Development of a novel biologic medical product for Dyskeratosis Congenita

Program Director Principal Investigator Last First Middle Ko Minoru S H Dyskeratosis congenita DKC is a rare genetic disease that occurs at the rate of in million births and caused by mutations in genes involved in the regulation of telomere lengths Although there are multiple gene mutations causing DKC all the patients carry significantly shorter telomeres and eventually develop bone marrow failure which is the main cause of premature mortality in DKC patients There has been no effective treatment for DKC patients Here we would like to propose the product of human ZSCAN gene as a biologic to treat DKC patients We have originally identified mouse Zscan a novel protein expressed specifically in cell stage mouse embryos and have published a number of unusual features of Zscan functions in mouse ES cells i to rapidly extend telomeres by homologous recombination called alternative lengthening of telomeres which is independent of telomerase ii to increase genome stability and maintain normal karyotype by transient and occasional expression iii to increase developmental potential iv to block de novo synthesis of proteins transiently v to increase the efficiency and quality of induced pluripotent stem iPS cells when used as one of the reprogramming factors and vi to function as a potent epigenetic modifier and transiently open chromatin Based on these functions of mouse Zscan we hypothesize that transient overexpression of human ZSCAN protein extends telomeres in bone marrow cells from DKC patients by homologous recombination based mechanisms and eventually alleviates bone marrow failure in DKC patients In this SBIR Phase I proposal we would like to demonstrate that transient overexpression of ZSCAN elongates telomeres in fibroblast cells derived from DKC patients We would also like to demonstrate that ZSCAN biologics can be delivered to bone marrow using a mouse model The proposed project if successful will offer a first step towards a dramatically new therapy for patients with DKC In addition the biologicandapos s mechanisms are very much applicable to other related bone marrow and telomere related disorders such as myelodysplastic syndrome and Fanconi anemia OMB No Rev Approved Through Page Continuation Format PageProgram Director Principal Investigator Last First Middle Ko Minoru S H Narrative A novel medical product will be developed to treat bone marrow failure in patients with dyskeratosis congenita and other diseases OMB No Rev Approved Through Page Continuation Format Page