New technique ‘wakes up’ silent genes in Prader-Willi in lab testing
Researchers say epigenome editing may be therapeutic approach for PWS
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Epigenome editing, a technique that alters the chemical switches that turn genes on or off, can reactivate genes from the mother that are usually silent in Prader-Willi syndrome (PWS), a study using stem cells has found.
According to the researchers, these laboratory findings provide new evidence that epigenome editing may offer a potential treatment pathway for essentially waking up silent genes in people with this rare genetic disease.
“This study highlights the utility of epigenome editing technology as a therapeutic approach in addressing PWS,” the team wrote, adding that the findings “[provide] proof of principle.”
The study, “Rescue of imprinted genes by epigenome editing in human cellular models of Prader-Willi syndrome,” was published in the journal Nature Communications by a research team from Japan.
Prader-Willi is caused by a failure in genomic imprinting, where usually only one copy of certain genes is meant to be active. In PWS, the father’s copy of a group of genes on chromosome 15 is either missing or nonfunctional. The mother’s copy is still present, but epigenetic silencing, whereby chemical marks on the DNA keep a gene in a switched-off state, acts like a lock that prevents those genes from being used.
Because this region on chromosome 15 helps control the brain’s hypothalamus — a region which regulates body temperature, hunger, thirst, sleep-wake cycles, and emotional responses — people with PWS develop a wide range of symptoms, the hallmarks of which are excessive hunger, low muscle tone, and learning and behavioral issues. Available treatments aim to ease symptoms and improve quality of life.
Researchers target genetic cause of PWS
This research team, led by scientists at Keio University School of Medicine in Tokyo, focused on developing a treatment that could target the genetic cause of the disease.
To that end, the scientists explored the possibility of activating the mother’s normally silent genes using CRISPR-based epigenome editing. This method changes chemical marks — in this case, methylation marks — without cutting the DNA itself.
The team worked with induced pluripotent stem cells derived from four patients diagnosed with PWS and three healthy individuals, who served as controls. These stem cells behave like early embryonic cells, which can develop into other cell types, allowing researchers to test new treatments on patient-derived material.
By targeting the main control switch in the region on chromosome 15 that is missing or inactive — the PWS imprinting control region, or PWS-ICR, which controls a gene called SNRPN — the methylation marks were removed. After editing, SNRPN was nearly as active as in healthy stem cells, which retained their ability to develop into other cell types, according to the researchers.
The application of … epigenome editing holds potential for reactivating silenced PWS-associated genes … offering a promising avenue for therapeutic exploration.
No unintended changes to other epigenetic marks were observed, indicating that the CRISPR-based epigenome editing was specific and precise. This confirmed that the increased activity of the SNRPN gene resulted directly from the targeted removal of methylation marks at the PWS-ICR.
However, the method did correct methylation patterns in other imprinted regions that are usually disrupted in PWS, at a later time point, suggesting a broader reset of gene activity over time following CRISPR-based epigenome editing.
When the edited stem cells were transformed into hypothalamic organoids — a 3D model of the hypothalamus — activated genes remained on, and the activity of nerve cell-specific genes was restored. Single-cell analysis confirmed that these patterns partially reversed PWS-related changes.
“The findings presented in this study not only advance the understanding and potential treatment avenues for PWS but also contribute to epigenome editing therapies for a wide spectrum of diseases,” the researchers wrote.
According to the team, “the application of CRISPR-based epigenome editing holds potential for reactivating silenced PWS-associated genes … offering a promising avenue for therapeutic exploration.”
