Distrofia Muscolare Duchenne

When research meets people: a novel potential therapy for Duchenne Muscular Dystrophy

The discovery of a genetic mechanism inherited from the mother capable of reactivating dystrophin production and improving patient conditions is the outcome of an almost ten-year study on the clinical history of a young asymptomatic patient. The study, coordinated by Sapienza and supported by ERC Advanced Grants, Telethon Foundation and Parent Project, has been published on the journal EMBO Molecular Medicine

When research meets people, it can lead to essential changes. That is the case of a patient suffering from an inexplicably mild form of Duchenne muscular dystrophy. Due to his anomalous condition, Irene Bozzoni and her team of the Department of Biology and Biotechnology Charles Darwin of Sapienza University and the Italian Institute of Technology, who had met him during a Telethon marathon in 2011, have been following his case for years.

Gerardo's is not only the clinical history of a disease that affects 1 in 3,500 male births (females are generally asymptomatic carriers) causing progressive degeneration of the various muscle tissues, but it is the experience of a young man who at 14 years old was still able to walk and move independently. Today, the 23-year-old Gerardo does not show respiratory or cardiac symptoms, and although he prefers his wheelchair to move, he still manages to stand and walk a few steps with some help.

Their meeting, which took place almost ten years ago, started a new line of research aimed at discovering further details on the mechanisms underlying the formation of muscles (myogenesis) while trying to clarify some unknowns related to the particular evolution of the disease in the young man.

Irene Bozzoni and her research team observed how Gerardo's cells spontaneously activated a particular molecular mechanism which bypasses the genetic error that causes the absence of dystrophin, restoring its production in sufficient quantities to improve physical conditions, during their first study in 2016. They noticed how this mechanism, based on the principle of exon skipping, is particularly favoured by the absence of a protein called Celf2a.

In a new study carried out by Sapienza University, the Italian Institute of Technology (IIT), and the Centre for Genomic Regulation (CRG) in Barcelona, the researchers coordinated by Irene Bozzoni have continued to characterize the molecular aspects of this interesting phenomenon, discovering that the genetic mechanism capable of reactivating dystrophin production is inherited from the mother.

The study, published on EMBO Molecular Medicine journal and supported by the Telethon Foundation, the Parent Project Association and a grant from the European Research Council (ERC), also shows that by "switching off" the Celf2a gene in the myoblasts of other patients with a DMD mutation similar to the study case, dystrophin production is restored to levels that could relieve the pathology.

"We saw that even in the young man's mother, the gene that produces the protein was inactivated - says Irene Bozzoni - and that the lack of expression of Celf2a is not due to mutations of its gene, but to a trans-generational epigenetic silencing that operates through a specific non-coding RNA. The real goal would be to reproduce this specific molecular condition in other patients, opening important new perspectives for treatment."

That is why the team's subsequent studies will investigate Celf2a as a therapeutic target and will aim to develop potential molecules capable of inhibiting this factor when present. These molecules could become a treatment, which to date does not exist, for other patients with the same type of mutation.



Trans-generational epigenetic regulation associated with the amelioration of Duchenne Muscular Dystrophy - J. Martone, M. Lisi, F. Castagnetti, A. Rosa, V. Di Carlo, E. Blanco, A. Setti, D. Mariani, A. Colantoni, T. Santini, L. Perone, L. Di Croce & I. Bozzoni - EMBO Molecular Medicine (2020) DOI https://doi.org/10.15252/emmm.202012063


Further Information

Irene Bozzoni
Department of Biology and Biotechnology Charles Darwin



Monday, 06 July 2020

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