Recently, a research paper published in Nature sheds some light on the treatment of Down syndrome, a genetic disorder due to an extra copy of chromosome 21 in human cells. A group in University of Massachusetts developed a strategy to silence the extra copy of chromosome 21 and restore the genes in Down syndrome cells to normal in the culture dish.
Down syndrome is a genetic disorder that affects one in 691 live births in US; it causes mental retardation, seizure, early onset of Alzheimer disease, heart disease, diabetes, cancer, and many others. The British physician John Langdon Down first described the syndrome in 1866, and the French physician Jerome Lejeune first identified the cause of Down syndrome as the presence of an extra copy of chromosome 21 in cells of patients. In the past 147 years, generations of scientists have extensively studied this disorder, and gained much knowledge on the genetics, pathology, diagnosis, and management of Down syndrome. However, due to the complexity of multiple genes over-expressed from the extra copy of chromosome 21 (more than 500 genes have been identified on chromosome 21), there is no cure for this syndrome yet.
Nature is always our best teacher: we learned to use sonar navigation from bats and lighten up cells with green fluorescence protein from jelly fish. Women have two copies of X chromosomes in their cells, but only one copy is activated, with the other copy shutting down during early fetal development. This is caused by a gene on X chromosome, named X-inactive specific transcript (XIST). In 1990s, scientists have discovered that XIST gene translocated to the other chromosomes can silence all the gene expression from that chromosome. But it is not until this year that scientists in University of Massachusetts use this strategy to shut down the genes on chromosome 21 in cells from Down syndrome.
The XIST gene was inserted into one selected location on chromosome 21 in induced pluripotent stem cells (iPS cells) from Down syndrome patients by using a Zinc Finger protein targeting technique. The iPS cells were made from skin cells of a Down syndrome patient; with the characteristics of embryonic stem cells, the iPS cells have the potential to develop into all types of tissues and organs. Because XIST functions in early embryonic development, they used iPS cells for XIST silencing. After the gene insertion by homologous recombination (a natural DNA replication and repair during cell division), they initiated the XIST gene expression by turning on a drug-controlled switch. They then analyzed the gene profiles including mRNA expression and DNA methylation level and found the cellular activities restored to the normal two-copy chromosome level.
The limits of this technique include very low efficiency of inserting XIST gene into chromosome 21, and use of stem cells for the gene integration. However, with the first working proof, the improvement and alternative approaches will grow, and this strategy may provide a real cure for Down syndrome in the future.
References:
Jiang J, Jing Y, Cost GJ, Chiang JC, Kolpa HJ, Cotton AM, Carone DM, Carone BR, Shivak DA, Guschin DY, Pearl JR, Rebar EJ, Byron M, Gregory PD, Brown CJ, Urnov FD, Hall LL, Lawrence JB. Translating dosage compensation to trisomy 21. Nature. 2013 Aug 15;500(7462):296-300. (http://www.nature.com/nature/journal/vaop/ncurrent/full/nature12394.html)
