with DMD swam faster and lived longer.
• Abnormal signaling in muscle cells from dogs, zebrafish and people with DMD was reversed. (Specifically, levels of phosphorylated Akt increased, and levels of PTEN decreased.)

Targeting Duchenne disease modifiers

Most strategies for treating DMD involve boosting production of the dystrophin protein, which is needed for muscle function and is lost or dysfunctional in DMD. Several such therapies are on the market or in clinical testing. But countering dystrophin loss by leveraging disease-modifying genes like Jagged1 and PITPNA could be another strategy.

“DMD is a multifaceted disease, so probably will need a combination of approaches,” says Kunkel, who is credited with the discovery of dystrophin in 1987. “Disease modifiers like PITPNA enhance our understanding of the disease and could be therapeutic targets.”

Kunkel is a consultant for Pfizer, Inc., Summit Corporation PLC and Sarepta Therapeutics for muscle disease drug therapies. The study was supported by the Duchenne Research Fund, Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Institutos Nacionais de Ciência e Tecnologia, Associação de Assistência à Criança Deficiente, the Bernard F. and Alva B. Gimbel Foundation, the National Institutes of Health, the Boston Children’s Hospital Intellectual and Developmental Disabilities Research Center, the Muscular Dystrophy Association and Pfizer, Inc.