Determining the effectiveness of increased SMCHD1 expression to suppress DUX4 in FSHD muscle cells and model mice

Budget

$50,566 (USD) in total, supported in partnership with the FSH Society (50:50)

Lay Abstract

There are two genetic types of FSHD: FSHD1 and FSHD2. FSHD1 (representing around 95% of FSHD cases) is associated with a loss of repetitive DNA units called D4Z4 on the end of chromosome 4.  The remaining 5% of FSHD cases are FSHD2, and the majority of these cases are associated with mutations in a gene known as SMCHD1, located on chromosome 18. This gene helps to maintain the repetitive D4Z4 region associated with FSHD1. Further, it is also known that SMCHD1 modifies the severity of symptoms in patients with FSHD1.

In both FSHD1 and FSHD2, these genetic changes result in the activation (or expression) of a gene called DUX4, which is toxic to muscle. This gene is normally not active in adult muscles, but in FSHD DUX4 gets expressed and is thought to weaken and kill muscles. In this project, Dr. Hiramuki will manipulate the level of SMCHD1 and study how this affects the expression of DUX4, comparing cells with 7-10 D4Z4 repeats (corresponding to less severe FSHD) and 1-6 repeats (more severe FSHD). Similarly, he will investigate different versions of SMCHD1 for their effectiveness in suppressing DUX4. These are proof of principle experiments showing that higher SMCHD1 will be effective as a potential therapy.

In a second set of experiments, Dr. Hiramuki will use a genetically engineered virus (called adeno associated virus 6, or AAV6) to introduce extra SMCHD1 into human FSHD muscle cells, as well as in mice. The hope is that this will increase levels of SMCHD1 and suppress DUX4. With these experiments, he hopes to develop a gene therapy method that one day could be used to deliver SMCHD1 into FSHD patients’ muscles.