Targeting SMCHD1 to address the underlying cause of PWS

Funding Summary

Inhibiting SMCHD1 is a potential new treatment for PWS and SYS. In the first year of this study Dr. Blewitt provided evidence that SMCHD1 acts in a similar way in human cells and quantitated the level of gene activation that occurs in a mouse model when SMCHD1 is removed. In this second year of funding, Dr. Blewitt will attempt to determine what level of activation of PWS genes is achievable by removing SMCHD1 in patient-derived brain lineage cells, and does removing SMCHD1 in a mouse model of PWS/SYS improves the PWS-like symptoms in these animals. The experiments described here lay the foundation for therapeutic inhibition of SMCHD1; they provide the critical proof-of-concept data required for investment from pharmaceutical companies into this exciting novel therapeutic target for PWS and SYS.

Dr. Theresa Strong, Director of Research Programs, explains the details of the project in this video clip.

Lay Abstract

Prader-Willi syndrome (PWS) is caused by lack of expression of a cluster of genes normally expressed only from the copy you inherit from your father; the copy from your mother is switched off. PWS occurs essentially because the copy from the father is absent, but as in people without disease, the maternal copy is switched off. Schaaf-Yang syndrome (SYS) is very similar but relates to only one gene in this cluster, rather than several genes. Therefore, a potential therapy for both diseases is to awaken the maternal copy of these genes by inhibiting factors that normally silence these genes on the maternal copy. SMCHD1 is one such factor, that we discovered 10 years ago, and have since shown in mouse models functions to switch off the PWS cluster of genes. Thus, inhibiting SMCHD1 is a potential new treatment for PWS and SYS. Importantly, targeting SMCHD1 would treat the cause of PWS and SYS, and thus have the best chance of most effectively treating the wide array of symptoms experienced by patients, unlike any current treatment. In the first funded period of the project we have provided evidence that SMCHD1 acts in a similar way in human cells. We have also quantitated the level of gene activation that occurs in a mouse model in vivo when SMCHD1 is removed at a time relevant to the treatment of infants. To move this project forward, there are two critical questions we now need to address: 1)    What level of activation of PWS genes is achievable by removing SMCHD1 in patient-derived brain lineage cells? It is impossible to sample brain cells. Instead, we will sample PWS patient cells from a cheek swab, and in the lab turn them into cells that have the capacity to make any cell in the body. We will use these cells to produce the cells we need. We will test if removing all of SMCHD1 results in quantitatively more activation of PWS genes from the maternal copy than just removing one part of SMCHD1, as we have done so far. This will provide vital proof-of-concept data in human patient-derived cells, to take SMCHD1 forward as a valid drug target in PWS and SYS. 2)    Does removing SMCHD1 in a mouse model of PWS/SYS improves the PWS-like symptoms in these animals? We will remove SMCHD1 at a time similar to when patients would be trated, then test whether there is an improvement to body composition, activity and behavior. These data will suggest whether the level of gene activation by removing SMCHD1 is likely to have therapeutic benefit for patients. Should our project prove successful, we would seek to develop the set of compounds we have that inhibit SMCHD1 function, into safe and effective medicines for patients. We are the only group world-wide to have such compounds, so we are well-placed to advance these findings to the clinic. The experiments described here lay the foundation for therapeutic inhibition of SMCHD1; they provide the critical proof-of-concept data required for investment from Pharmaceutical companies into this exciting novel therapeutic target for PWS and SYS.