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Article: FSHD Therapeutic Strategies: What Will It Take to Get to Clinic?

Himeda, Charis L / Jones, Peter L

2022 Volume 12, Issue 6

Abstract: Facioscapulohumeral muscular dystrophy (FSHD) is arguably one of the most challenging genetic diseases to understand and treat. The disease is caused by epigenetic dysregulation of a macrosatellite repeat, either by contraction of the repeat or by ... ...

Abstract	Facioscapulohumeral muscular dystrophy (FSHD) is arguably one of the most challenging genetic diseases to understand and treat. The disease is caused by epigenetic dysregulation of a macrosatellite repeat, either by contraction of the repeat or by mutations in silencing proteins. Both cases lead to chromatin relaxation and, in the context of a permissive allele, pathogenic misexpression of
Language	English
Publishing date	2022-05-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662248-8
ISSN	2075-4426
ISSN	2075-4426
DOI	10.3390/jpm12060865
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Article ; Online: FSHD Therapeutic Strategies

Charis L. Himeda / Peter L. Jones

Journal of Personalized Medicine, Vol 12, Iss 865, p

What Will It Take to Get to Clinic?

2022 Volume 865

Abstract	Facioscapulohumeral muscular dystrophy (FSHD) is arguably one of the most challenging genetic diseases to understand and treat. The disease is caused by epigenetic dysregulation of a macrosatellite repeat, either by contraction of the repeat or by mutations in silencing proteins. Both cases lead to chromatin relaxation and, in the context of a permissive allele, pathogenic misexpression of DUX4 in skeletal muscle. The complex nature of the locus and the fact that FSHD is a toxic, gain-of-function disease present unique challenges for the design of therapeutic strategies. There are three major DUX4-targeting avenues of therapy for FSHD: small molecules, oligonucleotide therapeutics, and CRISPR-based approaches. Here, we evaluate the preclinical progress of each avenue, and discuss efforts being made to overcome major hurdles to translation.
Keywords	facioscapulohumeral muscular dystrophy ; FSHD ; DUX4 ; skeletal muscle ; muscular dystrophy ; gene therapy ; Medicine ; R
Subject code	610
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: The Good, The Bad, and The Unexpected: Roles of DUX4 in Health and Disease.

Himeda, Charis L / Jones, Peter L

Developmental cell

2019 Volume 50, Issue 5, Page(s) 525–526

Abstract: In this issue of Developmental Cell, Chew et al. (2019) show that the pioneer factor DUX4 is misexpressed in tumors, where it suppresses anti-tumor immune activity. Their findings provide a new mechanism for immune evasion in cancer and highlight the ... ...

Abstract	In this issue of Developmental Cell, Chew et al. (2019) show that the pioneer factor DUX4 is misexpressed in tumors, where it suppresses anti-tumor immune activity. Their findings provide a new mechanism for immune evasion in cancer and highlight the pathogenic effects of re-expressing an embryonic program in adult cells.
MeSH term(s)	Homeodomain Proteins ; Humans ; Immune Evasion ; Muscular Dystrophy, Facioscapulohumeral ; Neoplasms
Chemical Substances	Homeodomain Proteins
Language	English
Publishing date	2019-09-10
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2054967-2
ISSN	1878-1551 ; 1534-5807
ISSN (online)	1878-1551
ISSN	1534-5807
DOI	10.1016/j.devcel.2019.08.010
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Article ; Online: The Genetics and Epigenetics of Facioscapulohumeral Muscular Dystrophy.

Himeda, Charis L / Jones, Peter L

Annual review of genomics and human genetics

2019 Volume 20, Page(s) 265–291

Abstract: Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, provides a powerful model of the complex interplay between genetic and epigenetic mechanisms of chromatin regulation. FSHD is caused by ... ...

Abstract	Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, provides a powerful model of the complex interplay between genetic and epigenetic mechanisms of chromatin regulation. FSHD is caused by dysregulation of a macrosatellite repeat, either by contraction of the repeat or by mutations in silencing proteins. Both cases lead to chromatin relaxation and, in the context of a permissive allele, aberrant expression of the
MeSH term(s)	CRISPR-Cas Systems ; Chromatin/chemistry ; Chromosomal Proteins, Non-Histone/genetics ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes, Human, Pair 4 ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA (Cytosine-5-)-Methyltransferases/metabolism ; DNA Methylation ; Epigenesis, Genetic ; Gene Editing ; Genetic Loci ; Genome, Human ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Humans ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; Muscular Dystrophy, Facioscapulohumeral/classification ; Muscular Dystrophy, Facioscapulohumeral/genetics ; Muscular Dystrophy, Facioscapulohumeral/metabolism ; Muscular Dystrophy, Facioscapulohumeral/pathology ; Mutation ; Severity of Illness Index ; DNA Methyltransferase 3B
Chemical Substances	Chromatin ; Chromosomal Proteins, Non-Histone ; DUX4L1 protein, human ; Homeodomain Proteins ; SMCHD1 protein, human ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37)
Language	English
Publishing date	2019-04-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2037670-4
ISSN	1545-293X ; 1527-8204
ISSN (online)	1545-293X
ISSN	1527-8204
DOI	10.1146/annurev-genom-083118-014933
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Article: Targeted epigenetic repression by CRISPR/dSaCas9 suppresses pathogenic

Himeda, Charis L / Jones, Takako I / Jones, Peter L

Molecular therapy. Methods & clinical development

2020 Volume 20, Page(s) 298–311

Abstract: Facioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete silencing of the disease locus, leading to pathogenic misexpression ... ...

Abstract	Facioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete silencing of the disease locus, leading to pathogenic misexpression of
Language	English
Publishing date	2020-12-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2872938-9
ISSN	2329-0501 ; 2329-0501
ISSN (online)	2329-0501
ISSN	2329-0501
DOI	10.1016/j.omtm.2020.12.001
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Article ; Online: Scalpel or Straitjacket: CRISPR/Cas9 Approaches for Muscular Dystrophies.

Himeda, Charis L / Jones, Takako I / Jones, Peter L

Trends in pharmacological sciences

2016 Volume 37, Issue 4, Page(s) 249–251

Abstract: Versatility of CRISPR/Cas9-based platforms makes them promising tools for the correction of diverse genetic/epigenetic disorders. Here we contrast the use of these genome editing tools in two myopathies with very different molecular origins: Duchenne ... ...

Abstract	Versatility of CRISPR/Cas9-based platforms makes them promising tools for the correction of diverse genetic/epigenetic disorders. Here we contrast the use of these genome editing tools in two myopathies with very different molecular origins: Duchenne muscular dystrophy, a monogenetic disease, and facioscapulohumeral muscular dystrophy, an epigenetic disorder with unique therapeutic challenges.
MeSH term(s)	Animals ; CRISPR-Cas Systems ; Clustered Regularly Interspaced Short Palindromic Repeats ; Homeodomain Proteins/genetics ; Humans ; Muscular Dystrophy, Duchenne/genetics
Chemical Substances	Homeodomain Proteins
Language	English
Publishing date	2016-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	282846-7
ISSN	1873-3735 ; 0165-6147
ISSN (online)	1873-3735
ISSN	0165-6147
DOI	10.1016/j.tips.2016.02.001
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Article ; Online: CRISPR/dCas9-mediated Transcriptional Inhibition Ameliorates the Epigenetic Dysregulation at D4Z4 and Represses DUX4-fl in FSH Muscular Dystrophy.

Himeda, Charis L / Jones, Takako I / Jones, Peter L

Molecular therapy : the journal of the American Society of Gene Therapy

2015 Volume 24, Issue 3, Page(s) 527–535

Abstract: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent myopathies, affecting males and females of all ages. Both forms of the disease are linked by epigenetic derepression of the D4Z4 macrosatellite repeat array at chromosome 4q35, ... ...

Abstract	Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent myopathies, affecting males and females of all ages. Both forms of the disease are linked by epigenetic derepression of the D4Z4 macrosatellite repeat array at chromosome 4q35, leading to aberrant expression of D4Z4-encoded RNAs in skeletal muscle. Production of full-length DUX4 (DUX4-fl) mRNA from the derepressed D4Z4 array results in misexpression of DUX4-FL protein and its transcriptional targets, and apoptosis, ultimately leading to accumulated muscle pathology. Returning the chromatin at the FSHD locus to its nonpathogenic, epigenetically repressed state would simultaneously affect all D4Z4 RNAs, inhibiting downstream pathogenic pathways, and is thus an attractive therapeutic strategy. Advances in CRISPR/Cas9-based genome editing make it possible to target epigenetic modifiers to an endogenous disease locus, although reports to date have focused on more typical genomic regions. Here, we demonstrate that a CRISPR/dCas9 transcriptional inhibitor can be specifically targeted to the highly repetitive FSHD macrosatellite array and alter the chromatin to repress expression of DUX4-fl in primary FSHD myocytes. These results implicate the promoter and exon 1 of DUX4 as potential therapeutic targets and demonstrate the utility of CRISPR technology for correction of the epigenetic dysregulation in FSHD.
MeSH term(s)	CRISPR-Cas Systems ; Clustered Regularly Interspaced Short Palindromic Repeats ; Epigenesis, Genetic ; Exons ; Gene Editing ; Gene Expression Regulation ; Gene Targeting ; Genetic Loci ; Homeodomain Proteins/genetics ; Humans ; Microsatellite Repeats ; Muscle Cells/metabolism ; Muscular Dystrophy, Facioscapulohumeral/genetics ; Promoter Regions, Genetic ; Protein Binding ; Recombinant Fusion Proteins/metabolism ; Transcription, Genetic ; Transcriptional Activation
Chemical Substances	DUX4L1 protein, human ; Homeodomain Proteins ; Recombinant Fusion Proteins
Language	English
Publishing date	2015-11-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1038/mt.2015.200
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Article ; Online: Large family cohorts of lymphoblastoid cells provide a new cellular model for investigating facioscapulohumeral muscular dystrophy.

Jones, Takako I / Himeda, Charis L / Perez, Daniel P / Jones, Peter L

Neuromuscular disorders : NMD

2016 Volume 27, Issue 3, Page(s) 221–238

Abstract: Facioscapulohumeral muscular dystrophy (FSHD) is associated with aberrant epigenetic regulation of the chromosome 4q35 D4Z4 macrosatellite repeat. The resulting DNA hypomethylation and relaxation of epigenetic repression leads to increased expression of ... ...

Abstract	Facioscapulohumeral muscular dystrophy (FSHD) is associated with aberrant epigenetic regulation of the chromosome 4q35 D4Z4 macrosatellite repeat. The resulting DNA hypomethylation and relaxation of epigenetic repression leads to increased expression of the deleterious DUX4-fl mRNA encoded within the distal D4Z4 repeat. With the typical late onset of muscle weakness, prevalence of asymptomatic individuals, and an autosomal dominant mode of inheritance, FSHD is often passed on from one generation to the next and affects multiple individuals within a family. Here we have characterized unique collections of 114 lymphoblastoid cell lines (LCLs) generated from 12 multigenerational FSHD families, including 56 LCLs from large, genetically homogeneous families in Utah. We found robust expression of DUX4-fl in most FSHD LCLs and a good correlation between DNA hypomethylation and repeat length. In addition, DUX4-fl levels can be manipulated using epigenetic drugs as in myocytes, suggesting that some epigenetic pathways regulating DUX4-fl in myocytes are maintained in LCLs. Overall, these FSHD LCLs provide an alternative cellular model in which to study many aspects of D4Z4, DUX4, and FSHD gene regulation in a background of low genetic variation. Significantly, these non-adherent immortal LCLs are amenable for high-throughput screening of potential therapeutics targeting DUX4-fl mRNA or protein expression.
MeSH term(s)	Cell Line ; DNA Methylation/genetics ; Epigenesis, Genetic/genetics ; Female ; Humans ; Male ; Muscular Dystrophy, Facioscapulohumeral/genetics ; Pedigree
Language	English
Publishing date	2016-12-23
Publishing country	England
Document type	Journal Article
ZDB-ID	1077681-3
ISSN	1873-2364 ; 0960-8966
ISSN (online)	1873-2364
ISSN	0960-8966
DOI	10.1016/j.nmd.2016.12.007
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Article ; Online: Facioscapulohumeral muscular dystrophy as a model for epigenetic regulation and disease.

Himeda, Charis L / Jones, Takako I / Jones, Peter L

Antioxidants & redox signaling

2014 Volume 22, Issue 16, Page(s) 1463–1482

Abstract: Significance: Aberrant epigenetic regulation is an integral aspect of many diseases and complex disorders. Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, is caused by disrupted genetic and ... ...

Abstract	Significance: Aberrant epigenetic regulation is an integral aspect of many diseases and complex disorders. Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, is caused by disrupted genetic and epigenetic regulation of a macrosatellite repeat. FSHD provides a powerful model to investigate disease-relevant epigenetic modifiers and general mechanisms of epigenetic regulation that govern gene expression. Recent advances: In the context of a genetically permissive allele, the one aspect of FSHD that is consistent across all known cases is the aberrant epigenetic state of the disease locus. In addition, certain mutations in the chromatin regulator SMCHD1 (structural maintenance of chromosomes hinge-domain protein 1) are sufficient to cause FSHD2 and enhance disease severity in FSHD1. Thus, there are multiple pathways to generate the epigenetic dysregulation required for FSHD. Critical issues: Why do some individuals with the genetic requirements for FSHD develop disease pathology, while others remain asymptomatic? Similarly, disease progression is highly variable among individuals. What are the relative contributions of genetic background and environmental factors in determining disease manifestation, progression, and severity in FSHD? What is the interplay between epigenetic factors regulating the disease locus and which, if any, are viable therapeutic targets? Future directions: Epigenetic regulation represents a potentially powerful therapeutic target for FSHD. Determining the epigenetic signatures that are predictive of disease severity and identifying the spectrum of disease modifiers in FSHD are vital to the development of effective therapies.
MeSH term(s)	Animals ; Disease Progression ; Epigenesis, Genetic/genetics ; Humans ; Muscular Dystrophy, Facioscapulohumeral/genetics ; Muscular Dystrophy, Facioscapulohumeral/metabolism
Language	English
Publishing date	2014-12-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1483836-9
ISSN	1557-7716 ; 1523-0864
ISSN (online)	1557-7716
ISSN	1523-0864
DOI	10.1089/ars.2014.6090
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Article ; Online: Pax3 synergizes with Gli2 and Zic1 in transactivating the Myf5 epaxial somite enhancer.

Himeda, Charis L / Barro, Marietta V / Emerson, Charles P

Developmental biology

2013 Volume 383, Issue 1, Page(s) 7–14

Abstract: Both Glis, the downstream effectors of hedgehog signaling, and Zic transcription factors are required for Myf5 expression in the epaxial somite. Here we demonstrate a novel synergistic interaction between members of both families and Pax3, a paired- ... ...

Abstract	Both Glis, the downstream effectors of hedgehog signaling, and Zic transcription factors are required for Myf5 expression in the epaxial somite. Here we demonstrate a novel synergistic interaction between members of both families and Pax3, a paired-domain transcription factor that is essential for both myogenesis and neural crest development. We show that Pax3 synergizes with both Gli2 and Zic1 in transactivating the Myf5 epaxial somite (ES) enhancer in concert with the Myf5 promoter. This synergy is dependent on conserved functional domains of the proteins, as well as on a novel homeodomain motif in the Myf5 promoter and the essential Gli motif in the ES enhancer. Importantly, overexpression of Zic1 and Pax3 in the 10T1/2 mesodermal cell model results in enrichment of these factors at the endogenous Myf5 locus and induction of Myf5 expression. In our previous work, we showed that by enhancing nuclear translocation of Gli factors, Zics provide spatiotemporal patterning for Gli family members in the epaxial induction of Myf5 expression. Our current study indicates a complementary mechanism in which association with DNA-bound Pax3 strengthens the ability of both Zic1 and Gli2 to transactivate Myf5 in the epaxial somite.
MeSH term(s)	Animals ; Blotting, Western ; Chromatin Immunoprecipitation ; DNA Primers/genetics ; Electrophoretic Mobility Shift Assay ; Embryonic Stem Cells/metabolism ; Immunoprecipitation ; Kruppel-Like Transcription Factors/metabolism ; Mesenchymal Stem Cells/metabolism ; Mice ; Myogenic Regulatory Factor 5/metabolism ; NIH 3T3 Cells ; PAX3 Transcription Factor ; Paired Box Transcription Factors/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Somites/embryology ; Somites/metabolism ; Transcription Factors/metabolism ; Transcriptional Activation/physiology ; Zinc Finger Protein Gli2
Chemical Substances	DNA Primers ; Gli2 protein, mouse ; Kruppel-Like Transcription Factors ; Myf5 protein, mouse ; Myogenic Regulatory Factor 5 ; PAX3 Transcription Factor ; Paired Box Transcription Factors ; Transcription Factors ; Zic1 protein, mouse ; Zinc Finger Protein Gli2 ; Pax3 protein, mouse (138016-91-8)
Language	English
Publishing date	2013-09-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2013.09.006
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