Is Chromosome Therapy Possible for Down Syndrome and Other Karyotypic Imbalances?

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ABSTRACT Trisomies, the presence of a third copy of a chromosome, are common human genetic defects that have enormous medical and social costs. Approximately 1 in every 300 live births carries a trisomy which can involve chromosome 13, 18, 21, X (XXY, XXX), or Y (XYY). Trisomy 21, or Down syndrome (DS), is the most common of these, and results in impaired cognitive abilities, altered facial structure and numerous other health issues, including greatly increased incidence of cardiac defects, early onset Alzheimer Disease, and childhood leukemia. While developmental milestones are closer to normal at birth, and gross brain structure is relatively normal, DS children most typically show moderate or mild mental retardation. DS children are often happy and loving, and can show improved outcomes with early educational intervention. However, no systemic medical treatment is available. Cognitive deficits may worsen with age, as there is evidence for progressive neuronal dysfunction since DS individuals often score as severely retarded later in life. Treatment of any chromosomal disorder is a daunting task. DS involves imbalanced expression of hundreds of genes present on the extra chromosome 21, affecting numerous biological processes. Thus, unlike single gene defects, it is challenging to imagine how an effective genetic approach to therapy in DS can be devised. What is needed is a means to deal with the problem at its root, the extra chromosome. This proposal presents a series of studies intended to utilize a naturally occurring mechanism for chromosome silencing, found in every mammalian female, to demonstrate feasibility of a "chromosome therapy' approach for trisomy. Dosage compensation of the X- chromosome in female mammals is realized through a unique non-coding RNA from the X-linked XIST genes, which initiates a cascade of events that silences one X chromosome. Using mouse and human experimental systems, we propose to test the ability of a targeted XIST transgene to inactivate somatic chromosomes in a variety of trisomic cells and attempt to demonstrate a rescue of normal phenotype in treated cells and mice. Due to the novelty of this concept, its inherent risks, and enormous medical and scientific potential, this project is an excellent candidate for EUREKA funding. We will test the feasibility of this singular, revolutionary idea. If we can demonstrate feasibility in human somatic cells and/or in the murine mouse model of DS, these findings would forge a new path and promote future efforts to translate "chromosome therapy" to a viable approach for humans. For the sake of the millions of DS individuals across the world, their families and the societies that support them, this important, novel idea should be tested.