Fred Hutchinson Cancer Center

University of Rochester

Ionis Pharmaceuticals, Inc.

Saint Louis University

Leiden University Medical Center

Fred Hutchinson Cancer Research Center

Snider, Lauren

Stephen J Tapscott

Frank Rigo

James M Olson

Theodore D Palmer

Harold M Weintraub, Deceased

Galina N Filippova

Sean Shadle

Richard J L F Lemmers

Amy Campbell

Silvere M Van Der Maarel

Linda Geng

Paula D Ladd

Lauren Snider

Harold M Weintraub

Silvère M Van Der Maarel

Stanley M Hollenberg

Rabi Tawil

Francis M Sverdrup

Jacqueline E Lee

Richard JLF Lemmers

Silvere Van Der Maarel

Zizhen Yao

Disclosed herein are methods of treating facioscapulohumeral muscular dystrophy (FSHD). In an example, a method of treatment includes administering to a subject an agent that increases NuRD and/or CAF-1 complex repression of DUX4, thereby reducing or inhibiting one or more signs or symptoms associated with muscular dystrophy. In other examples, the treatment method includes administering an agent that increases the activity and/or expression of NuRD/MBD2 and/or MBD1/CAF-1 complex members, thereby reducing or inhibiting one or more signs or symptoms associated with muscular dystrophy. Also disclosed is a method of treatment of FSHD including administering to a subject an effective amount of an MBD3L protein inhibitor to treat one or more signs or symptoms associated with FSHD.

Methods for treating facioscapulohumeral muscular dystrophy

In one aspect, the invention provides a method of screening a human subject to determine if said subject has a genetic predisposition to develop, or is suffering from Facioscapulohumeral Dystrophy (FSHD), said method comprising: (a) providing a biological sample comprising genomic DNA from the subject; and (b) analyzing the portion of the genomic DNA in the sample corresponding to the distal D4Z4-pLAM region on chromosome 4 and determining the presence or absence of a polymorphism resulting in a functional polyadenylation sequence operationally linked to exon 3 of the DUX4 gene, wherein a determination of the absence of a functional polyadenylation sequence operationally linked to exon 3 of the DUX4 gene indicates that the subject does not have a genetic predisposition to develop, and is not suffering from FSHD, and/or wherein a determination of the presence of a functional polyadenylation sequence operationally linked to exon 3 of the DUX4 gene indicates that the subject has a genetic predisposition to develop, or is suffering from Facioscapulohumeral Dystrophy (FSHD).

Methods for alleviating facioscapulohumeral dystrophy (FSHD) by N siRNA molecule inhibiting the expression of DUX4-FL

The present disclosure pertains generally to double-stranded small interfering RNAs that modulate gene expression for use in research, diagnostics, and/or therapeutics. In certain embodiments, the present disclosure provides double-stranded small interfering RNAs that modulate DUX4 gene expression. In certain embodiments, the present disclosure provides methods of inhibiting DUX4 gene expression by contacting a cell with double-stranded small interfering RNAs.

Compounds and methods for modulation of DUX4

The use of BETi as a potential treatment for FSHD is provided. Specifically, the use of BETi, and particularly selective BETi for BRD4, are shown to inhibit DUX4 expression which is expected to result in a decrease in the severity of symptoms of FSHD. Further, the treatments are shown to work when pulsed as opposed to continuous. This allows for a BETi to be supplied to a human in a pulse, and then allows the human to not need any additional treatment for a window at least as long as the one of the treatment pulse.

Inhibition of DUX4 expression using bromodomain and extra-terminal domain protein inhibitors (BETi)

The present invention provides compositions and methods of identifying a subject as having an increased risk of developing fragile X-associated tremor and ataxia syndrome (FXTAS) or identifying a subject having an increased risk of developing fragile X syndrome (FXS), comprising analyzing messenger RNA (mRNA) transcripts and/or translation products of the antisense gene ASFMR1.

Methods and compositions for identifying increased risk of developing fragile X-associated disorders

Provided are methods of classifying and prognosticating human neuroectodermal tumors by analyzing a sample of the tumor to determine whether various bHLH proteins are detectably expressed in the sample. In the methods disclosed herein, expression of the bHLH genes is assessed by measuring transcripts or proteins expressed from the genes.

Neurogenic differentiation gene neurod3 and methods for inducing differentiation of cells

Expression of neurogenic bHLH genes in primitive neuroectodermal tumors

Neurogenic differentiation genes and proteins are identified, isolated, and sequenced. Expression of neuroD has been demonstrated in neural, pancreatic, and gastrointestinal cells. Ectopic expression of neuroD in non-neuronal cells of Xenopus embryos induced formation of neurons.

Neurogenic differentiation (neurod) genes

Isolated DNA or RNA molecules capable of hybridizing under stringent conditions to the myoD regulatory region, its proximal promoter and distal enhancer regulatory regions, and regulatory elements within the proximal and distal regions for binding basic helix-loop-helix proteins, MyoD, and proteins binding at SP1, AP1, CAAT, M-CAT, CArG, and MEF sites in DNA. DNA or RNA expression vectors for introducing a gene into a cell under the regulatory control of the myoD regulatory region. Transduced or transfected pre-muscle cells, myocytes, or myoblasts. Methods of inducing a muscle phenotype in a non-muscle cell, positively selecting for a cells expressing MyoD, and negatively selecting for cells expressing MyoD.

Myod regulatory region

Growing community of inventors

Seattle, WA, United States of America

Stephen J Tapscott