Genetic therapy has the potential to address the root cause of PWS, however, several feasibility questions need to be answered before we can consider genetic therapy for PWS. For example: Does activation of the PWS genes reverse symptoms in models of PWS? Which genes must be turned on? Does gene activation need to occur before a specific age in order to have an effect?
In this study, Dr. Resnick aims to address many of these feasibility questions in a mouse model of PWS. Dr. Resnick will develop a mouse model that will allow him to turn on the SNORD116 gene at various stages of development (either before or after birth). The model will then be observed to determine if there is any reversal of PWS symptoms after the genes are turned on, and if so, how early the genes need to be turned onto have a beneficial effect. This will help determine the overall feasibility and promise of genetic therapy for PWS and will allow the research team to answer questions about the best timing, location, and potential side effects of genetic therapy for PWS.
Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.
Watch the full webinar describing the 8 research projects funded in this grant cycle here.
Individuals with Prader-Willi syndrome lack the activity of several genes that are normally expressed from only the paternally inherited copy of chromosome 15. Genetic therapies often seek to re-establish the absent gene products. In some syndromes, the missing gene products are necessary only transiently, even though the gene normally continues to be expressed. The proposed research seeks to determine whether gene replacement therapies can be of value in the treatment of PWS, and if so, when the missing gene products must be re-established to have effect. We propose to generate a novel mouse mutant that will undergo development in the absence of Snord116, a PWS gene strongly implicated in many traits. The mutation will be constructed so that the absent gene products can be readily turned on at predetermined times either before or after birth. Reversal of traits following re-establishment of gene expression will indicate that genetic therapies can be of value. As time permits, we will also re-establish PWS gene expression at various times in order to determine how late in pre or postnatal development Snord116 expression must be restored to have a beneficial effect.
We have created a novel mouse mutation that leads to conditionally active expression of the large transcript that produces Snrpn, all SnoRNAs, Ipw, and the Ube3a-ats.