Pier Lorenzo Puri, M.D., an associate professor at Sanford-Burnham Medical Research Institute (Sanford-Burnham), has led a research team that work in collaboration with Fondazione Santa Lucia in Rome, Italy, to characterize the mechanism by which a class of drugs called “HDACis” drive muscle-cell regeneration in the early stages of dystrophic muscles, but fail to work in late stages. These findings are integral for designing HDACis drugs for Duchenne muscular dystrophy (DMD), which presently, is an incurable muscle-wasting disease.
Puri’s research was published April 15th, 2014 edition of the journal Genes and Development. In their paper, Puri and his colleagues used mouse models of DMD to show how special cells known as “fibro-adipogenic progenitor cells” or FAPs, direct muscle regeneration. FAPs reside in the spaces between muscle fibers and detect those cues that indicate that muscles have been damaged. In response to muscle damage, FAPs direct muscle stem cells, known as satellite cells, to rebuild muscle.
“HDACis create an environment conducive for FAPs to direct muscle regeneration—but only during the early stages of DMD progression in mice,” said Puri. “At some point, DMD progresses to a pathological point of no return and become permanently resistant to muscle-regeneration cures and to HDACis.”
Indeed, Puri’s research showed exactly that; namely that FAPs embedded in muscle that was in the earlier stages of muscular dystrophy responded robustly to HDACis and upregulated a wide range of muscle-specific genes. In contrast, FAPs from late-stage dystrophic muscles were resistant to HDACi-induced muscle-specific gene expression and failed to activate satellite cells.
HDACis stands for histone deacetylase inhibitors. These are epigenetic drugs that regulate the accessibility of those genes that code for muscle proteins. HDACis ensure that the DNA within cells is open and easily accessible to the gene expression machinery. In the presence of FAPs, in particular, rev up their support for muscle regeneration. Under conditions of normal wear and tear, FAPs direct stem cells within the muscle to regenerate and repair damaged muscle. However in patients with DMD, the persistent breakdown of muscle cells creates a chaotic environment that overwhelms the ability of the FAP’s to direct muscle regeneration.
Puri collaborated with Italian colleagues at Fondazione Santa Lucia, Italfarmaco, and Parent Project Muscular Dystrophy, an advocacy association. The goal of this research is to develop HDACis for the treatment of DMD. To that end, Puri and others have launched a clinical trial with DMD boys.
“Our study is important because it provides the rationale for the clinical development of HDACis to treat DMD,” said Puri. “And, now that we understand the mechanics and sensitivities of the muscle-regeneration system, we have the rationale and can use new tools to select patients most likely to benefit from HDACIs based on their FAP profile, predict outcomes, and see how long patients should remain on the therapy.”
“Duchenne muscular dystrophy patients and their families rely on important research such as that performed by Dr. Puri,” said Debra Miller, Founder of Cure Duchenne, a patient advocacy group. “Our efforts at Cure Duchenne are to support leading scientists in the world to bring life-saving drugs to help this generation of Duchenne boys, and our vision is to cure Duchenne muscular dystrophy. Every added piece of knowledge about the disease brings us closer to realizing our goals.”
The Puri paper also shows why trying to regenerate muscle cells in severely affected individuals is not feasible, since the dystrophic muscles have deteriorated to the point of no return. This will definitely influence the construction of treatment strategies for patients with muscular dystrophy.