Translating Dosage Compensation to Trisomy

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DESCRIPTION (provided by applicant): Down Syndrome is a very common and clinically important genetic disorder, yet it receives very little attention for gene therapy, unlike many less common single-gene disorders. About 1 in 300 live births carries a trisomy, which can involve chromosome 13, 18, 21, X (XXY, XXX), or Y (XYY). The most common is Trisomy 21, or Down syndrome (DS), which results in impaired cognitive abilities, altered facial structure and numerous other health issues, including greatly increased incidence of early Alzheimer Disease cardiac defects, and hematological defects and early childhood leukemia. While developmental milestones are closer to normal at birth and gross brain structure is relatively normal, DS children typically show moderate or mild intellectual disability and cognitive deficits appear to worsen with progressive neuronal dysfunction, such that DS individuals often score as severely impaired later in life. DS children are often happy and loving, but are too often confronted with a variety of other medical issues, including a common transient leukemia that can progress to acute leukemia. Given that DS involves over-expression of genes across a whole chromosome, gene therapy for any aspect of this complex disorder seems a distant dream. We request funds to push forward an innovative approach to change that, and to generate reagents that would facilitate further study of this new strategy by other labs. We propose to translate the mechanism that nature devised to silence one X chromosome in mammalian female embryos to "dosage compensate" trisomy 21, primarily in induced pluripotent stem cells which have strong therapeutic potential. This exceptional opportunity is afforded by a nexus of new developments: in understanding the biology of XIST RNA in chromosome regulation and in technological innovations for induced-pluripotent stem cell (iPSC) programming, zinc finger nuclease (ZFN) genome editing, and non-viral delivery of DNA to cells. We propose to establish that the daunting problem of over-expression of genes across a chromosome can be reduced to the targeted integration of a single "dosage compensating transgene" (DCT) in pluripotent (embryonic-like) DS stem cells, and in two DS mouse models, including one which carries human chr. 21. The scientific foundation for this project is strong, and the key reagents and technology are "shovel ready", as is the highly-qualified and motivated team of investigators (PhD and MD), representing three inter-disciplinary laboratories. The huge potential impact for the DS research and family communities well warrants this investment. This funding will save and create several jobs, support economic activity and promote public and private collaborations. PUBLIC HEALTH RELEVANCE: Lay Summary: Down Syndrome is the leading genetic cause of mental retardation and is caused by an extra copy of Chromosome 21. We propose to demonstrate a new approach that makes genetic therapy for DS feasible, by rendering silent (non-functional) genes across the whole extra Chr. 21 in stem cells (from non embryonic sources) that have therapeutic value.