The FSH Society has awarded grants totaling $616,467 to seven research projects submitted during the February 2017 grant cycle. This brings the Society’s total new research commitments to $1,167,260 for the year. Reviewed by the Society’s world-class Scientific Advisory Board, these cutting-edge projects will help to accelerate the development of treatments.
Michael Kyba’s project will carry out detailed analyses of a new mouse that expresses very low levels of DUX4 and develops skeletal muscle disease. DUX4 is the gene widely viewed as a key instigator of muscle weakness and degeneration in FSHD. See related story.
Projects by Camille Dion, Yosuke Hiramuki, and Sanxiong Liu take aim at the regulation of DUX4. One of the regulators of DUX4 is a gene called SMCHD1. Mutations in SMCHD1 are associated with FSHD Type 2, and also with exacerbating FSHD Type 1. SMCHD1 is thought to normally play a role in repressing DUX4, and the FSHD-associated mutations make the gene less effective at doing its job.
Dion’s project will investigate SMCHD1’s role in regulating DUX4 and the process by which muscle damage occurs, particularly during the maturation of muscle cells. Hiramuki is exploring ways to make SMCHD1 more effective at repressing DUX4, possibly by blocking enzymes that degrade SMCHD1, which might be targets for new drug development. And Liu will search more broadly for factors that regulate DUX4 expression. All of these efforts aim to uncover potential targets for future drugs.
Angela Lek is harnessing CRISPR gene-editing technology to silence thousands of genes, one by one, in muscle cells that express DUX4. Ordinarily, the expression of DUX4 causes the cells to die. Lek’s project aims to find other genes that, when disabled, allow the cells to survive. These genes, as DUX4’s accomplices in harming cells, could be keys to unlocking a treatment strategy.
Past investigations have indicated that DUX4 expression can trigger a variety of potentially destructive processes, including oxidative stress and apoptosis (“programmed cell death”). Tissue can also be destroyed through necrosis, a less well-understood biological process commonly found in FSHD biopsies. Julie Dumonceaux’s project would, for the first time, investigate whether necrosis plays a role in FSHD. If she finds evidence that it does, this would suggest that blocking necrosis could be an avenue for treatment.
Gabsang Lee’s project aims to understand how FSHD affects the earliest development of skeletal muscle. Previous research has suggested that DUX4 is expressed in muscle stem cells that also express the PAX7 gene, so Lee proposes to create induced pluripotent stem cells (iPSCs) derived from FSHD patients as well as controls; these cells contain a “reporter” that shows if the cells are expressing PAX7. His goal is to carry out detailed cellular and molecular analysis on these cells as they develop into skeletal muscles. This, he hopes, will provide insight into whether DUX4 affects the early development of skeletal muscle in ways that might predispose it to the disease.
Here are the grants awarded from the February 2017 cycle
A GENOME-WIDE CRISPR KNOCK-OUT STRATEGY TO IDENTIFY MODIFIERS OF FSHD
Angela Lek, PhD, Genetics and Genomics; Louis Kunkel, PhD, Genetics and Genomics, Boston Children’s Hospital, Massachusetts, USA.
$75,860 for one year
DETERMINING THE EFFECTIVENESS OF INCREASED SMCHD1 EXPRESSION TO SUPPRESS DUX4 IN FSHD MUSCLE CELLS AND MODEL MICE.
Yosuke Hiramuki, PhD, and Stephen Tapscott, MD PhD, (mentor), Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
$53,520 for one year
SMCHD1 AN EPIGENETIC KEY PLAYER OF CHROMATIN REGULATION IN TWO UNRELATED DISEASES: FSHD AND BAMS SYNDROME
Camille Dion, PhD student, INSERM UMR_S910, Aix Marseille Université, FRANCE; Frédérique Magdinier, PhD, (mentor), INSERM UMR S910, Faculté de médecine de la Timone, Aix Marseille Université, FRANCE.
$25,000 for six months
SKELETAL MUSCLE DEGENERATION IN THE IDUX4PA MOUSE MODEL
Michael Kyba, PhD, University of Minnesota, Minneapolis, USA.
$100,000 total ($50,000 annually) over two years
DERIVATION OF MULTIPLE PAX7:GFP FSHD-SPECIFIC HUMAN IPSC LINES
Gabsang Lee, DVM PhD, Johns Hopkins University, Baltimore, Maryland, USA.
$94,696 for one year
DUX4 TOXICITY: DECIPHERING NECROTIC PATHWAYS IN FSHD
Julie Dumonceaux, PhD, University College London, UK.
$142,400 for 18 months
TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF D4Z4 AT CHROMOSOME 4Q35.2
Sanxiong Liu, PhD, and Danny Reinberg, PhD, New York University School of Medicine, New York City, USA.
$125,000 for one year