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Reprogramming Pediatric Genetic Disorders: Pearson Syndrome, Ring 14 Syndrome, and Fanconi Anemia

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Reprogramming Pediatric Genetic Disorders: Pearson Syndrome, Ring 14 Syndrome, and Fanconi Anemia Reprogramming Pediatric Genetic Disorders: Pearson Syndrome, Ring 14 Syndrome, and Fanconi Anemia The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Cherry, Anne Blanche Cresswell. 2014. Reprogramming Pediatric Genetic Disorders: Pearson Syndrome, Ring 14 Syndrome, and Fanconi Anemia. Doctoral dissertation, Harvard University. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274294 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Reprogramming Pediatric Genetic Disorders: Pearson Syndrome, Ring 14 Syndrome, and Fanconi Anemia A dissertation presented by Anne Blanche Cresswell Cherry to the Division of Medical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Biological Chemistry and Molecular Pharmacology Harvard University Cambridge, Massachusetts April 2014 © 2014 Anne B. C. Cherry All rights reserved Dissertation Advisor: Professor George Q. Daley Author: Anne B. C. Cherry Abstract Reprogramming Pediatric Genetic Disorders: Pearson Syndrome, Ring 14 Syndrome, and Fanconi Anemia The effect of a single genetic mutation can vary greatly between different types of cells. The mutated gene may not be expressed in one tissue but may cause a devastating loss of function in another. To learn about disease mechanisms and generate novel therapies, genetic disorders must be studied in the types of cells where the mutations are most deleterious. Recently, scientists have begun manipulating cellular identity to create the cell types most affected by various genetic diseases. This dissertation describes the experience of generating reprogramming models for three genetic disorders: Ring 14 syndrome, Pearson syndrome, and Fanconi anemia. Pearson syndrome is a mitochondrial disorder caused by large deletions in mitochondrial DNA (mtDNA). We generated a Pearson syndrome iPS line and an isogenic line that carried only healthy mitochondria. We investigated the effect of the mutant mtDNA on pluripotent cell growth and metabolism, then differentiated both lines into blood cells. Erythroid progenitors carrying the mtDNA mutation showed a clear pathological phenotype associated with the disease. iii Ring chromosome 14 causes developmental delay and severe seizures. Until the work described here, there was no opportunity to study cells from ring 14 patients in any cell type other than fibroblasts or peripheral blood. We generated multiple iPS lines that carried the ring chromosome, and were able to identify an isogenic, disease-free control line derived from non- disjunction. R14-iPS cells were then differentiated down a neuronal lineage, marking the first ever neural cells from a ring 14 patient available for study. Many laboratories have found that Fanconi anemia cells reprogram very poorly. In our non-viral reprogramming system, we were surprised to find that Fanconi cells reprogrammed nearly as well as cells from their wild-type littermates. These results provide new insight into why published attempts to reprogram FA cells have failed. This dissertation contains these three examples of manipulating cellular identity to learn about rare genetic diseases. iv Table of Contents Chapter 1: Introduction and Background.................................................................................. 1 Introduction............................................................................................................................... 1 Design and verification of an iPS cell-based disease model..................................................... 7 Applications of iPS cell-based disease models....................................................................... 11 History of clinical stem cell therapy ....................................................................................... 13 In vitro differentiation of pluripotent cells into blood ............................................................ 15 Summary of work described in this dissertation..................................................................... 17 Chapter 2: Pearson Syndrome................................................................................................... 19 Introduction............................................................................................................................. 19 Cybrids, the mitochondrial mutation research tool ...............................................................................19 Reprogramming cells that carry deleted mtDNA ...................................................................................20 Materials and Methods............................................................................................................ 21 Studies and Results ................................................................................................................. 28 Induced pluripotent stem cells from a patient with Pearson syndrome..................................................28 mtDNA heteroplasmy in PS-iPS varies as a function of passage...........................................................32 Functional characterization of PS-iPS cells ..........................................................................................34 Hematopoietic differentiation of PS-iPS cells........................................................................................37 Reprogramming cells from other patients with mtDNA deletion syndromes .........................................40 Discussion and Future Directions ........................................................................................... 43 Conclusion .............................................................................................................................. 48 Chapter 3: Ring 14 Syndrome ................................................................................................... 49 Introduction............................................................................................................................. 49 Mosaicism in ring 14 syndrome .............................................................................................................49 Types of ring 14 chromosomes...............................................................................................................50 Disease mechanisms in ring 14 syndrome..............................................................................................50 Generation of ring 14 iPS cells..............................................................................................................51 Materials and Methods............................................................................................................ 52 Studies and Results ................................................................................................................. 55 Comparison of ring 14 mosaicism between two patients .......................................................................55 Generation of iPS cells carrying a ring chromosome 14 .......................................................................56 Changes in R14-iPS karyotype over time...............................................................................................58 Isolation of a disomic control line..........................................................................................................60 Neural differentiation of R14-iPS cells ..................................................................................................61 Discussion and Future Directions ........................................................................................... 61 Conclusion .............................................................................................................................. 67 v Chapter 4: Fanconi Anemia....................................................................................................... 68 Introduction............................................................................................................................. 68 Molecular phenotype of Fanconi anemia...............................................................................................69 Clinical syndrome ..................................................................................................................................70 Attempts to reprogram: the FA reprogramming defect..........................................................................71 Hypothesized role of FA proteins in reprogramming.............................................................................72 Materials and Methods............................................................................................................ 73 Studies and results................................................................................................................... 79 Reprogrammable mouse.........................................................................................................................79 FANCC knockout cells in secondary reprogramming............................................................................83 Episomal reprogramming of human samples.........................................................................................88 Discussion and
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