Trisomy Correction in Down Syndrome Induced Pluripotent Stem Cells

Li, Li B.; Chang, Kai Hsin; Wang, Pei Rong; Hirata, Roli K.; Papayannopoulou, Thalia; Russell, David W.

doi:10.1016/j.stem.2012.08.004

Cited by 133 publications

(138 citation statements)

References 25 publications

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“…Comparisons have been made between euploid and trisomy 21 iPSCs derived from multiple sources, including different individuals (nonisogenic) 122,209 ; isogenic lines generated in cell culture, spontaneously or by selection 154,210 ; lines in which one of the three copies of chromosome 21 has been silenced 211 ; monozygotic twins that were discordant for trisomy 21 (REF. 169); and nonintegration-reprogrammed isogenic lines from an adult with mosaic DS (a condition in which only a percentage of an individual's cells carry an extra copy of chromosome 21) 121 .…”

Section: Box 2 Modelling Ad-ds In Mice and In Human Ipscsmentioning

confidence: 99%

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) -an Alzheimer disease risk factor -although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.Down syndrome (DS) is a complex, highly variable disorder that arises from trisomy of chromosome 21. It was one of the first chromosomal disorders to be identified 1 and occurs with an incidence of approximately 1 in 800 births 2 . Its prevalence within a given population is influenced by infant mortality rates, access to health care, termination rates, average maternal age 3 and life expectancy. Indeed, despite the increased availability of prenatal diagnosis and access to the option of termination, the global prevalence of DS is rising because of improvements in life expectancy: the number of adults with DS aged over 40 years has doubled in northern Europe since 1990 and, in the United Kingdom, one-third of the estimated 40,000 people with DS are thought to be over 40 years of age 4 .DS is the most common form of intellectual disability. In addition to the features that are found in everyone with the disorder, such as the characteristic facial dysmorphology, there are many DS-associated phenotypes that have variable penetrance and severity. For example, approximately 40% of individuals with DS have heart malformations (usually atrioventricular septal defects) 5 . A key feature of DS is a striking propensity to develop early-onset Alzheimer disease (EOAD). Complete trisomy of chromosome 21 universally causes the development of amyloid plaques and neurofibrillary tangles (NFTs), which are typical characteristics of AD brain pathology, by the age of 40, and approximately twothirds of individuals with DS develop dementia by the age of 60 (REFS 6,7). However, rates of dementia do not reach 100%, even in older individuals, suggesting that some individuals with DS are protected from the onset of AD (FIG. 1).All of the features of DS arise because of aberrant dosages of coding and/or non-coding sequences present on chromosome 21. Among these sequences, the gene encoding amyloid precursor protein (APP) is thought to have a key role in the pathology of AD. The additional copy of APP may drive the development of AD in individuals with DS (AD-DS) by increasing the levels of amyloid-β (Aβ), a cleavage product of APP that misfolds and accumulates in the brain in people with AD. Consistent with this hypothesis, individuals with small internal chromosome 21 duplications that result in three copies of APP -a rare familial trait known as duplic...

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Section: Box 2 Modelling Ad-ds In Mice and In Human Ipscsmentioning

confidence: 99%

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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“…However, a number of techniques have been described and tested in animal experiments which are working toward that end [39][40][41]. A means of correcting human trisomy 21 using this method has also already been described in principle [42][43][44]. If the option to perform such corrections should become an established procedure, then it would be useful to undertake such corrections as early as possible [45].…”

Section: Preimplantation Therapy (Pit)mentioning

confidence: 99%

Non-embryo-destructive Extraction of Pluripotent Embryonic Stem Cells: Implications for Regenerative Medicine and Reproductive Medicine

Dittrich

Beckmann

Würfel³

2015

Geburtshilfe Frauenheilkd

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On August 1, 2013, the German Patent and Trademark Office issued a patent for the ?Non-embryo-destructive extraction of pluripotent embryonic stem cells, stem cells obtained by this process and their uses? (DE 10 2004 062 184 B4). The patent document describes a non-embryo-destructive process to harvest embryonic stem cells from the inner cell mass (ICM) during the blastocyst development stage. The patent application was filed with the German Patent Office in Munich on December 23, 2004 and the patent claim was published in 2006. The patent was granted on August 1, 2013. Processing the patent application was a lengthy affair due to the fact that, for a long time, the prevailing opinion in Germany was that genetic screening of embryos (preimplantation genetic diagnosis) was prohibited under the German Embryo Protection Act (ESchG). A ruling by the German Federal Court in 2010 proved this opinion to be false. Animal studies have provided the evidence that the described procedure is technically feasible; healthy offspring were born after stem cells were harvested from the blastocyst and stored. We report here on a technique for the non-embryo-destructive extraction of pluripotent embryonic stem cells together with potential future applications for stem cells harvested in this manner.

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“…8 When selecting against TKNEO, spontaneous loss of chromosome 21 occurred through a natural cellular selection process, and iPS cells trisomic for chromosome 21 became disomic. Regardless of approach, Russell said that differentiating iPS cells into somatic cell types complicates comparison between trisomic and disomic cells.…”

Section: Breaking Down Trisomy 21mentioning

confidence: 99%

Chromosome shutdown

Baas¹

2013

Science-Business eXchange

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Trisomy Correction in Down Syndrome Induced Pluripotent Stem Cells

Cited by 133 publications

References 25 publications

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

Non-embryo-destructive Extraction of Pluripotent Embryonic Stem Cells: Implications for Regenerative Medicine and Reproductive Medicine

Chromosome shutdown

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