Grant 25


Research Institution: B​aker IDI Heart & Diabetes Institute

Principle Investigator:

 Doctor Paul Gregorevic

Type: ​Australian

Project title: ​Enhancing BMP signaling to treat FSHD

Status: Active

Summary

The Team’s first objective was to develop a new mouse model in which to study how muscles are affected by FSHD, which can be used to test new therapeutic strategies. To achieve this, the Team designed a gene delivery tool that enables controllable expression of the FSHD-related gene Dux in the muscles of mice. This mouse model has a number of advantages over existing approaches including a) the ability to express Dux at extremely low levels as reported in human FSHD muscles and b) to profile the earliest changes that occur in response to low-levels of Dux expression using time points that precede any disease pathology. Having designed and validated the tunable Dux expression system during the initial months of the project, the Team has used this model to show that Dux can activate genes that promote skeletal muscle wasting. Based on these findings, they have developed a specific inhibitor against one of these genes. Current studies are focused on determining if this inhibitor is sufficient to block the development of FSHD-like symptoms in the Team’s mouse model and in FSHD muscle cells.

 

PROGRESS REPORTS


October 2014

Our research will explore a new strategy for treating muscle wasting associated with FSHD. Our plan is based on increasing the activity of Bone Morphogenetic Proteins in muscles, as we predict this approach can correct the processes that cause muscle wasting in FSHD. An exciting aspect of our research is that we will test an existing drug that increases Bone Morphogenetic Protein signaling in diseased muscles. As this drug has been given to patients for other conditions, encouraging results could support adapting the use of this drug as a new treatment for FSHD.


Update March 2015

The group has designed genes that switch Dux4 “on” and “off”, and delivered these to cells grown in the lab, and the muscles of mice. They confirmed that cells produced Dux4 when switched “on”, but not in the “off” state, in cells in the laboratory. Dux4 “on” caused cell death, consistent with other reports on Dux4 effects. In mice, switching on Dux4 caused muscle disease. In mice where the Dux4 gene was not switched on, no disease was observed. Expression of Dux4 at lower levels seems to produce a milder disease, with slower progression. Consequently they are now undertaking studies to optimise dose and test intermittent Dux4 expression, to mimic the sporadic, low level Dux4 expression found in FSHD in humans. This approach differs from others using chronic high level Dux4 expression, not evident in human patients. Their short term goal is to provide a useful model for low-level Dux4 expression as in humans, and study the signalling pathways and specific genes affected. They also plan to make this model available for others to use, and compare with other models.


Update March 2016

The Team’s first objective has been to develop a new mouse model in which to study how muscles are affected by FSHD, which can be used to test new therapeutic strategies. To achieve this, the Team designed a gene delivery tool that enables expression of the FSHD related gene DUX4 to be controlled in the muscles of mice. Having designed the tunable DUX4 expression system during the initial 6 months of the project, the Team has subsequently focused on defining the conditions required to reproduce intermittent DUX4 expression of varying degrees in the muscles of treated mice. This approach to controlling DUX4 expression is an important feature, as human FSHD muscles express more DUX4 than normal, but intermittently and still at low levels.

Using specific conditions, the Team is now undertaking longer-term studies to a) examine how intermittent, low-level increases in DUX4 expression contribute to the development of FSHD-like symptoms, and b) profile changes in the expression of genes as a consequence of DUX4 regulation, to identify cellular processes that could be targeted by new therapeutics. With this information in hand, the Team intends to progress to the next objective of investigating whether manipulating the activity of specific signalling mechanisms of interest is protective or restorative in mouse muscles that model FSHD.


Update July 2016

The Team’s first objective was to develop a new mouse model in which to study how muscles are affected by FSHD, which can be used to test new therapeutic strategies. To achieve this, the Team designed a gene delivery tool that enables controllable expression of the FSHD-related gene Dux in the muscles of mice. This mouse model has a number of advantages over existing approaches including a) the ability to express Dux at extremely low levels as reported in human FSHD muscles and b) to profile the earliest changes that occur in response to low-levels of Dux expression using time points that precede any disease pathology. Having designed and validated the tunable Dux expression system during the initial months of the project, the Team has used this model to show that Dux can activate genes that promote skeletal muscle wasting. Based on these findings, they have developed a specific inhibitor against one of these genes. Current studies are focused on determining if this inhibitor is sufficient to block the development of FSHD-like symptoms in the Team’s mouse model and in FSHD muscle cells.