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Ad hoc 2019 award
Facioscapulohumeral Muscular Dystrophy Clinical Trial Research Network (FSHD CTRN). Jeffery Statland, PhD, University of Kansas Medical Center. $63,788 for one year.
Awards for the August 2018 cycle
Investigating the molecular consequences of reduced NMD in FSHD skeletal muscle myoblasts Michael Dyle, PhD Laboratory of Sujatha Jagannathan, PhD, University of Colorado Denver | Anschutz Medical Campus 01/01/2019 – 12/31/2020 $ 115,937 for 2 years
Significance: A project proposed by a young promising post-doctoral fellow focused on providing insight into the molecular underpinnings of FSHD, which may lead to the development of novel diagnostic biomarkers and therapeutic strategies. Done by determining the consequences of diminished RNA quality control in FSHD skeletal muscle. Previous studies by this lab have found that DUX4 expression in skeletal muscle leads to severe perturbation of an evolutionarily conserved RNA quality control pathway: nonsense mediated decay (NMD). In healthy skeletal muscle, NMD plays a beneficial role in surveying and eliminating aberrant RNA molecules, as well as suppressing levels of stress response proteins that can cause cell death. Their preliminary data indicate that perturbed NMD in FSHD skeletal muscle leads to increased levels of aberrant RNAs, hyperactivation of cell stress response pathways, and muscle cell death. These findings reveal that diminished RNA quality control is a pivotal event that contributes to skeletal muscle deterioration in FSHD. Project might help clarify if rescuing NMD function can slow or prevent skeletal muscle deterioration in FSHD.
Optimizing gapmer therapy for facioscapulohumeral muscular dystrophy Yi-Wen Chen, DVM, PhD Children’s National Health System, Washington, DC 03/01/2019 – 02/29/2020 US$ 125,969 for one year
Significance: Antisense oligonucleotide (AON) therapy shows promise for treating FSHD, however, several issues arise with AONs including 1) difficulty in systemic drug delivery; 2) harmful off-target effects and toxicities; 3) low stability due to degradation; and 4) immune responses. The 2’-O-methoxyethyl (2’MOE) and locked nucleic acids (LNAs) modification are two chemistries for designing gapmer-type antisense oligonucleotides, which overcome issues associated with AONs. Previous support by the FSH Society helped this lab in developing an effective antisense oligonucleotide (AON) strategy to target DUX4 and reduce its expression. The LNA gapmer under investigation was able to effectively knockdown DUX4 both in cell culture and mice. In the FSHD mouse model generated by Dr. Peter Jones’ group, Chen showed functional recovery of muscle strength after systemic delivery of the LNA gapmers. In this proposal, they will compare the LNA gapmers to 2’MOE gapmers which are targeting the same target sequences of the DUX4. The 2’MOE was recently approved for treating spinal muscular atrophy by the FDA. It is considered less potent but safer than LNA. In an in vitro experiment done by collaborator, Dr Yokota, he showed that the 2’MOE gapmers targeting the same DUX4 region effectively knocked down the DUX4 transcripts. In this proposal Chen will compare the in vivo efficacy and the safety of the 2’MOE gapmers to the LNA gapmers. The goal is to carefully characterize and identify the compound that will be moved forward for drug development.
Identification of natural human DUX4-targeted miRNAs and development of a novel DUX4-targeted miRNA-based gene therapy for FSHD Nizar Y. Saad, PhD Postdoctoral fellow, the Harper lab Center for Gene Therapy, Nationwide Children’s Hospital 03/01/2019 – 02/29/2020 $ 91,000 for one year
Significance: Dr. Saad has with FSH Society funding for past two years been investigating endogenous microRNAs (miRNAs) that could target the DUX4 transcript, thereby reducing DUX4 expression. So far, he found that H19 and miR-675 reduce DUX4 expression and toxicity. Drs. Harper/Saad seek to develop new therapeutic approaches by targeting or using natural miRNAs such as miR-675. Project aims to create DUX4-targeted miRNA-based gene therapy for FSHD by using miR-675 as a new miRNA-based gene therapy candidate. First by functionally identify every natural human miRNA capable of targeting DUX4 in cell culture. Then by developing a DUX4-targeted miR-675-based gene therapy for FSHD.
Awards for the February 2018 cycle
DETERMINING THE THERAPEUTIC POTENTIAL OF PLURIPOTENT STEM CELL-DERIVED MYOGENIC PROGENITORS IN THE IDUX4PA MOUSE MODEL. Rita Perlingeiro, PhD, University of Minnesota, Minneapolis, USA. US$99,998 total, US$49,999 annually for two years.
This project builds on the Perlingeiro lab’s successful studies developing such cell therapies specifically in mouse models of Duchenne and limb-girdle muscular dystrophy (LGMD). The intent of this cell product is to replace diseased muscle with normal functional muscle fibers as well as muscle stem cells, which have the potential to provide long-term therapeutic effect in Duchenne and other devastating types of muscular dystrophies, including FSHD. Because all of the Perlingeiro lab’s work to date has been with Duchenne and LGMD models, it will be essential to understand how effectively cell replacement can address muscle damage due to the distinct mechanism underlying FSHD.
Now that an FSHD mouse model (iDUX4pA) is available that can be induced to produce very low levels of DUX4, resulting in a slow decline in muscle over several months, it will be possible to evaluate the effectiveness of cell therapy in the context of such a relevant muscle damage mechanism. The work proposed in this grant will provide proof of principle for including FSHD in the pipeline for future clinical trials of cell-based regenerative therapies.
A DECOY TRAPPING DUX4 FOR THE TREATMENT OF FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY. Virginie Mariot, PhD, University College London; Great Ormond Street Institute of Child Health, London, United Kingdom. US$163,447 for 18 months.
This application uses a “decoy” approach, which represents a new conceptual approach in the neuromuscular field. Unlike antisense oligonucleotides (ASO/AO) or siRNAs which target DUX4 messenger (mRNA) prior to the creation of the DUX4 protein, the decoy mechanism of action is to trap the DUX4 protein itself post-RNA translation. The decoy will attach to the DUX4 protein so that it cannot bind to DNA and trigger the downstream toxic effects of DUX4. Notably, this method is independent of the nucleus that produces DUX4 mRNA (which can be one out of 1000 nuclei) allowing the decoy to sequester the DUX4 protein during its cellular journey wherever it occurs.
This decoy strategy may be highly powerful as shown by proof-of-principle studies already performed. The aim of this project is now to validate these results in the FLEx ACTA MCM mice.
THE ROLE OF ESTROGEN RECEPTORS IN FSHD1 MECHANISM. Anna Pakula, PhD, Boston Children’s Hospital, Boston, Massachusetts USA. US$125,000 for one year.
Dr. Pakula utilizes fish embryos, which when programmed to synthesize Dux4, develop features that resemble FSHD symptoms. This model is very helpful for studying the mechanism and potential treatments of this disease. By performing analysis of DUX4 binding sites, her team has discovered that, at 12 hours of embryo development, ER-like (estrogen receptor-like) protein interacts with DUX4. The advantage of their model is that DUX4 and estrogen receptor (ER) interaction can be detected at the very early stages of disease development, which is not feasible in humans. The investigators hypothesize that one of the estrogen receptors could help DUX4 reach its binding sites in DNA. Their hypothesis is that in males (having less estrogen than females), DUX4 binds to different DNA regions and regulates different genes, which possibly leads to more severe disease.
Dr. Kunkel and Dr. Pakula, together with Drs. Martha Bulyk and Yuliya Sytnikova from Brigham and Women’s Hospital, who are well established in studying transcription factors and chromatin, will unravel the mechanism of ER-like driven recruitment of the DUX4, which they believe may help to uncover new ways to treat FSHD.
Ad hoc 2017 cycle
Facioscapulohumeral Muscular Dystrophy Clinical Trial Research Network (FSHD CTRN) Jeffrey Statland, MD. Assistant Professor of Neurology, University of Kansas Medical Center, Fairway, Kansas USA. 02/01/2018 - 08/31/2018, US$133,254 for 6 months.
Awards for the August 2017 cycle
Natural microRNAs as potential modifiers of DUX4 toxicity Nizar Saad, Ph.D. The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio USA. 02/01/2018 - 01/31/2019, US$80,000 for 1 year. FSH Society Sylvia & Leonard Marx Foundation Fellowship.
Hypermorphic SMCHD1 variants. Jessica C. de Greef, Ph.D. Leiden University Medical Center, Leiden, The Netherlands. 07/01/2018 – 06/30/2021, US$171,000 for 3 years (US$ 57,000 per year). FSH Society Sylvia & Leonard Marx Foundation Fellowship.
SMCHD1 encodes a well-conserved protein, but its function is largely unknown. Studies in mice suggest that Smchd1 has roles in the establishment and/or maintenance of DNA methylation, in X chromosome inactivation, and in the regulation of several imprinted and clustered genes. Our group has an ongoing collaboration with Dr. Marnie Blewitt (The Walter and Eliza Hall Institute of Medical Research, Australia), who was involved in an N-ethyl-N-nitrosourea (ENU) mutagenesis screen to identify modifiers of epigenetic reprogramming. Apart from the well-known Smchd1 loss-of-function mutant Smchd1MommeD1, she identified a missense Smchd1 variant, which we now call the Smchd1Fresia variant, which may act as a hypermorphic variant. This is an exciting finding as it suggests that naturally occurring SMCHD1 variants might exist that protect muscle from expressing DUX4.
In this project I will test the hypothesis that specific SMCHD1 variants either increase SMCHD1 activity or lead to increased SMCHD1 expression with consequences for the chromatin structure of the D4Z4 repeat array and for DUX4 expression. In Specific Aim 1, I will determine the functional consequences of the Smchd1Fresia variant at the chromatin and expression level of the D4Z4 repeat array in vivo using our transgenic D4Z4- 2.5 mice. In Specific Aim 2, I will determine the effect of the Smchd1Fresia variant and five SMCHD1 variants that may act as hypermorphic alleles in muscle cell cultures. In Specific Aim 3, I will search for novel potential hypermorphic SMCHD1 variants in our extensive and well characterized biorepository.
Stryka-001 treatment in the FSHD-like mouse model. Ryan Wuebbles, Ph.D. Takako Jones, Ph.D. University of Nevada, Reno School of Medicine, Reno, Nevada USA. 01/01/2018 - 12/3l/2018, US$$190,000 for 1 year. FSH Society FSHD Canada Foundation fellowship.
Characterization of a novel inhibitor of DUX4 activity. Davide Gabellini, Ph.D. Fondazione Centro San Raffaele, Milan, Italy. 02/01/2018 - 01/31/2019, US$85,000 for 1 year.
We identified a novel molecule able to block DUX4 activity.
We plan to address the following questions: 1. Which are the molecular determinants of DUX4-inhibitor interaction? 2. Can the inhibitor be used for therapeutic purposes?
Our project will provide a better understanding of DUX4 mechanism of action and how its toxic activity could be blocked for the treatment of FSHD.
Interplay between myogenesis and the immune system in FSHD pathology. Peter Steven Zammit, Ph.D. Maryna Panamarova, Ph.D. King’s College London, London, England. 04/08/2018 – 04/07/2019, US$99,894 for 1 year.
In work partially funded by the FSH Society Shack Family and Friends research grant FSHS-82013-06), we have recently completed an extensive RNA-seq transcriptomics analysis of myogenic differentiation of immortalised and primary myoblasts isolated from FSHD patients alongside matched controls (Banerji C.R.S, Panamarova M., Hebaishi H., White R.B., Relaix F., Severini S. and Zammit P.S. (2017). PAX7 target genes are globally repressed in FSHD skeletal muscle. Nature Communications 8: 2152 (10.1038/s41467-017-01200-4). Multivariate regression analysis revealed 180 genes strongly associated with FSHD in every dataset analysed. Gene Set Enrichment analysis of these 180 genes revealed that the target genes of a transcription factor central to macrophage-coordinated muscle repair were significantly repressed in all FSHD cell lines. However, the effects of suppression of this transcription factor on muscle repair in FSHD, is currently unknown.
This research aims to determine the role of this transcription factor in FSHD, which could help augment muscle repair in FSHD to ameliorate muscle wasting. An overarching aim of this project is to better understand the interplay between muscle repair and the immune system in FSHD.
Biomarker identification by high-resolution proteomic approach in facioscapulohumeral muscular dystrophy (FSHD). Giorgio Tasca, M.D., Ph.D. Università Cattolica del Sacro Cuore, Rome, Italy. 05/03/2018 – 04/30/2019, US$65,000 for 1 year.
The results of our study could provide information valuable for the discovery and characterization of novel tissue and circulating biomarkers with a comprehensive approach, as well as preliminary evidence for the application of an innovative technique in FSHD and potentially other neuromuscular disorders. Getting further insights into disease pathophysiology through the identification of biochemical pathways dysregulated in FSHD muscles could help in the development of new targeted therapies.
Awards for the February 2017 cycle
A genome-wide CRISPR knock-out strategy to identify modifiers of FSHD. Angela Lek, Ph.D., Genetics and Genomics, Boston Children’s Hospital, Boston Massachusetts USA Louis Kunkel, Ph.D., Genetics and Genomics, Boston Children’s Hospital, Boston Massachusetts USA 08/01/2017- 07/31/2018. US$75,860 for one year
Project Summary: Facioscapulohumeral dystrophy (FSHD) is a common but unique form of muscular dystrophy requiring multiple factors to create a ‘permissive’ state for disease manifestation. Over recent years, several genetic (DUX4) and epigenetic (hypo-methylation) factors have been linked to FSHD pathogenesis; however, it has become clear that the field has not elucidated all factors required for disease manifestation. Mounting clinical evidence suggests the existence of modifier genes with the capacity to regulate DUX4 transcript and/or protein function. Recent advances in genome-editing technologies proposed for use in this project now should enable us to uncover these remaining missing links. Through the systematic introduction of loss-of-function mutations into genomic DNA, we can interrogate the genome for answers that may explain the phenotypic variability between patients, as well as the non-penetrant effects of DUX4 in some individuals. In this project, we propose a targeted genome-scale knock-out screen to identify genes that can reduce the phenotypic impact of DUX4 expression when inactivated. We hypothesize that there exists gene targets of DUX4 whose loss will render DUX4 unable to trigger a dysregulated cascade of gene expression, thus abrogating its toxicity. These candidates likely serve as genetic modifiers of FSHD, and will be readily identified by downstream sequencing and computational analysis for detection of CRISPR target genes enriched within these DUX4 ‘resistant’ cell populations. This will allow the generation of a complete list of gene candidates with the potential to influence the pathogenic outcomes associated with DUX4 misexpression. Identified gene hits will be cross-referenced to our whole-genome sequencing data of nonmanifesting carriers to search for sequence variants that may enable us to narrow down promising candidates for functional follow up studies. Validation of candidate modifier genes will be performed in our established zebrafish model of FSHD for rescue of phenotype to confirm functional significance. Additionally, we will revert to our repository of FSHD patient cells to genome edit our candidate genes under these permissive allelic conditions, and subsequently measure changes in known FSHD biomarker expression. FSHD is a challenging disease whose remaining unanswered questions cannot be accomplished alone. Hence, our proposal involves a multi-institute collaboration, bringing together a wealth of patient resources (Wellstone Center), the latest in genomic technology (Broad Institute), and a well-established animal model of FSHD (Boston Children’s Hospital). Not only will the identification of these modifier genes for DUX4 resistance provide valuable insights into FSHD disease pathogenesis, but they will also present as solid leads that can be directly targeted for therapeutic intervention in humans with FSHD.
Determining the effectiveness of increased SMCHD1 expression to suppress DUX4 in FSHD muscle cells and model mice. Yosuke Hiramuki, Ph.D., Fred Hutchinson Cancer Research Center, Seattle, Washington USA Stephen Tapscott, M.D., PhD., Fred Hutchinson Cancer Research Center, Seattle, WA USA (mentor) 9/23/2017-9/22/2018 for one year. US$53,520
SMCHD1 an epigenetic key player of chromatin regulation in two unrelated disease: FSHD and BAMS syndrome. Camille DION, Ph.D. Student, INSERM UMR_S910, Aix Marseille Universite, FRANCE Frederique Magdinier, Ph.D., INSERM UMR_S910, Faculté de médecine de la Timone, Aix Marseille Universite, FRANCE (mentor). US$25,000
Skeletal muscle degeneration in the iDUX4pA mouse model. Michael Kyba, Ph.D., University of Minnesota, Minneapolis, Minnesota USA. US$100,000 total ($50,000 annually)
Derivation of multiple PAX7::GFP FSHD-specific human iPSC lines. Gabsang Lee, D.V.M., Ph.D., Johns Hopkins University, Baltimore, Maryland USA. US$ 94,696 for one year.
DUX4 toxicity: Deciphering necrotic pathways in FSHD. Julie Dumonceaux, Ph.D., University College London, London, United Kingdom. US$142,400 for 18 months.
DUX4 is often described as toxic for muscle cells in FSHD but cell loss mechanism driven by DUX4 expression remains largely unknown. In the literature, several articles have already investigated DUX4-dependent cell death mechanisms in vitro and in vivo, but focusing on apoptosis pathways. However, whereas FSHD mainly involves cells dying with necrotic morphology in patients biopsies, the necrotic death pathway has never been investigated. Our goal is to investigate necrotic mechanisms in this pathology.
This work will allow a better understanding of FSHD pathophysiology, may explain the link between DUX4 expression and FSHD pathophysiology and may help to define new therapeutic targets.
Transcriptional and epigenetic regulation of D4Z4 at chromosome 4q35.2. Sanxiong Liu, Ph.D., and Danny Reinberg, Ph.D., New York University School of Medicine, New York, New York USA. US$125,000 for one year.
April 2017 Ad Hoc Award
Patients’ stratification and eligibility in myostatin clinical trials. Julie Dumonceaux PhD, University College London, Institute of Child Health. $9,659.43 for one year
Several hypotheses have been proposed among them the poor efficacy of the anti-myostatin molecules or the specificity of the drugs themselves. In our study we are investigating another possibility based on the expression levels of several effectors of the myostatin pathway. Our experiments indicate that patient’ stratification (based on the expression of these effectors) might be useful to determine patient eligibility.
The funding provided by the FSH society will help us to finish performing the experiments which may be of importance for neuromuscular patients, and FSHD patients in particular, and may deeply impact future and current clinical trials using myostatin inhibitors.
Awards for the August 2016 cycle
FSH Society-NDRI Tissue Procurement Project Tom Bell, M.D., Ph.D. Jeffrey Thomas, Ph.D. Denee Tidwell National Disease Research Interchange, Philadelphia, Pennsylvania, USA 03/15/2017 - 03/14/2018 $38,202 for one year + $26,500 for tissue recovery costs FSHS-82016-01 cont. FSH Society Grant FSHS-22015-08
Inhibited protein turnover and TDP-43 aggregation in FSHD pathogenesis Sachiko Homma, Ph.D., Boston University, Boston, Massachusetts USA Jeffrey Miller, Ph.D., Boston University, Boston, Massachusetts USA 03/15/2017 - 03/14/2018 $58,920 for one year FSHS-82016-02 cont. FSH Society Grant FSHS-22015-01
Dynamic Mapping of Perturbed Signaling Underlying FSHD Peter Zammit, Ph.D., King's College London, London England, UK Chris Banerji, Ph.D., King's College London, London England, UK 03/15/2017 - 03/14/2018 $83,207.71 for one year FSHS-82016-03 cont. FSH Society Grant FSHS-82013-06 (3rd year)
Developing LNA-based therapy for facioscapulohumeral muscular dystrophy Yi-Wen Chen, D.V.M., Ph.D. Children’s National Health System, Washington DC, USA Toshifumi Yokota, Ph.D. University of Alberta Faculty of Medicine and Dentistry Alberta, Canada 04/01/2017 - 03/31/2019 $179,104 for two years FSHS-82016-04
Activity of estrogen on FSHD muscle differentiation Fabiola Moretti, Ph.D. Institute of Cell Biology and Neurobiology - National Research Council of Italy (CNR), Rome, Italy 03/15/2017 – 03/14/2019 $155,200 for two years Page 5 of 5 FSHS-82016-05
Awards for the February 2016 cycle
Sujatha Jagannathan (Robert Bradley and Stephen Tapscott, mentors). Fred Hutchinson Cancer Research Center, Seattle, Washington. Novel role for reduced RNA quality control in FSHD pathogenesis. $ 59,225 for 1 year.
Peter L. Jones/ Robert Bloch. University of Massachusetts Medical School, Worcester. CRISPR approaches targeting DUX4 in vivo. $ 240,014 for 2 years.
Eugénie Ansseau (Frédérique Coppée and Alexandra Belayew, mentors). University of Mons, Belgium. Study of the unexpected cytoplasmic functions of double homeodomain proteins DUX4 and DUX4c during differentiation: focus on healthy and pathological muscle cells. $ 124,807 for 1 year.
Amber Mueller (Robert Bloch, mentor). University of Maryland, Baltimore. Assessing the pathologic role of DUX4 in a humanized mouse model of FSHD. $ 134,728 for 3 years.
Nizar Saad (Scott Q. Harper, mentor). Nationwide Children’s Hospital, Columbus, Ohio. MicroRNAs as potential modifiers of Facioscapulohumeral Muscular Dystrophy (FSHD). $ 90,000 for 1 year.
2016 Research Grant Award
Jeffrey Statland, MD, University of Kansas Medical Center, Kansas City, Kansas. To expedite the development of new therapies for FSHD by developing a core FSHD Clinical Trial Research Network (CTRN). $121,000 for one year. With the generous support of the Geraldi Norton Foundation and Anonymous Donor.
Aim 1: Establish an FSHD CTRN infrastructure. To this end, we will:
- a. Develop standard operating procedures (SOPs) and a governance document for the Network
- b. Establish reliance agreements between the IRBs in the CTRN using the existing CTSA IRB reliance model
- c. Institute a data sharing agreement between the network sites.
- d. Create common data dictionary for a RedCap database at the University of Rochester, which can be rolled out at multiple sites, to allow for distributed, online data entry of anonymized data from all four sites.
- e. Create a manual of operations and standard regulatory language for a core set of outcome measures, to improve the efficiency of IRB regulatory submissions.
- f. We will create standardized protocols and CRFs for important FSHD clinical outcomes – wherever possible we will incorporate established NIH FSHD common data elements
- g. Train site clinical evaluators to insure that outcome measure procedures are performed in an identical manner at all sites. Establish inter rater reliability for each of the outcome measures.
Deliverable: All components of Aim 1 will be drafted in CTRN Year 1, then completed by the end CTRN Year 2
Aim 2: Create a system of committees to ensure engagement of all major stakeholders. To this end we will convene:
- a) Patient Engagement Circles comprised of patients willing to convene focus groups on an as needed basis to address specific aims or difficulties encountered in developing the FSHD CTRN, for example defining what would be clinically meaningful to people with FSHD, addressing concerns related to participating in clinical studies, and issues with recruitment and retention.
- b) A Guidance Committee comprised of investigators, patient advocates, patients and industry. This committee will assist the network in fashioning network wide SOPs, public outreach, and selection of projects to be run on the FSHD CTRN.
- c) Steering committee will be fashioned from site investigators, and an FSH Society representative to assist in the day to day running of CTRN network activities
Deliverable: rosters for each committee will be established and meetings held at network start up and prior to implementing the first project in CTRN Year 1.
Aim 3: Conduct a prospective study of outcome measures with funding from the NIH, MDA, and personal philanthropy: A prospective study of 150 patients followed over 18 months will be needed to definitively validate the outcome measures. We will be applying simultaneously to the NIH in a new request for application announcement (http://grants.nih.gov/grants/guide/pa-files/PAR-16-020.html) designed to fund applications for trial readiness in rare neurologic and neuromuscular diseases. The MDA has implemented a new clinical trial pathway for study funding. We feel that we are well positioned for such an application. Moreover, our chances for funding will be significantly improved if we can show that we already have a core FSHD Clinical Trial Network in place.
Deliverable: Funding will be pursued through the NIH, MDA, and personal philanthropic support with a goal of securing funding for a study by the end of CTRN year 1, first patient entered beginning of CTRN Year2. If funding from these sources is limited than the scope of our prospective study will have to be curtailed as a consequence.
Awards for the August 2015 cycle
Alec DeSimone (Charles Emerson mentor), UMass Medical School, Worcester. Investigation of 4-methylumbelliferone as a C1QBP-targeting FSHD therapeutic. $150,000 for 2 years.
In this project we will evaluate the ability of 4MU to serve as an FSHD therapeutic and investigate its mechanism of action. We have observed that 4MU inhibits the expression of DUX4-target genes, both in myotubes and when DUX4 is overexpressed in myoblasts. We have hypothesized that this is a result of the loss of HA altering the post- translational modifications of C1QBP, which would interfere with its ability to interact with DUX4 and act as a transcriptional cofactor. This could take the form of preventing C1QBP from binding to DUX4 directly, altering the subcellular localization of C1QBP, or by causing changes in C1QBP stability. We will perform studies to evaluate each of these possibilities. Finally, we will use an FSHD mouse xenograft model, established in our lab, to conduct dose-escalation studies to determine if 4MU treatment can inhibit DUX4-target gene expression in vivo. This will better evaluate 4MU as a potential FSHD therapeutic.
Julie Dumonceaux. Association Institut de myologie, Paris, France. Development of antisense oligonucleotide drugs as a therapeutic agents for FSHD. $94,606 for 1.5 years.
The overall objective of our project is to suppress DUX4 expression and develop a therapeutic approach for FSHD based on AOs. We have chosen to target the 3’ key elements of DUX4 mRNA and have already obtained robust results demonstrating the feasibility of such an approach. For the first time, we demonstrated in vitro that targeting a functional PAS can be an efficient therapeutic strategy for a genetic disease. We observed that targeting DUX4 3’key elements leads to an efficient extinction of DUX4, does not redirect polyadenylation and prevents aberrant expression of genes downstream of DUX4.
Our goal is now to (i) improve DUX4 mRNA extinction by developing sequence optimized AONs and to (ii) validate these AOs in vivo. Int the first aim, we will otpimize the sequence and chemistry of AO drugs targeting the 3’ key elements of DUX4 mRNA. In the second aim, we will test the body-wide administration of the most active anti-FSHD AO drugs for delivery and effectiveness in animal models after the creation of a new mouse model carrying a reporter gene (LacZ) with the 3’UTR of DUX4 mRNA. Two strategies will be developed: the direct injection of vivo-PMO and the vectorization of the PMO in an AAV vector. In the first case, mice will be subjected to treatment regimens of intravenous systemic delivery of therapeutic optimised AOs in naked form or conjugated to cell-penetrating moieties (eg octaguanidine or CPPs). In the second case, AOs will be vectorized under the control of the U7 promoter as it has been done for exon skipping for DMD for instance. AAVs are now well known to be able to target the muscles in a whole body without toxic effects.
Jocelyn Eidahl (Scott Harper mentor), Nationwide Children’s Hospital, Columbus, Ohio. Protein Chemistry and Protein-Protein Interactions of DUX4 and DUX4-FSHD mouse. $70,000 (request one year extension).
The DUX4 gene encodes a transcription factor that activates downstream toxic pathways, including apoptotic cascades. I hypothesized that post translational modification (PTM) may be one important mechanism affecting DUX4 protein function. PTMs play key roles in ligand binding affinity, subcellular localization and protein stability. My primary goal was to first identify whether DUX4 could be post translationally modified, then subsequently map DUX4 PTMs and determine their contribution to DUX4-induced toxicity. My aims are designed to define the role of DUX4 PTMs, which will allow us to potentially understand its protein function and regulation. By accomplishing this goal, we hope to establish a framework for therapeutic intervention designed to disrupt DUX4 modifications and prevent myotoxicity.
Aim 1: To define DUX4 post-translational modifications The DUX4 transcription factor is associated with muscle pathology in FSHD and is toxic to numerous other non-muscle cell types. However, some cells and tissues seem to resist DUX4-associated damage, including the testes, where DUX4 is naturally expressed at high levels, as well as muscles of non-manifesting FSHD carriers. The mechanisms by which some cells resist DUX4-associated damage are unknown, but it is likely that DUX4-modifier genes may impact disease penetrance. Since PTMs can profoundly influence transcription factor activity, I hypothesized that the DUX4 protein may also be regulated by PTMs, and the enzymes that mediate these PTMs could therefore impact DUX4 toxicity. In preliminary studies, I found that the DUX4 protein is modified by methylation and phosphorylation using mass spectrometric analysis of DUX4. In this aim, I will define the PTM signature of DUX4 in numerous cell types, including human myoblasts and primate testes, which endogenously express DUX4. Differences in the modification signature of DUX4 isolated from these cell types will provide insight about tissue-specific regulation of DUX4 protein, and may provide information about the differential toxicity of DUX4 in tissues or cells.
Aim 2: To examine the role of phosphorylation on DUX4 function My preliminary results revealed phosphorylation of numerous DUX4 residues in both the N and C-terminal domains. In this aim, I propose to examine the effects of each phosphorylation event using mutagenesis to irreversibly mimic or ablate DUX4 phosphorylated residues. I will then determine the effects of these DUX4 mutants in vitro using several outcome measures that I have previously established in my preliminary studies. These include DUX4 DNA binding affinity, assessment of the impacts on key ligand interactions, DUX4 dimerization, cellular toxicity and gene target activation. This work will help establish an important first step toward developing therapies that could prevent DUX4-mediated toxicity, by differentially affecting the phosphorylation status of DUX4.
Scott Harper, Nationwide Children’s Hospital, Columbus, Ohio. Characterization of a Tamoxifen-inducible DUX4 knockin mouse. $25,000 for 3-6 month bridge funding.
Sabrina Pagnoni and Constanza Cioffi (Alberto Rosa mentor), Catholic University of Cordoba (UCC) / National Research Council from Argentina (CONICET). Study of the co-regulatory role of DUX4 on sex hormone nuclear receptors and the protective effect of sex hormones on DUX4-mediated cell toxicity. $120,000 for 2 years.
Angela Lek (Louis Kunkel mentor), Boston Children’s Hospital, Boston, Massachusetts. A genome-wide CRISPR knock-out strategy to identify modifiers of FSHD. $78,000 for 1 year.
Jeffrey Statland MD, University of Kansas, Kansas City. To determine the initial responsiveness to FSHD disease progression of a system of synchronized wireless motion sensors. $39,044 for 1 year.
The long term goal of this research project is to establish a quantitative assessment tool to evaluate changes in mobility status of persons with FSHD. We will use a portable wireless motion analysis system to instrument a timed up and go, postural sway during quiet standing, and arm range of motion. We plan to build on an existing University of Kansas Medical Center Frontier’s pilot grant which will identify the specific outcome metrics obtained with portable wireless motion sensors which are important for examination in persons with FSHD and determine the reliability and cross sectional validity of those metrics. In the present FSHD Society study, we propose to extend our current pilot study to add 6 and 12 month follow up visits. We will conduct a 12 month longitudinal study in 20 genetically confirmed and clinically affected FSHD participants (10 mild to moderately affected, and 10 moderate to severely affected) to determine the responsiveness of wireless motion analysis to disease progression in FSHD, determine the minimal detectible change and minimally clinically important change in these metrics, and use factor analysis to create summary scores (e.g. upper extremity, lower extremity) for future clinical trials.
Tracy Zhang (Kathryn Wagner mentor), Kennedy Krieger Institute, Baltimore, Maryland. To cover the remaining months of graduate student Yuanfan “Tracy” Zhang in the Kathryn Wagner lab. FSH Society Musclepalooza graduate research award, $21,592 for 3 months.
Awards for the February 2015 cycle
Sachiko Homma, PhD / Jeff Boone Miller, PhD. Boston University, Boston, MA USA. Inhibited protein turnover in FSHD pathogenesis. $68,920 for 1 year
Yosuke Hiramuki, PhD / Stephen Tapscott, MD, PhD. Fred Hutchinson Cancer Research Center, Seattle, WA USA. Determining the effectiveness of increased SMCHD1 expression to suppress DUX4 in FSHD muscle cells and model mice. $101,132 for 2 years. FSH Society FSHD Canada Foundation research fellowship.
Aim 1. Doxycycline inducible lentivirus-SMCHD1 in FSHD1 and FSHD2 muscle cells. We will determine the effectiveness of increased SMCHD1 expression to suppress DUX4 in FSHD with different mutations using doxycycline inducible lentivirus-SMCHD1 (a and b). SMCHD1 is composed of exons 48 and has ATPase and Hinge domain. We will determine the critical region of SMCHD1 to suppress abnormal DUX4 in FSHD muscle cells using doxycycline inducible lentivirus-SMCHD1 that has short SMCHD1 coding sequence (c). a. Ability to suppress DUX4 in FSHD1 with i) Slightly lower than normal repeat size (7-10 unit) ii) Severe contraction (1-6 unit) b. Ability to suppress DUX4 in FSHD2 with i) Haploinsufficient mutation ii) Dominant negative mutation c. Ability to suppress DUX4 in a range of SMCHD1 coding sequence in FSHD muscle cells. i) Full length (exons 1-48) ii) Short length (exons 1-10, 1-20, 1-30, 1-40)
Aim 2. rAAV6-SMCHD1 in FSHD muscle cells and D4Z4-2.5 mice. We will determine the effectiveness of increased SMCHD1 expression to suppress DUX4 with recombinant adenoassociated virus 6 (rAAV6) – cytomegalovirus (CMV) – SMCHD1 in FSHD1 and FSHD2 muscle cells and D4Z4-2.5 mice (FSHD1 model mice). In addition, to distinguish the effect of SMCHD1 in whole body from muscle on suppression of DUX4 in FSHD, we will choose CMV promoter and enhancer/promoter regions of muscle creatine kinase and α-myosin heavy-chain (MHCK) genes and administrate rAAV6-CMV-SMCHD1 and rAAV6-MHCK-SMCHD1 into D4Z4-2.5 mice. a. Ability to suppress DUX4 in FSHD1 and FSHD2 muscle cells using rAAV6-CMV-SMCHD1. b. Ability to suppress DUX4 in D4Z4-2.5 mice using rAAV6-CMV-SMCHD1 and rAAV6-MHCK- SMCHD1.
In this application, Aim 1 will be the proof of principle experiments showing that higher SMCHD1 will be effective as a potential therapy and Aim 2 will develop a method for delivery that might eventually be suitable for pre-clinical or clinical studies based on rAAV6.
Eugenie Ansseau, PhD / with Frederique Coppee, PhD and Alexandra Belayew, PhD. University Mons, Mons, BELGIUM. Functional study of the DUX4 and DUX4c double homeodomain proteins in skeletal muscle. $93,450 for 1 year.
Jonathan Lonsdale, PhD. National Disease Research Interchange (NDRI), Philadelphia, PA USA. FSH Society-NDRI Tissue Procurement Project. $265,835 for 3.25 years -- was recommended for one year instead of three; and in addition one-third of the one year at $30,000 contingent on co-funding from other FSHD funding organizations. Fund if other FSHD research non-profits and FSHD Champions will co-fund.
2015 Grant renewal award
Exploiting genome editing technology to modify and regulate the FSHD disease locus. Michael Kyba, PhD. Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota USA. $125,000 over 1 year. FSH Society FSHD Canada Foundation research fellowship.
Awards for the August 2014 Cycle
“Detailed transcriptional analysis of stage-specific early FSHD myogenesis.” Gabsang Lee, PhD, DVM, Johns Hopkins University School of Medicine, Baltimore, Maryland. $70,977 for 1 year (FSH Society Max Weintraub Memorial Research Fellowship)
“Development of a new methylation assay for FSHD diagnosis.” Giancarlo Deidda, PhD, Institute of Cell Biology and Neurobiology, Rome, Italy. $56,000 for 18 months
- To develop additional assays to quantify the number of permissive alleles in order to assess whether different allelic combinations are relevant in the identification of diagnostic threshold;
- To analyze a large cohort of well genotyped FSHD patients and normal controls for precise evaluation of methylation threshold between affected and unaffected subjects;
- To assess specificity of this assay for FSHD disease by testing peripheral blood leukocytes DNA (PBLs) from individuals with unrelated muscular dystrophies;
- To analyze the prognostic potential of this assay by correlating methylation levels with different clinical severity scores;
- To study possible methylation differences distal to the D4Z4 array, between PBLs and muscle biopsies.
“Physiological Studies of Muscle Weakness in FSHD.” Jun Udaka, MD, PhD, and Charles Emerson, PhD, University of Massachusetts Medical School, Worcester. $212,060 for 2 years (FSH Society Helen Younger and David Younger Research Fellowship)
“Identification of the underlying genetic defect in a family with FSHD-like and optic atrophy phenotype.” Lionel Van Maldergem, MD, PhD, Université de Franche-Comté, Besançon, France, and Björn Fischer-Zirnsak, PhD, Charité-Universitaetsmedizin Berlin, Germany. $8,000 for 1 year
“Deciphering the contribution of FAT1-dependent phenotypes to FSHD symptoms and relevance for therapeutic design.” Françoise Helmbacher, PhD, IBDM, CNRS UMR 7288, Marseille, FRANCE. $138,803 for 2 years
Awards for the February 2014 Cycle
Novel role for reduced RNA quality control in FSHD pathogenesis. Sujatha Jagannathan, PhD, and Stephen Tapscott, MD, PhD. Fred Hutchinson Cancer Research Center. July 1, 2014 – June 30, 2016. Amount Requested for Project: US$ 116,725 over 2 years. (FSH Society Dotty Lynch Memorial Postdoctoral Fellowship Grant)
BET Proteins as Therapeutic Targets in FSHD. Francis M. Sverdrup, PhD. Center for World Health & Medicine, Saint Louis University. August 1, 2014 – July 31, 2015. One year $51,425. (FSH Society William Michael Postdoctoral Fellowship Grant)
FSHD Clinical Trials Network Workshop. Rabi Tawil, M.D. – University of Rochester Medical Center (Rochester, NY), May 2015. $25,000
Awards for the August 2013 Cycle
Investigating effects of PARP1 inhibitors in DUX4 expression. Yi-Wen Chen, D.V.M., Ph.D. George Washington University & Children’s National Medical Center, Washington DC, USA. $89,267 over 2 years
Gene surgery using TALEN technology: a therapy for FSHD. Julie Dumonceaux, Ph.D. Institut de Myologie, University of Paris, U974 – Inserm, Paris, France. $117,500 over 1 year
Protein chemistry and protein-protein interactions of DUX4. Jocelyn Eidahl, Ph.D. The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio USA. $70,000 over 1 year
Exploiting genome editing technology to modify and regulate the FSHD disease locus. Michael Kyba, Ph.D. Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota USA. $125,000 over 1 year. FSH Society FSHD Canada Foundation research fellowship.
Microdialysis for the study of inflammatory features in Facioscapulohumeral muscular dystrophy. Giorgio Tasca, M.D. Institute of Neurology Catholic University School of Medicine, Rome, Italy. $70,000 over 1 year
Dynamic mapping of perturbed signaling underlying FSHD. Peter S. Zammit, Ph.D. King's College London, London, England. FSH Society Shack Family and Friends research grant, $137,798 over 1 year to 18 months
Awards for the February 2013 Cycle
1. Pilot Study of Electrical Impedance Myography in Facioscapulohumeral Muscular Dystrophy. Jeffrey Statland, MD, University of Rochester, Rochester, New York. $48,909 for one year.
2. Development of a Novel ChIP-Based Diagnostic Assay for FSHD. Kyoko Yokomori, DVM PhD, University of California, Irvine, California and Shohei Koide, PhD, The University of Chicago, Chicago, Illinois. $40,000 for one year.
1. Role of Polycomb Group Proteins in Facioscapulohumeral Dystrophy. Valentina Casà, MS, and Davide Gabellini, PhD, Division of Regenerative Medicine, Fondazione Centro San Raffaele, Milan, Italy. $45,000 over 18 months.
2. Derivation of Human Induced Pluripotent Stem Cells From FSH Patient Fibroblasts. Gabsang Lee, PhD, Johns Hopkins University, Baltimore, Maryland. $49,705 over one year. FSH Society FSHD Canada Foundation research fellowship.
3. Autophagy Defects in FSHD. Sachchida Nand Pandey, PhD, Children's Research Institute, Washington, DC. $99,599 over two years.
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5. Specific Silencing of FAT1: Role in Pathogenesis of FSHD. Angela K. Zimmermann, PhD, Centre National de la Recherche Scientifique, IBDML – Development Biology, Institute of Marseille, Campus de Luminy, Marseille, France. $140,000 over two years.
1. A Transgenic Mdel of DUX4-Mediated FSHD. Peter Jones, PhD, Boston Biomedical Research Institute, Watertown, Massachusetts. $105,000 over two years; $60,000 year 1, $45,000 year 2.
2. Expression of Human DUX4 in Zebrafish Development. Hiroaki Mitsuhashi, PhD, and Louis Kunkel, PhD, Children's Hospital Boston, Boston, Massachusetts. $60,000 over one year.
3. FAT1 Roles in Muscular Physiology and FSHD Onset. Virginie Mariot, PhD; Julie Dumonceaux, PhD; and Gillian Butler-Browne, PhD, Thérapie maladies du muscle strié, Institut de myologie, Paris, France. $68,000 over one year.
4. A Humanized Mouse Model for Investigations of FSHD Pathology and Therapeutic Development. James Windleborn, PhD, and Charles Emerson, PhD, Boston Biomedical Research Institute, Watertown, Massachusetts. $60,000 over one year.
5. Tri-dimensional Organization of the FSHD Locus During Proliferation and Differentiation of Muscle Cells in FSHD Patients and Controls. Marie Gaillard, MS, and Frederique Magdinier, PhD, INSERM UMR_S 910, Epigenetics, chromatin & diseases team, Faculté de Médecine de Marseille, France. $30,000 over one year.
1. Identification of the Epigenetic Mechanisms That Regulate DUX4 Activity in Skeletal Muscle. Richard J.L.F. Lemmers, PhD, and Silvere van der Maarel, PhD, Leiden University Medical Center (LUMC) Department of Human Genetics, Leiden, Netherlands. $80,000 over two years.
2. Resonance Imaging and Spectroscopy Biomarkers in FSHD. Doris G. Leung, MD, and Kathryn R. Wagner, MD, PhD, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland. $43,650 over one year.
3. Additional Support for Medicinal Chemistry Developing Anti-DUX4 Therapeutics for FSHD. Michael Kyba, PhD, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota. $25,000 over two years.
1. Antisense Strategies Against DUX4 as Therapeutic Approaches for FSHD. Eugénie Ansseau, PhD, and Alexandra Belayew, PhD, Universite de Mons, Mons, Belgium. $70,500 over two years; $25,000 year 1, $45,500 year 2.
2. Humanized Mouse Model for the Study of Facioscapulohumeral Dystrophy. Marietta Barro, PhD, and Charles P. Emerson Jr., PhD, Boston Biomedical Research Institute, Watertown, Massachusetts. $40,000 over one year.
3. Testing a Therapeutic Approach for FSHD: Evaluation of the Efficacy of AOs Blocking DUX4 in a Mouse Model of Isolated Myofibres. Alexandra Tassin, PhD, and Alexandra Belayew, PhD, Universite de Mons, Mons, Belgium. $15,000 over one year.
4.Investigating Mouse Models of FSHD. Paraskevi Sakellariou, PhD, and Robert J. Bloch, PhD, University of Maryland School of Medicine, Baltimore, Maryland. $40,000 over one year.
5. Epigenetic Abnormality in FSHD. Weihua Zeng, PhD, and Kyoko Yokomori, PhD, University of California, Irvine, California. $8,875 for three-month extension.
6. Analysis of DUX4-fl Expression. Peter L. Jones, PhD, Boston Biomedical Research Institute, Watertown, Massachusetts. $7,500 for one year.
Awards for the August 2010 Cycle
1. Small Molecule Screen to Identify Inhibitors of DUX4-Mediated Toxicity, Therapeutic Approach for FSHD. Darko Bosnakovski, DVM PhD, University Goce Delcev Stip Faculty of Medical Sciences. Krste Misirkov bb, 2000 Stip R. Macedonia. $90,000 over two years.
2. Defining the Tissue and Cell Specificity of the Human DUX4 Promoter in Mice. Scott Harper, PhD, Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, The Ohio State University Room WA3015, 700 Children’s Drive, Columbus, OH 43205 USA. $50,000 over one year.
3. Identification of a Novel FSHD Biomarker (an Unknown 50 kDa Polypeptide Highly Expressed in FSHD Samples). Jessica Sun, PhD, and Peter Jones, PhD, Boston Biomedical Research Institute, 64 Grove Street, Watertown, MA 02472 USA. Partial funding for more preliminary data $10,000 over one year.
4. Toward Therapeutics for FSHD: Understanding mRNA Processing. Thomas A. Rando, MD PhD, and Antoine de Morree, PhD, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford Neurology Clinic, 300 Pasteur Drive, Boswell A-301, Stanford, CA 94305 USA. $100,000 over two years. Project is being matched dollar for dollar by the Stanford Office of Medical Development and Dr. Gary Steinberg, Stanford Institute for Neuro-Innovation and Translational Medicine (SINTN).
5. A Multicenter Collaborative Study on the Clinical Features, Expression Profiling, and Quality of Life of Pediatric Facioscapulohumeral Muscular Dystrophy. Jean Mah, MD, Alberta Children’s Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta, CANADA T3B 6A8. $96,669 over two years; $51,434 year 1, $45,235 year 2. Project is being co-funded by the FSHD Fund Muscular Dystrophy Canada FSHD Fund.