{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T12:39:55Z","timestamp":1793363995581,"version":"4.5.0"},"reference-count":45,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2016,7,14]],"date-time":"2016-07-14T00:00:00Z","timestamp":1468454400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL117720\u201003"],"award-info":[{"award-number":["HL117720\u201003"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:p>Recent advances in gene therapy and genome\u2010engineering technologies offer the opportunity to correct sickle cell disease (SCD), a heritable disorder caused by a point mutation in the \u03b2\u2010globin gene. The developmental switch from fetal \u03b3\u2010globin to adult \u03b2\u2010globin is governed in part by the transcription factor (TF) BCL11A. This TF has been proposed as a therapeutic target for reactivation of \u03b3\u2010globin and concomitant reduction of \u03b2\u2010sickle globin. In this and other approaches, genetic alteration of a portion of the hematopoietic stem cell (HSC) compartment leads to a mixture of sickling and corrected red blood cells (RBCs) in periphery. To reverse the sickling phenotype, a certain proportion of corrected RBCs is necessary; the degree of HSC alteration required to achieve a desired fraction of corrected RBCs remains unknown. To address this issue, we developed a mathematical model describing aging and survival of sickle\u2010susceptible and normal RBCs; the former can have a selective survival advantage leading to their overrepresentation. We identified the level of bone marrow chimerism required for successful stem cell\u2010based gene therapies in SCD. Our findings were further informed using an experimental mouse model, where we transplanted mixtures of Berkeley SCD and normal murine bone marrow cells to establish chimeric grafts in murine hosts. Our integrative theoretical and experimental approach identifies the target frequency of HSC alterations required for effective treatment of sickling syndromes in humans. Our work replaces episodic observations of such target frequencies with a mathematical modeling framework that covers a large and continuous spectrum of chimerism conditions. Am. J. Hematol. 91:931\u2013937, 2016. \u00a9 2016 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/ajh.24449","type":"journal-article","created":{"date-parts":[[2016,6,15]],"date-time":"2016-06-15T12:31:50Z","timestamp":1465993910000},"page":"931-937","source":"Crossref","is-referenced-by-count":31,"title":["Mathematical modeling of erythrocyte chimerism informs genetic intervention strategies for sickle cell disease"],"prefix":"10.1002","volume":"91","author":[{"given":"Philipp M.","family":"Altrock","sequence":"first","affiliation":[{"name":"Department of Biostatistics and Computational Biology Dana\u2010Farber Cancer Institute Boston Massachusetts"},{"name":"Department of Biostatistics Harvard T.H. 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