Exploring new therapeutic approaches in FSHD by small molecules modulation of endogenous microRNA

by Enrico Bugiardini


Human miRNA miR-675 inhibits DUX4 expression and may be exploited as a potential treatment for Facioscapulohumeral muscular dystrophy.
Saad, Nizar Y; Al-Kharsan, Mustafa; Garwick-Coppens, Sara E; Chermahini, Gholamhossein Amini; Harper, Madison A; Palo, Andrew; Boudreau, Ryan L; Harper, Scott Q
Nat Commun. 2021 Dec 8;12(1):7128. doi: 10.1038/s41467-021-27430-1.


Facioscapulohumeral muscular dystrophy (FSHD) is the third most common muscular dystrophy. Since the identification of DUX4 aberrant expression in muscle as major player in FSHD pathogenesis, many research lines have started focusing on therapeutic approaches targeting DUX4.

In this manuscript Saad et al. elegantly explored the modulation of endogenous human microRNA genes as potential therapy in FSHD. There are 1917 known endogenous human microRNA but none yet known to regulate DUX4. First, they used two target prediction bioinformatic algorithms to screen candidate microRNA and identify miR-675. They then confirmed the role of miR675 as negative regulator of DUX4 expression using multiple in vitro assays. Their findings were corroborated by demonstrating miR675 protective effect on DUX-4 induced damage in cell models. After collating evidence for miR-675 as a DUX4 regulator, the Authors wanted to explore whether miR-675 could be considered a viable therapeutic option. Interestingly, they applied two different approaches. First, they used a more standard gene therapy strategy. They overexpressed miR-675 in DUX4-expressing mouse model and showed a suppression of DUX-4 responsive biomarkers and protection against DUX-4 associated toxicity. Second, they explored whether small molecules able to upregulate miR-675 could be used as potential DUX4-targeting therapies. The Authors tested melatonin, estrogen and progesterone, known miR-675 regulator, and showed that they were able to increase miR-675 and decrease DUX4 and related biomarkers in FSHD patient myotubes.

In conclusion, this study identifies and highlights the importance of miR-675 as endogenous regulator of DUX4 expression opening new therapeutic venues in FSHD. This paper also demonstrates the potential of using small molecules as therapeutic approach through an RNA interference mechanism. The latter represents an interesting and innovative approach that can be extended to other neurogenetic conditions.

About the Author

Dr Nizar Saad

Dr. Saad obtained his bachelor’s degree in biochemistry from the Lebanese University, and received his Master’s degree in molecular biology and his PhD in life sciences from the University of Strasbourg in France. Dr. Saad was then engaged in two consecutive postdoctoral scientist positions, in the laboratories of Dr. Tina Henkin at the Ohio State University (OSU) and Dr. Scott Q. Harper at the Center for Gene Therapy at Nationwide Children’s Hospital (NCH). As a graduate student, and then as a postdoc at OSU, Dr. Saad investigated bacterial tRNA-sensing riboswitch-based gene regulatory mechanisms. Aiming to pursue a career in translational research, Dr. Saad investigated microRNA-based mechanisms related to the progression and treatment of facioscapulohumeral muscular dystrophy (FSHD) in vitro and in vivo in the laboratory of Dr. Harper. This was a completely new project exploring a new hypothesis that natural microRNAs regulate the DUX4 gene underlying FSHD. Dr. Saad and Dr. Harper identified a natural microRNA that specifically targets DUX4, which they exploit to develop an AAV-based gene therapy and a drug-based therapy to upregulate its expression in skeletal muscle. During his career, Dr. Saad obtained numerous fellowships and grants to support his research, and received an award from WMS in recognition of his research. In his future work, Dr. Saad will investigate the pathobiology of other muscular dystrophies and genetic diseases for which he hopes to develop viral, non-viral and drug-based therapies.

Published on 10 January 2022.


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This article is presented by the Publication Highlights Committee.

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