Meeting report: the 2021 FSHD International Research Congress

Sujatha Jagannathan, Jessica C de Greef, Lawrence J Hayward, Kyoko Yokomori, Davide Gabellini, Karlien Mul, Sabrina Sacconi, Jamshid Arjomand, June Kinoshita, Scott Q Harper, Sujatha Jagannathan, Jessica C de Greef, Lawrence J Hayward, Kyoko Yokomori, Davide Gabellini, Karlien Mul, Sabrina Sacconi, Jamshid Arjomand, June Kinoshita, Scott Q Harper

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is the second most common genetic myopathy, characterized by slowly progressing and highly heterogeneous muscle wasting with a typical onset in the late teens/early adulthood [1]. Although the etiology of the disease for both FSHD type 1 and type 2 has been attributed to gain-of-toxic function stemming from aberrant DUX4 expression, the exact pathogenic mechanisms involved in muscle wasting have yet to be elucidated [2-4]. The 2021 FSHD International Research Congress, held virtually on June 24-25, convened over 350 researchers and clinicians to share the most recent advances in the understanding of the disease mechanism, discuss the proliferation of interventional strategies and refinement of clinical outcome measures, including results from the ReDUX4 trial, a phase 2b clinical trial of losmapimod in FSHD [NCT04003974].

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

References

    1. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy. Continuum (Minneap Minn) 2016;22(6, Muscle and Neuromuscular Junction Disorders):1916–1931. doi: 10.1212/CON.0000000000000399.
    1. Kowaljow V, Marcowycz A, Ansseau E, Conde CB, Sauvage S, Matteotti C, et al. The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein. Neuromuscul Disord. 2007;17(8):611–623. doi: 10.1016/j.nmd.2007.04.002.
    1. Lemmers RJ, Tawil R, Petek LM, Balog J, Block GJ, Santen GW, et al. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet. 2012;44(12):1370–1374. doi: 10.1038/ng.2454.
    1. Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camano P, Dauwerse JG, et al. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science. 2010. 10.1126/science.1189044 Epub 2010/08/21. doi: science.1189044 [pii]. PubMed PMID: .
    1. Flanigan KM, Coffeen CM, Sexton L, Stauffer D, Brunner S, Leppert MF. Genetic characterization of a large, historically significant Utah kindred with facioscapulohumeral dystrophy. Neuromuscul Disord. 2001;11(6-7):525–529. doi: 10.1016/s0960-8966(01)00201-2.
    1. Tyler FH, Stephens FE. Studies in disorders of muscle. II Clinical manifestations and inheritance of facioscapulohumeral dystrophy in a large family. Ann Intern Med. 1950;32(4):640–660. doi: 10.7326/0003-4819-32-4-640.
    1. Rickard AM, Petek LM, Miller DG. Endogenous DUX4 expression in FSHD myotubes is sufficient to cause cell death and disrupts RNA splicing and cell migration pathways. Hum Mol Genet. 2015;24(20):5901–5914. doi: 10.1093/hmg/ddv315.
    1. Bosnakovski D, Chan SSK, Recht OO, Hartweck LM, Gustafson CJ, Athman LL, et al. Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model. Nat Commun. 2017;8(1):550. doi: 10.1038/s41467-017-00730-1.
    1. Cabianca DS, Casa V, Bodega B, Xynos A, Ginelli E, Tanaka Y, et al. A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy. Cell. 2012;149(4):819–831. doi: 10.1016/j.cell.2012.03.035.
    1. Gordon CT, Xue S, Yigit G, Filali H, Chen K, Rosin N, et al. De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development. Nat Genet. 2017;49(2):249–255. doi: 10.1038/ng.3765.
    1. Assarsson E, Lundberg M, Holmquist G, Bjorkesten J, Thorsen SB, Ekman D, et al. Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS One. 2014;9(4):e95192. doi: 10.1371/journal.pone.0095192.
    1. Mueller AL, O’Neill A, Jones TI, Llach A, Rojas LA, Sakellariou P, et al. Muscle xenografts reproduce key molecular features of facioscapulohumeral muscular dystrophy. Exp Neurol. 2019;320:113011. doi: 10.1016/j.expneurol.2019.113011.
    1. Jones T, Jones PL. A cre-inducible DUX4 transgenic mouse model for investigating facioscapulohumeral muscular dystrophy. PLoS One. 2018;13(2):e0192657. doi: 10.1371/journal.pone.0192657.
    1. Gros M, Nunes AM, Daoudlarian D, Pini J, Martinuzzi E, Barbosa S, et al. Identification of serum interleukin 6 levels as a disease severity biomarker in facioscapulohumeral muscular dystrophy. J Neuromuscul Dis. 2021. 10.3233/JND-210711 Epub 2021/08/31. PubMed PMID: 34459413.
    1. Saad, et al. Human miRNA mir-675 inhibits DUX4 expression and may be exploited as a potential treatment for Facioscapulohumeral muscular dystrophy. Nat Commun. 2021;12(1):7128.
    1. Roberts TC, Langer R, Wood MJA. Advances in oligonucleotide drug delivery. Nat Rev Drug Discov. 2020;19(10):673–694. doi: 10.1038/s41573-020-0075-7.
    1. Bouwman LF, den Hamer B, van den Heuvel A, Franken M, Jackson M, Dwyer CA, et al. Systemic delivery of a DUX4-targeting antisense oligonucleotide to treat facioscapulohumeral muscular dystrophy. Mol Ther Nucleic Acids. 2021;26:813–827. doi: 10.1016/j.omtn.2021.09.010.
    1. Chen JC, King OD, Zhang Y, Clayton NP, Spencer C, Wentworth BM, et al. Morpholino-mediated knockdown of DUX4 toward facioscapulohumeral muscular dystrophy therapeutics. Mol Ther. 2016;24(8):1405–1411. doi: 10.1038/mt.2016.111.
    1. Lu-Nguyen N, Malerba A, Herath S, Dickson G, Popplewell L. Systemic antisense therapeutics inhibiting DUX4 expression ameliorates FSHD-like pathology in an FSHD mouse model. Hum Mol Genet. 2021;30(15):1398–1412. doi: 10.1093/hmg/ddab136.
    1. Wallace LM, Liu J, Domire JS, Garwick-Coppens SE, Guckes SM, Mendell JR, et al. RNA interference inhibits DUX4-induced muscle toxicity in vivo: implications for a targeted FSHD therapy. Mol Ther. 2012;20(7):1417–1423. doi: 10.1038/mt.2012.68.
    1. Wallace LM, Saad NY, Pyne NK, Fowler AM, Eidahl JO, Domire JS, et al. Pre-clinical safety and off-target studies to support translation of AAV-mediated RNAi therapy for FSHD. Mol Ther Methods Clin Dev. 2018;8:121–130. doi: 10.1016/j.omtm.2017.12.005.
    1. Giesige CR, Wallace LM, Heller KN, Eidahl JO, Saad NY, Fowler AM, et al. AAV-mediated follistatin gene therapy improves functional outcomes in the TIC-DUX4 mouse model of FSHD. JCI Insight. 2018;3(22). 10.1172/jci.insight.123538 PubMed PMID: 30429376; PubMed Central PMCID: PMCPMC6302942.
    1. Lim KRQ, Maruyama R, Echigoya Y, Nguyen Q, Zhang A, Khawaja H, et al. Inhibition of DUX4 expression with antisense LNA gapmers as a therapy for facioscapulohumeral muscular dystrophy. Proc Natl Acad Sci U S A. 2020;117(28):16509–16515. doi: 10.1073/pnas.1909649117.

Source: PubMed

3
订阅