Targeting FSHD With Designed Antisense RNAs

Targeting FSHD With Designed Antisense RNAs 1024 683 Abbie Miller

Researchers describe small nuclear RNA antisense expression cassettes as a way to silence the DUX4 gene underlying facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) arises from genetic and epigenetic changes that result in expression of the DUX4 gene in muscle. DUX4 is a developmental gene that is normally off in healthy muscle.  When expressed in FSHD muscle, DUX4 activates pathways involved in cell death, oxidative stress, impaired muscle differentiation, immune responses and muscle atrophy.

Currently, FSHD affects up to 870,000 individuals world-wide, with no treatments to alter the course of this progressive, life-long disease are available.

Researchers in the lab of Scott Harper, PhD, principal investigator in the Center for Gene Therapy, have been dedicated to understanding the role of DUX4 in FSHD and developing potential therapies. In their recent publication in Molecular Therapy: Nucleic Acids, they describe three U7 small nuclear RNA antisense expression cassettes (U7-asDUX4) as a way to silence DUX4 expression in human cells, including those derived from FSHD patient muscles.

“These noncoding RNAs inhibit the production or maturation of the full-length DUX4 pre-mRNA by masking either the DUX4 start codon, the splice sites or the polyadenylation signal,” says Dr. Harper. “Targeting these sites enables us to stop the production of DUX4 protein.”

The U7-asDUX4 cassettes act similarly to the previously described antisense oligonucleotides, but with the added advantage of a potential one-time delivery approach.

“With antisense oligonucleotides, uptake into the muscles is poor, and we need repeated, lifelong dosing,” says Dr. Harper. “With U7-asDUX4, though, we can use a gene therapy vector for delivery, and one dose might be sufficient for sustained silencing.”

The team demonstrated the ability of the U7-asDUX4 constructs in cotransfected cells and myotubes derived from individuals with FSHD. The study serves as a proof of concept for the potential therapy. Translation of this approach will require safety and efficacy studies in the Harper lab’s TIC-DUX4 mouse model, which are currently ongoing in the Harper Lab.

“We believe that this approach has the potential to be a new therapeutic option for individuals with FSHD,” Dr. Harper says. “We expect that these could be used in combination with RNAi therapy to maximize DUX4 silencing, or even as a standalone therapy. We look forward to seeing the translation of this therapy through preclinical studies and the prospect of future clinical studies.”



Rashnonejad A, Amini-Chermahini G, Taylor NK, Wein N, Harper SQ. Designed U7 snRNAs inhibit DUX4 expression and improve FSHD-associated outcomes in overexpressing cells and FSHD patient myotubes. Molecular Therapy: Nucleic Acids. 2021 Mar;23:476-486.

Image credit: Adobe Stock

About the author

Abbie (Roth) Miller, MWC, is a passionate communicator of science. As the manager, medical and science content, at Nationwide Children’s Hospital, she shares stories about innovative research and discovery with audiences ranging from parents to preeminent researchers and leaders. Before coming to Nationwide Children’s, Abbie used her communication skills to engage audiences with a wide variety of science topics. She is a Medical Writer Certified®, credentialed by the American Medical Writers Association.