One of the exciting breakthroughs in PWS research in recent years has been the development of induced pluripotent stem cells or “iPSCs”. Although there is tremendous excitement among the scientific community about iPSCs, many parents, patients, and advocates still have a lot of questions about what exactly they are,
and more importantly, how they can be used to help advance PWS research and therapies. Several exciting recent publications highlight the value of this tremendous resource!
As a quick review, iPSCs are basically cells that have been collected from an individual (usually skin or blood cells) and then in the lab, they are “rebooted” to a more primitive (undifferentiated) state. From this state, researchers can then direct the cells to grow into specific cell types (e.g. muscle, neuron). Basically, the technology allows scientists to make the kinds of cells that are very difficult to collect from cells that are much easier to collect. This is particularly important for a neurodevelopmental disorder such as PWS, where being able to conduct research and comparisons with human PWS and non-PWS neurons is critical. For a more in depth description, please visit the FPWR press release (here) from when PWS iPSC were first generated by Dr. Marc Lalande’s group at the University of Connecticut as a result of an FPWR funded project titled “Derivation of live Prader-Willi syndrome neurons from induced pluripotent stem (iPS) cells”.
Drs. Lalande and Martins-Taylor have now built upon their initial work in two recently published papers: “Imprinted expression of UBE3A in non-neuronal cells from a Prader-Willi syndrome patient with an atypical deletion”; and “Reactivation of Maternal SNORD116 Cluster via SETDB1 knockdown in Prader-Willi Syndrome iPSCs”. Both of these reports highlight how iPSCs are being used to better understand the role of genes in the PWS region as well as epigenetic regulation of the PWS region. Specifically, in the first report, they are using iPSCs from PWS individuals with deletions and comparing how small differences between the deleted regions impacts neurons. This may help better explain the role of each gene in the PWS region. The second paper highlights the use of iPSCs to determine how the maternal chromosome 15 is “silenced” in the PWS region, and how it might be possible to “reactivate” that genetic region. This FPWR-funded study represents a first step towards potentially treating PWS at the genetic level.
At the same time, halfway around the world, a group in Israel is using PWS iPSCs to demonstrate how the PWS region of chromosome 15 has significant impacts on a set of genes located on chromosome 14. In their paper “The noncoding RNA IPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome” they show that a non-coding RNA (called IPW) in the PWS region regulates a series of maternal genes (DLK1-DIO3) on a completely separate chromosome (chromosome 14). Although this adds to the genetic complexity of PWS, the fact that genes outside of the PWS region contribute to the PWS phenotype (characteristics) also brings new hope as new therapeutic targets are identified. This paper also stresses the importance of human iPSCs in that the IPW gene studied in this paper is very different between humans and mice.
We look forward to learning about additional advances in PWS research as a results of iPSCs. Recent FPWR funded projects using iPS cells include “The role of SNORD116 in Prader-Willi syndrome”, and “Use of stem cell-derived neurons to identify the molecular basis of the PWS” both from Dr. Rudolph Leibel at Coumbia University.