Fshd Mouse Model

June 28, 2018 — A dietary supplement derived from glucose increases muscle-force production in the Duchenne muscular dystrophy (DMD) mouse model by 50 percent in ten days, according to a new. Domire, Lindsay M. In this blog Facioscapulohumeral Muscular Dystrophy is referred to by the following: FSH, FSHD, or Facioscapulohumeral MD. About 30,792 results Sort by: Relevance; Most Recent Per Page: 20; 50; 100. 3 splicing by FRG1 in a mouse model of. Non-coding RNA expression is regulated in the active phase of muscle fiber necrosis and degeneration that develops at 4 to 6 weeks of age in the mdx mouse model. 76 Muscular dystrophies and congenital myopathi P5. DUX4 sets in motion a cascade of biochemical events that eventually result in the devastating effects of FSHD. Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary disease of muscle. A unifying genetic model for the mechanism of FSHD was recently discovered which raises the hope for disease-directed therapies. Retinal abnormalities are frequently described in patients with facioscapulohumeral dystrophy. This region is composed mainly of a polymorphic repeat structure consisting of 3. The major form of FSHD (FSHD1A, OMIM #158900) is associated with a reduction of subtelomeric repeats (D4Z4) on the long arm of chromosome 4 (4q35). Early 2019, we entered an agreement with the Centre for Human Drug Research (CHDR; Leiden, the Netherlands) on a study aimed at discovering FSHD clinical outcome measures based on real-world patient data. Erratum Author Correction: Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model (Nature communications (2017) 8 1 (550)). Here, we report such a model - the tamoxifen-inducible FSHD mouse model called TIC-DUX4. Mouse model: Increases frequency of central nuclei in muscle fibers Brain: Aberrantly spliced RNA produces altered splicing of several proteins NMDA receptor 1 (NMDAR1): 3-fold increase in fraction of mRNA that includes exon 5 Altered pharmacology, gating & cellular distribution (somatic rather than somato-dendritic expression). These processes involve linc-MD1, miR-1, and miR-133a, displaying complex expression patterns that change over time. FSHD is a complex genetic disorder for which the relative lack of clinical trials is attributable in part to the absence of an accepted mouse model for preclinical testing. Many different cell culture models have been developed to study the pathophysiology of FSHD, frequently based on endogenous expression of DUX4 in FSHD cells or by mis-expression of DUX4 in control human muscle cells. Our studies also provide insights into the biological function of DNA repetitive elements in gene transcription and. ” Stem Cells 19:e1402. FSHD is an autosomal dominant disease that affects 1:20000 individuals. A genomic fragment from the terminal D4Z4 repeat of an FSHD 4qA161 allele including the DUX4 ORF, 3ʹ UTR and DUX4 pA was introduced at the same location b d WT iDux4pA WT iDux4pA 0 20 40 60 Expected # of progeny. These practice guidelines will deal with issues such as genetic testing, physical therapy, exercise, bracing. Only contractions associated with the 4qA161 haplotype cause FSHD. Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common hereditary muscular disorders. Michael Kyba a $100,000 grant to begin developing a mouse model for FSHD focusing on the gene, DUX4 (See D4Z4/DUX4 Induced Pathologies in Mice ). Project: Research. FSHD Therapeutics. This enzyme participates in the urea cycle, a series of reactions that occurs in liver cells. Finally, p38 inhibitors effectively suppress DUX4 expression in a mouse xenograft model of human FSHD gene regulation. In order to address this deficit, these studies propose to create a novel mouse model using muscle tissue grafts from FSHD human donors. "In genetic diseases for which therapies have been developed, like Duchenne muscular dystrophy, mouse model like the one we discovered were essential to the development and testing for potential therapies," Kyba said, "Now that this hurdle has been overcome for FSHD, we have great hope for a therapy development. In this model, biceps muscles from FSHD patients (expressing DUX4-fl) and their unaffected family members were collected and grafted into. June 28, 2018 — A dietary supplement derived from glucose increases muscle-force production in the Duchenne muscular dystrophy (DMD) mouse model by 50 percent in ten days, according to a new. Furthermore, conventional transgenic studies suffer from high variability due to integration site‐specific. 1126/science. Results: In the context of myogenic differentiation, we compared the chromatin structure and tridimensional interaction of the D4Z4 array and FRG1 gene promoter, and FRG1 expression, in control and FSHD cells. Hanel1,* and Peter L. Giesige, Nettie K. View Show abstract. 69 Bulbofacial myopathy with anti-amphiphysin 2 [Role of associated alleles and hypomethylation st Gene expression during normal and FSHD myogenesis. In addition we show that DUX4 is able to activate similar functional gene groups in mouse muscle cells as it does in human muscle cells. Mouse models are important tools for studying disease and developing treatments. Facio is the first in the FSHD field to achieve proof of principle in an animal model (“in vivo”). In an attempt to generate an FSHD mouse model independent of candidate genes, Zhang et al. 00046 Cell and Developmental Biology Review Pitx2 in Embryonic and Adult Myogenesis Hernandez-Torres Francisco 1 2 Rodríguez-Outeiriño Lara 1 2 Franco Diego 1 2 Aranega Amelia E. Here we show that systemic delivery of RNA interference expression cassettes in the FRG1 mouse, after the onset of disease, led to a dose-dependent long-term FRG1 knockdown without signs of toxicity. FSHD, and clinical trials with novel therapeutics have been dis-couraged by the lack of a recognized mouse model. Grant 16 Re­creating the human chromosomal genetic defect responsible for FSHD in a mouse model. Erratum Author Correction: Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model (Nature communications (2017) 8 1 (550)). FSHD Global Research Foundation (Harper, PI) 1/1/2019 - 12/31/2020 "Developing AAV-follistatin gene therapy alone or in combination with RNAi in a novel mouse model of FSHD" The goal of this project is to test AAV. \ud Mapping studies have associated the disease with a reduced number\ud (1-10) of the D4Z4 macrosatellite repeats from the usual ~100. Since DUX4 is toxic, animal model development has been challenging, but progress has been made, revealing that tight regulation of DUX4 expression is critical for creating viable animals that develop myopathy. Amy Campbell, a dedicated professional highly skilled in FSHD research who oversees the completion of high-impact studies on FSHD and provides scientific and technical oversight for graduate students, postdoctoral fellows, and collaborators seeking to initiate and/or advance projects in FSHD. When they activated the gene in the mice skeletal muscle cells, the animals developed a slow progressive muscular dystrophy with key features of the human disease. FSHD is a complex genetic disorder for which the relative lack of clinical trials is attributable in part to the absence of an accepted mouse model for preclinical testing. We recently generated a mouse model of facioscapulohumeral muscular dystrophy (FSHD) by selectively overexpressing FRG1, a candidate gene for FSHD, in skeletal muscle. Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model. Building an FSHD model has proven to be a substantial challenge. 5 unit containing D4Z4 repeat (D4Z4-12. Serum biomarkers related to disease activity will be important for proof of concept or early phase clinical studies. In this model, biceps muscles from FSHD patients (expressing DUX4-fl) and their unaffected family members were collected and grafted into. Researchers find animal model for understudied type of muscular dystrophy Date: August 28, 2014 The mouse model designed by Kyba and his team allows the disease-associated DUX4 protein to be. National patient registries. D4Z4 is a primate-specific repeat (Clark et al. Scientific Projects Current Fields Center projects are focused on the following areas of FSHD (FSH dystrophy) research: Clinical Research. The Board of Directors of the Chris Carrino Foundation for FSHD has proudly approved the funding of $107,777 to Peter Jones, PhD and Takako Jones, PhD at the University of Massachusetts for their mouse model research project. Clinical Care: Develop clinical practice guidelines for the care of individuals with FSHD. , Giesige Carlee R. A similar effect has been observed previously in a mouse model with simultaneous up-regulation of a microRNA, namely miR-206, and its target gene urotropin. Lemmers, et al. In addition, we are continuing to test the DUX4 RNAi sequences in the D4Z4-2. Because of this divergence, it is possible that the expression of mouse Dux in mouse skeletal muscle might better recapitulate the full scope of the disease transcriptome and mechanisms and provide a model that more broadly recapitulates FSHD. contraction can be recapitulated in the mouse, independent from its subtelomeric location. DUX4 sets in motion a cascade of biochemical events that eventually result in the devastating effects of FSHD. Publications from the Stephen Tapscott Lab at Fred Hutchinson Cancer Research Center studies gene transcription and expression in normal development and disease, with an additional emphasis on rhabdomysarcomas (cancers with characteristics of skeletal muscle) and human muscular dystrophies. These transgenic mice therefore represent a valuable animal model for FSHD and will be a useful resource to study the molecular mechanisms underlying FSHD and to test new therapeutic intervention strategies. Facioscapulohumeral dystrophy (FSHD; OMIM #158900, #158901) is caused by mis-expression of the DUX4 transcription factor in skeletal muscle1. Researchers from Duke University have succeeded in treating an adult mouse model of Duchenne muscular dystrophy using the gene editing system CRISPR — the first successful treatment of a genetic disease in an adult animal utilizing a method that has the potential to be used in humans. In addition we show that DUX4 is able to activate similar functional gene groups in mouse muscle cells as it does in human muscle cells. FSHD Disease Mechanisms and Models. The DUX4-full length (DUX4-fl) mRNA splice isoform encodes a transcriptional activator; however, DUX4 and its unique DNA binding preferences are specific to old-world primates. In a study published in JCI Insights, Harper and his team describe a mouse model of FSHD that can be used for the development of therapeutics. Each D4Z4 repeat unit has an open reading frame (named DUX4) that contains two homeoboxes; the repeat-array and ORF is conserved in other mammals. & Mcgrath, M. In addition we show that DUX4 is able to activate similar functional gene groups in mouse muscle cells as it does in human muscle cells. JCI Insight - AAV-mediated follistatin gene therapy improves functional outcomes in the TIC-DUX4 mouse model of FSHD. Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary disease of muscle. Michael Kyba's latest mouse model of FSHD Posted by Gregory J Block MSc PhD on Sep 2, 2014 In 2008 and 2009, Friends of FSH Research awarded Dr. 5 transgenic strain carrying a D4Z4 genomic region from a contracted pathogenic FSHD1 allele (Stock No. We will provide a well-characterized mouse model of FSHD that we will distribute to the field. "We present an extensively characterized model that recapitulates many features of FSHD, and we showed it to be useful in studying the effectiveness of experimental therapeutics," says Harper. NIH funds collaborative research to investigate the role of innate immunity in FSHD. Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model (2017) Nat Commun. In a study published [today] in JCI Insights, Dr. Clinical trials have also been discouraged by the fact that FSHD is a highly variable and slowly progressive disease, whereas the efficacy of therapeutic interventions is ideally established over short periods of time. Here, we report such a model — the tamoxifen-inducible FSHD mouse model called TIC-DUX4. Grant 16 Re­creating the human chromosomal genetic defect responsible for FSHD in a mouse model. A xenograft model of facioscapulohumeral muscular dystrophy To test the suitability of the xenograft as a model for muscle disease, we grafted mildly weak muscle from subjects with FSHD intotheanteriorcompartment ofNOD-Rag1nullIL2rgnull host mice. A genomic fragment from the terminal D4Z4 repeat of an FSHD 4qA161 allele including the DUX4 ORF, 3ʹ UTR and DUX4 pA was introduced at the same location b d WT iDux4pA WT iDux4pA 0 20 40 60 Expected # of progeny. Facioscapulohumeral muscular dystrophy is a severe myopathy that is caused by abnormal activation of DUX4, and for which a suitable mouse model does not exist. Genetically, FSHD is characterized by contraction or hypomethylation of repeat D4Z4 units on chromosome 4, which causes aberrant expression of the transcription factor DUX4 from the last repeat. In 2017, Burkin and Wuebbles published a study on the use of one of these small molecules, called SU9516, in successfully slowing disease progression in the mdx mouse model. explored the feasibility of using a human to mouse muscle xenograft as a model of FSHD. 5 units (D4Z4-2. The aim of this work is to determine whether human DUX4 and mouse Dux genes have equivalent functions with the long-term goal of producing a mouse model for FSHD Skip Navigation Nottingham. The ARG1 gene provides instructions for producing the enzyme arginase. In humans, copy number variations (CNVs) are a common source of phenotypic diversity and disease susceptibility. Walking through Dr. This invention provides a patented chimeric mouse model for Facioscapulohumeral muscular dystrophy (FSHD) that can be used to further characterize the disease or identify potential therapeutic agents. Developing and testing therapeutics for FSHD would be significantly advanced if a valid mouse model of the disease were available. Facioscapulohumeral muscular dystrophy (sometimes switched as faciohumeroscapular) (FSHMD, FSHD or FSH), which is also known as Landouzy-Dejerine, is a usually autosomal dominant inherited form of muscular dystrophy (MD) that initially affects the skeletal muscles of the face (facio), scapula (scapulo) and upper arms (). Researchers at the University of Minnesota have developed an animal research model for facioscapulohumeral muscular dystrophy (FSHD) to be used for muscle regeneration research as well as studies of the effectiveness of potential therapies for FSHD. Lemmers, et al. 20:2662-2672 (Abstract from PubMed). Any disease model for FSHD should take into account –Mouse models with normal-sized and FSHD-sized D4Z4. Data on the use of this conditional model to test anti-DUX4 therapeutics, specifically gene therapy targeting the DUX4 message in transplanted satellite cells will be presented. Although no gene has been conclusively linked to FSHD development, recent evidence supports a role for the D4Z4‐encoded DUX4 gene in FSHD. Here, we report such a model - the tamoxifen-inducible FSHD mouse model called TIC-DUX4. Facioscapulohumeral muscular dystrophy is the third most common hereditary disease of muscle after Duchenne (DMD; 310200) and myotonic dystrophy. Michael Kyba’s latest mouse model of FSHD Posted by Gregory J Block MSc PhD on Sep 2, 2014 In 2008 and 2009, Friends of FSH Research awarded Dr. Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a transgenic mouse model for FSHD YD Krom, PE Thijssen, JM Young, B den Hamer, J Balog, Z Yao, L Maves, PLoS genetics 9 (4), e1003415 , 2013. Mouse Resources & Model Organism Links; FRG2, FSHD region gene 2 Orthology source: HomoloGene FRG2B, FSHD region gene 2 family member B. In most individuals with FSHD, symptoms are restricted to muscles of the face, arms, legs, and trunk. We tested the vision and the retina of 26 patients with early onset FSHD (age 8–68 years). Grant 18 Study on the clinical features, expression profiling, and quality of life of infantile onset FSHD. , why, how and when [6,16,17]. FSHD Global Research Foundation Ltd. Harper and his team describe a mouse model of FSHD that can be used for the development of therapeutics. It is characterized by progressive weakness and wasting of facial, shoulder girdle, and upper-arm muscles from which the disease takes its name, and also trunk, hip, and leg muscles in some patients (). We are laser-focused on speeding the development of treatments and a cure for the nearly one million people worldwide who are affected. Although no gene has been conclusively linked to FSHD development, recent evidence supports a role for the D4Z4‐encoded DUX4 gene in FSHD. Grant 16 Re­creating the human chromosomal genetic defect responsible for FSHD in a mouse model. D4Z4 is a primate-specific repeat (Clark et al. In facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy, recent advances in understanding the complex genetics and epigenetics have led to the identification of a disease mechanism, moving the field towards targeted therapy development. A genomic fragment from the terminal D4Z4 repeat of an FSHD 4qA161 allele including the DUX4 ORF, 3ʹ UTR and DUX4 pA was introduced at the same location b d WT iDux4pA WT iDux4pA 0 20 40 60 Expected # of progeny. A xenograft model of facioscapulohumeral muscular dystrophy To test the suitability of the xenograft as a model for muscle disease, we grafted mildly weak muscle from subjects with FSHD intotheanteriorcompartment ofNOD-Rag1nullIL2rgnull host mice. The mouse model was created by Dr Scott Harper and his team at Nationwide Children’s Hospital, Ohio, USA. To fill this need, the Jones Lab has created the first mouse models of FSHD that exhibit key aspects of disease pathology, invented a simple and reliable diagnostic test for FSHD, and identified promising potential therapies that are currently in preclinical testing. • Mouse models, with. We discuss how funding by the Chris Carrino foundation for FSHD has enabled us to generate an FSHD-like mouse model and advance our FSHD CRISPR work. In this model, two polymorphisms create a polyadenylation site for the distal DUX4 transcript, located in the pLAM sequence. explored the feasibility of using a human to mouse muscle xenograft as a model of FSHD. title = "High frequency hearing loss and hyperactivity in DUX4 transgenic mice", abstract = "Facioscapulohumeral muscular dystrophy (FSHD) is caused by mutations leading to ectopic expression of the transcription factor DUX4, and encompasses both muscle-related and non-muscle phenotypes. Since DUX4 is toxic, animal model development has been challenging, but progress has been made, revealing that tight regulation of DUX4 expression is critical for creating viable animals that develop myopathy. More information on the prevalence, aetiology and severity could improve our understanding of the pathophysiology of FSHD and improve clinical care. In a study published in JCI Insights, Dr. Project: Research. We are particularly interested in the regulation of muscle- and B-cell differentiation, and the associated diseases using FSHD muscular dystrophy and acute lymphoblastic leukemia, respectively, as paradigms. Facioscapulohumeral dystrophy (FSHD; OMIM #158900, #158901) is caused by mis-expression of the DUX4 transcription factor in skeletal muscle1. These\ud repeats lie adjacent to the telomeres and are usually present in a highly\ud silenced epigenetic state. 1A), the endogenous DUX4-FL protein was expected to have well-defined tertiary structures in each of the two DNA-binding homeodomains (amino acids 19-79 and 94-154) and in the most C-terminal region (amino acids ∼365-424). We present data from two approaches to model FSHD: the generation of a mouse bearing a doxycycline‐inducible Dux4 gene, and the differentiation of iPS cells derived from myoblasts cultures established from FSHD and control biopsies. 5,16–18 Collectively, these results suggest that the FRG1 mouse is a valid model of FSHD. If you are a patient (or parent/guardian of a patient) with FSHD and would like to register in a patient registry, you should do this via the registry in your country if one is available. It is among the three most common muscular dystrophies, and between one and two percent of the general population carries a genetic risk factor linked to FSHD. Hanel1,* and Peter L. click here to visit our Facebook page click here to follow us on Twitter click here to see our Youtube channel click here to find us on Linkedin click here to find us. We will provide a well-characterized mouse model of FSHD that we will distribute to the field. Secondly, the mechanism causing FSHD is so complex that it isn't fully understood yet, which makes it difficult to design therapies and assess their. Facioscapulohumeral dystrophy (FSHD; OMIM #158900, #158901) is caused by mis-expression of the DUX4 transcription factor in skeletal muscle1. Moreover, comparisons with the splicing profile of the mouse model of Duchenne muscular dystrophy strongly indicate that the identified splicing changes are specific for the FSHD model rather than as a signature of diseased muscle (Figure 5a). Our new manuscript entitled "AAV-mediated follistatin gene therapy improves functional outcomes in the TIC-DUX4 mouse model of FSHD" was published today at the Journal of Clinical Investigation Insight. 1A), the endogenous DUX4-FL protein was expected to have well-defined tertiary structures in each of the two DNA-binding homeodomains (amino acids 19-79 and 94-154) and in the most C-terminal region (amino acids ∼365-424). , Guckes Susan M. The humanized mouse model of FSHD is the first to demonstrate the feasibility of this novel xenograft approach for modeling a myopathy, using both fresh and autopsy-derived human muscle samples. Although no gene has been conclusively linked to FSHD development, recent evidence supports a role for the D4Z4‐encoded DUX4 gene in FSHD. National patient registries. About 32,630 results Sort by: Relevance; Most Recent Per Page: 20; 50; 100. A similar effect has been observed previously in a mouse model with simultaneous up-regulation of a microRNA, namely miR-206, and its target gene urotropin. Around 500,000 people have FSHD worldwide. Therefore, we propose to generate human FSHD-affected muscle within mice. The Board of Directors of the Chris Carrino Foundation for FSHD has proudly approved the funding of $107,777 to Peter Jones, PhD and Takako Jones, PhD at the University of Massachusetts for their mouse model research project. Amy Campbell, a dedicated professional highly skilled in FSHD research who oversees the completion of high-impact studies on FSHD and provides scientific and technical oversight for graduate students, postdoctoral fellows, and collaborators seeking to initiate and/or advance projects in FSHD. It is among the three most common muscular dystrophies, and between one and two percent of the general population carries a genetic risk factor linked to FSHD. 027991), and both strains are useful in studying facioscapulohumeral dystrophy. 1/01/11 → 31/12/11. 19th International Congress of the World Muscle Society. A genomic fragment from the terminal D4Z4 repeat of an FSHD 4qA161 allele including the DUX4 ORF, 3ʹ UTR and DUX4 pA was introduced at the same location b d WT iDux4pA WT iDux4pA 0 20 40 60 Expected # of progeny. that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat. 2017 Dec 1;8(1). , "Aberrant Splicing in Transgenes Containing Introns, Exons, and V5 Epitopes: Lessons from Developing an FSHD Mouse Model Expressing a D4Z4 Repeat with Flanking Genomic Sequences. Individual small interfering RNA-mediated knockdown of either p38 or p38 suppresses expression, demonstrating that each kinase isoform plays a distinct requisite role in activating Finally, p38 inhibitors effectively suppress expression in a mouse xenograft model of human FSHD gene regulation. Giesige, Nettie K. Candidate - "Therapeutic intervention using third generation antisense oligonucleotides in a new FSHD mouse model". Smchd1 haploinsufficiency exacerbates the phenotype of a transgenic FSHD1 mouse model 29 January 2018 In humans, a copy of the DUX4 retrogene is located in each unit of the D4Z4 macrosatellite repeat that normally comprises 8-100 units. These data support the repurposing of existing clinical p38 inhibitors as potential therapeutics for FSHD. Facioscapulohumeral muscular dystrophy (sometimes switched as faciohumeroscapular) (FSHMD, FSHD or FSH), which is also known as Landouzy-Dejerine, is a usually autosomal dominant inherited form of muscular dystrophy (MD) that initially affects the skeletal muscles of the face (facio), scapula (scapulo) and upper arms (). This list deals exclusively with FSHD, while organizations that deal with all neuromuscular diseases including FSHD are listed on the following page. Xenografts of whole-mouse muscles from the mdx model into an immunodeficient mouse have proven to be successful in retaining their dystrophic. Here, we report such a model — the tamoxifen-inducible FSHD mouse model called TIC-DUX4. FSHD is a form of muscular dystrophy, a progressive and untreatable muscle wasting disease. 20 A mouse model that recapitulates features of O. Only contractions associated with the 4qA161 haplotype cause FSHD. In a study published [today] in JCI Insights, Dr. Moreover, we hope that this model will be useful for testing therapies that can be brought forward toward the clinic. iDUX4pA mice possess a tetracycline operator (tetO) upstream of human double homeobox 4 (DUX4) gene from the terminal D4Z4 repeat of an FSHD-affected individual, including its downstream introns and poly A signal, inserted upstream of the hypoxanthine guanine phosphoribosyl transferase (Hprt) gene on the X chromosome. Eidahl, Susan M. The funding provided by Friends of FSH Research and the Carrino Foundation has supported Dr. Researchers replicate FSH muscular dystrophy. The Board of Directors of the Chris Carrino Foundation for FSHD has proudly approved the funding of $107,777 to Peter Jones, PhD and Takako Jones, PhD at the University of Massachusetts for their mouse model research project. Uninduced animals are viable, born in Mendelian ratios, and overtly indistinguishable from WT animals. 1126/science. Currently FSHD has no known effective treatment and detailed data on the natural history are lacking. 76 Muscular dystrophies and congenital myopathi P5. Wallace, Jocelyn O. Giesige, Nettie K. We use a broad range of tools, including molecular techniques, biochemistry, viral vectors, and mouse models of disease. The mouse model they created, called. A mouse model allowing doxycycline-regulated DUX4 expression has recapitulated these phenotypes in primary myoblasts (Dandapat et al. 20 A mouse model that recapitulates features of O. Determination of the efficacy of a given therapeutic approach might be difficult in FSHD given the slow and highly variable disease progression. Our new manuscript entitled "AAV-mediated follistatin gene therapy improves functional outcomes in the TIC-DUX4 mouse model of FSHD" was published today at the Journal of Clinical Investigation Insight. The FRG1 mouse is a useful model of FSHD. Patients with FSHD have a chromosomal rearrangement within the subtelomeric region of chromosome 4 (4q35). The molecular mechanisms and the signaling pathways remain poorly studied so far. Peter Jones, associate professor in cell and developmental biology and neurology at University of Massachusetts Medical School in Worcester, was awarded an MDA research grant totaling $300,000 over a period of three years to develop a research mouse model for facioscapulohumeral muscular dystrophy (FSHD). About 30,792 results Sort by: Relevance; Most Recent Per Page: 20; 50; 100. , Giesige Carlee R. In this blog Facioscapulohumeral Muscular Dystrophy is referred to by the following: FSH, FSHD, or Facioscapulohumeral MD. A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy Richard J. This award supports the Tapscott Lab's high-impact studies on FSHD research in identifying biomarkers for disease activity and progression, generation of mouse models for therapeutics studies, and training of new investigators. We are laser-focused on speeding the development of treatments and a cure for the nearly one million people worldwide who are affected. explored the feasibility of using a human to mouse muscle xenograft as a model of FSHD. "We present an extensively characterized model that recapitulates many features of FSHD, and we showed it to be useful in studying the effectiveness of experimental therapeutics," says Harper. DUX4 sets in motion a cascade of biochemical events that eventually result in the devastating effects of FSHD. FSHD candidate gene able to recapitulate both muscular and vas-cular FSHD-like defects. The molecular mechanisms and the signaling pathways remain poorly studied so far. , Pyne Nettie K. The first is that there isn’t a good mouse model of FSHD, so it is difficult to reliably test potential gene silencing treatments. This invention provides a patented chimeric mouse model for Facioscapulohumeral muscular dystrophy (FSHD) that can be used to further characterize the disease or identify potential therapeutic agents. 5 units (D4Z4-2. Facio's FSHD mouse model showing human FSHD cells (white) growing in mouse muscle tissue (green). Facioscapulohumeral dystrophy (FSHD; OMIM #158900, #158901) is caused by mis-expression of the DUX4 transcription factor in skeletal muscle1. A similar effect has been observed previously in a mouse model with simultaneous up-regulation of a microRNA, namely miR-206, and its target gene urotropin. Follistatin gene therapy in a mouse model of FSHD. To generate a humanized model of FSHD in mice, we developed methods to grow human muscle within the TA compartment of the mouse hindlimb from immortalized human muscle precursor cells (hMPCs, Appendix A, S. Eidahl, Susan M. A cre-inducible DUX4 transgenic mouse model for investigating facioscapulohumeral muscular dystrophy  Jones, Takako ; Jones, Peter L. Furthermore, conventional transgenic studies suffer from high variability due to integration site‐specific. They serve as templates for replication and transcription, and undergo mitosis to maintain genetic information over generations. FSHD Global Research Foundation Ltd. Individual small interfering RNA-mediated knockdown of either p38 or p38 suppresses expression, demonstrating that each kinase isoform plays a distinct requisite role in activating Finally, p38 inhibitors effectively suppress expression in a mouse xenograft model of human FSHD gene regulation. Developing and testing therapeutics for FSHD would be significantly advanced if a valid mouse model of the disease were available. iDUX4pA mice possess a tetracycline operator (tetO) upstream of human double homeobox 4 (DUX4) gene from the terminal D4Z4 repeat of an FSHD-affected individual, including its downstream introns and poly A signal, inserted upstream of the hypoxanthine guanine phosphoribosyl transferase (Hprt) gene on the X chromosome. This study is the first to extensively investigate muscle fiber physiology in FSHD following an earlier pilot study suggesting sarcomeric dysfunction in FSHD. Facioscapulohumeral muscular dystrophy is a severe myopathy that is caused by abnormal activation of DUX4, and for which a suitable mouse model does not exist. Jones T & Jones PL A cre-inducible DUX4 transgenic mouse model for. Remarkably, using 10×10 cv instead of 5×5 cv in Algorithm 1, it was found that the final result fully coincided with the FSHD-DB1 model. Therefore, we propose to generate human FSHD-affected muscle within mice. In this model, biceps muscles from FSHD patients (expressing DUX4-fl) and their unaffected family members were collected and grafted into. Eugénie Ansseau, Jacqueline S. This model can be used to evaluate and optimise future therapeutic strategies for FSHD. This will create a better tool for the study of the process of FSHD and the development of new medicines to treat the condition. Scientific Projects Current Fields Center projects are focused on the following areas of FSHD (FSH dystrophy) research: Clinical Research. Begam M, Abro V, Mueller A, Roche J. It is an expansion of research funded by our foundation last year, which was a tremendous success. Researchers find animal model for understudied type of muscular dystrophy Date: August 28, 2014 The mouse model designed by Kyba and his team allows the disease-associated DUX4 protein to be. , Giesige Carlee R. elegans homolog of the FSHD candidate gene FRG1 (FSHD region gene 1), ZK1010. Mitchell, C. A mouse model allowing doxycycline-regulated DUX4 expression has recapitulated these phenotypes in primary myoblasts (Dandapat et al. The key event in FSHD is the undue production of the DUX4 protein in skeletal muscle. Building an FSHD model has proven to be a substantial challenge. Genetically, FSHD is characterized by contraction or hypomethylation of repeat D4Z4 units on chromosome 4, which causes aberrant expression of the transcription factor DUX4 from the last repeat. Erratum Author Correction: Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model (Nature communications (2017) 8 1 (550)). FSHD Global Research Foundation (Harper, PI) 1/1/2019 - 12/31/2020 "Developing AAV-follistatin gene therapy alone or in combination with RNAi in a novel mouse model of FSHD" The goal of this project is to test AAV. The funding provided by Friends of FSH Research and the Carrino Foundation has supported Dr. These transgenic mice therefore represent a valuable animal model for FSHD and will be a useful resource to study the molecular mechanisms underlying FSHD and to test new therapeutic intervention strategies. Secondly, the mechanism causing FSHD is so complex that it isn't fully understood yet, which makes it difficult to design therapies and assess their. , 2014) while also having several non-muscle related phenotypes due to low basal levels of DUX4 expression in the absence of doxycycline (Dandapat et al. The Board of Directors of the Chris Carrino Foundation for FSHD has proudly approved the funding of $107,777 to Peter Jones, PhD and Takako Jones, PhD at the University of Massachusetts for their mouse model research project. The newly published mouse model contains 2. , "Aberrant Splicing in Transgenes Containing Introns, Exons, and V5 Epitopes: Lessons from Developing an FSHD Mouse Model Expressing a D4Z4 Repeat with Flanking Genomic Sequences. A genomic fragment from the terminal D4Z4 repeat of an FSHD 4qA161 allele including the DUX4 ORF, 3ʹ UTR and DUX4 pA was introduced at the same location b d WT iDux4pA WT iDux4pA 0 20 40 60 Expected # of progeny. Although no gene has been conclusively linked to FSHD development, recent evidence supports a role for the D4Z4‐encoded DUX4 gene in FSHD. Secondly, the mechanism causing FSHD is so complex that it isn't fully understood yet, which makes it difficult to design therapies and assess their. Candidate - "Therapeutic intervention using third generation antisense oligonucleotides in a new FSHD mouse model". Lemmers, et al. Nature communications. Our studies also provide insights into the biological function of DNA repetitive elements in gene transcription and. The first is that there isn't a good mouse model of FSHD, so it is difficult to reliably test potential gene silencing treatments. 9(4):e1003415. Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder caused by aberrant expression of the double homeobox 4 (DUX4) gene. More information on the prevalence, aetiology and severity could improve our understanding of the pathophysiology of FSHD and improve clinical care. Mice are the most widely used animal model, as they are easy to handle and breed. What do you feel people impacted by FSHD can have the most hope about with respect to research right now?. Moreover, specifically focusing on FSHD, limited research has been conducted on the use of antioxidants as a therapy in either preclinical or clinical models. A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy Richard J. "In genetic diseases for which therapies have been developed, like Duchenne muscular dystrophy, mouse. June 28, 2018 — A dietary supplement derived from glucose increases muscle-force production in the Duchenne muscular dystrophy (DMD) mouse model by 50 percent in ten days, according to a new. Clinical trials have also been discouraged by the fact that FSHD is a highly variable and slowly progressive disease, whereas the efficacy of therapeutic interventions is ideally established over short periods of time. In addition we show that DUX4 is able to activate similar functional gene groups in mouse muscle cells as it does in human muscle cells. We are also pursuing basic mechanistic studies related to two such disorders: Facioscapulohumeral Muscular Dystrophy (FSHD) and Limb-Girdle Muscular Dystrophy Type 1A (LGMD1A). A 40-year-old male with history of facioscapulohumeral muscular dystrophy with significant facial diplegia and lagophthalmos presents for an evaluation of bilateral choroiditis with vasculitis and optic disc edema. Non-coding RNA expression is regulated in the active phase of muscle fiber necrosis and degeneration that develops at 4 to 6 weeks of age in the mdx mouse model. In order to address this deficit, these studies propose to create a novel mouse model using muscle tissue grafts from FSHD human donors. In 2017, Burkin and Wuebbles published a study on the use of one of these small molecules, called SU9516, in successfully slowing disease progression in the mdx mouse model. Peter Jones, associate professor in cell and developmental biology and neurology at University of Massachusetts Medical School in Worcester, was awarded an MDA research grant totaling $300,000 over a period of three years to develop a research mouse model for facioscapulohumeral muscular dystrophy (FSHD). Sodium 4-phenylbutyrate reduces myofiber damage in a mouse model of Duchenne muscular dystrophy. Many different cell culture models have been developed to study the pathophysiology of FSHD, frequently based on endogenous expression of DUX4 in FSHD cells or by mis-expression of DUX4 in control human muscle cells. See more ideas about Muscular dystrophies, Duchenne muscular dystrophy and News today. Facioscapulohumeral muscular dystrophy (FSHD) is an important genetic disease caused by CNVs. "We present an extensively characterized model that recapitulates many features of FSHD, and we showed it to be useful in studying the effectiveness of experimental therapeutics," says Harper. Biceps muscle was donated from families (cohort numbers 29, 30, 32, 33 and 37) with affected. The humanized mouse model of FSHD is the first to demonstrate the feasibility of this novel xenograft approach for modeling a myopathy, using both fresh and autopsy-derived human muscle samples. Michael Kyba a $100,000 grant to begin developing a mouse model for FSHD focusing on the gene, DUX4 (See D4Z4/DUX4 Induced Pathologies in Mice ). View Publication. FSHD candidate gene able to recapitulate both muscular and vas-cular FSHD-like defects. , Guckes Susan M. In a study published [today] in JCI Insights, Dr. 5 mouse model. This will be a useful model to study de-repression of DUX4, but as the lack of muscle pathology in this model suggests, it may not be as helpful in studying. Based on previous findings as well as our own observations, we propose a potential model of how up-regulation of miR-411 can be involved in the myogenic defect observed in FSHD myoblasts. The development of a faithful animal model of FSHD should. Pacific Northwest Friends of FSH Research Mission - To increase the funding available to research Facioscapulohumeral Muscular Dystrophy in the hopes of finding a treatment or cure for this disabling condition. Facioscapulohumeral muscular dystrophy (FSHD) is a relatively common myopathy affecting 1/8500–15,000 individuals. expression has been shown to be the cause of FSHD. 19th International Congress of the World Muscle Society. 1/01/11 → 31/12/11. The goal is to identify potential therapeutic targets for treating FSHD. The key event in FSHD is the undue production of the DUX4 protein in skeletal muscle. Follistatin gene therapy in a mouse model of FSHD. Panamarova Maryna, Tassin Alexandra, Moyle Louise, Belayew Alexandra, Zammit Peter, "Generation of a mouse model of FSHD to reveal the DUX4 expression profile and dynamics" in "10th Neuromuscular Translational Research Conference " , London, UK (2017) panamarova2017. Uninduced animals are viable, born in Mendelian ratios, and overtly indistinguishable from WT animals. The aim of this work is to determine whether human DUX4 and mouse Dux genes have equivalent functions with the long-term goal of producing a mouse model for FSHD Skip Navigation Nottingham. DUX4 sets in motion a cascade of biochemical events that eventually result in the devastating effects of FSHD. As a reminder, Fasioscapulohumeral muscular dystrophy (FSH, or FSHD) is caused by the aberrant expression of DUX4 in muscle. Hanel1,* and Peter L. Coming full circle, Peter and Takako Jones arrived at the University in 2017, bringing with them a novel DUX4-expressing FSHD mouse model that they had created. View mouse Frg2f9 Chr14:106464822-106465870 with: sequences, polymorphisms, references, function Mouse Resources & Model Organism Links; FSHD region gene 2. Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a transgenic mouse model for FSHD. Currently FSHD has no known effective treatment and detailed data on the natural history are lacking. In an attempt to generate an FSHD mouse model independent of candidate genes, Zhang et al. Patients with FSHD are clearly at risk for an exudative retinopathy due to bilateral retinal telangiectasias. Each of the proposed animal models of FSHD has its own distinct strengths and weakness. Pacific Northwest Friends of FSH Research Mission - To increase the funding available to research Facioscapulohumeral Muscular Dystrophy in the hopes of finding a treatment or cure for this disabling condition. contraction can be recapitulated in the mouse, independent from its subtelomeric location. Uninduced animals are viable, born in Mendelian ratios, and overtly indistinguishable from WT animals. 1/01/11 → 31/12/11. 0925-0001/0002 (Rev.