Over 50% of all human conceptions have too much or little genetic material, often due to the gain or loss of entire chromosomes. The majority of these are spontaneously aborted, but a significant fraction develop to term. Perhaps the most well known is trisomy 21, Downs syndrome, in which the individual bears three rather than the normal two copies of chromosome 21. Aneuploidy results in severe developmental abnormalities including mental retardation and severe physiological abnormalities. In spite of its frequency and biomedical relevance, we known little about the primary causes of the developmental defects associated with aneuploidy. Unlike Mendelian inherited disease genes, aneuploidy is not due to disruptions in gene sequence rather it is due to changes in gene copy number. Until recently, we did not have the tools to determine the primary molecular defects in aneuplid individuals and studies necessary focused on secondary defects. However the development of human embryonic stem cells and more specifically the isolation of a human embryonic stem cell line containing three rather than the normal two copies of chromosome 13 now enables us to explore the primary defects associated with human aneuploidy. In this proposal we plan to use newly developed methods to explore global patterns of gene expression in normal and trisomic lines. In is our hope that these will provide a glimpse of the initial defects associated with human aneuploidy. If the primary defects are due to the misexpression of only one or two genes, this would offer the possibility of developing theurapetic drugs to compensate for the mis-expressed gene(s). In addition, we propose to explore strategies for rapidly establishing normal cell lines from the trisomic human embryonic stem cell line as a first step toward cell replacement therapy.
This grant focuses on the primary molecular and cellular defects associated with trisomy 13, also known as Patau syndrome. Approximately 1 in 8,000 live births are trisomic for chromosome 13. Trisomy 13 together with trisomy 18 and 21 account for about 2 of every 1,000 live births and therefore classify as rare diseases. Approximately 25 million Americans (and between 2 and 3 million Californians) suffer from over 6,000 rare diseases for which there is no financial incentive for companies to develop drugs. In response, congress enacted the very successful Orphan drug act that has resulted in an over tenfold increase in the number of drugs targeting rare diseases. More recently, congress enacted The Rare Diseases Act of 2002 in order to produce NIH-sponsored centers of excellence for research on rare diseases. Three of these centers are in California(UCSF, UCLA, UCSD).
Due to the severe restrictions on federally funded research with human embryonic stem cells, to my knowledge there is no institutional backing for the application of hESC technologies toward the study and treatment of rare diseases. Funding the project proposed in this grant would be the first step towards laying the groundwork for a general strategy for CIRM to apply their resources toward helping the millions of Californians afflicted by rare diseases.