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Mathematical modeling of erythrocyte chimerism informs genetic intervention strategies for sickle cell disease.

ABSTRACT: Recent advances in gene therapy and genome-engineering technologies offer the opportunity to correct sickle cell disease (SCD), a heritable disorder caused by a point mutation in the ?-globin gene. The developmental switch from fetal ?-globin to adult ?-globin is governed in part by the transcription factor (TF) BCL11A. This TF has been proposed as a therapeutic target for reactivation of ?-globin and concomitant reduction of ?-sickle 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-susceptible 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-based 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. 91:931-937, 2016. © 2016 Wiley Periodicals, Inc.

SUBMITTER: Altrock PM

PROVIDER: S-EPMC5093908 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Mathematical modeling of erythrocyte chimerism informs genetic intervention strategies for sickle cell disease.

Altrock Philipp M PM Brendel Christian C Renella Raffaele R Orkin Stuart H SH Williams David A DA Michor Franziska F

American journal of hematology 20160714 9

Recent advances in gene therapy and genome-engineering technologies offer the opportunity to correct sickle cell disease (SCD), a heritable disorder caused by a point mutation in the β-globin gene. The developmental switch from fetal γ-globin to adult β-globin is governed in part by the transcription factor (TF) BCL11A. This TF has been proposed as a therapeutic target for reactivation of γ-globin and concomitant reduction of β-sickle globin. In this and other approaches, genetic alteration of a ...[more]

PMID: 27299299

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Project description:34,354,966 active cases and 460,787 deaths because of COVID-19 pandemic were recorded on November 06, 2021, in India. To end this ongoing global COVID-19 pandemic, there is an urgent need to implement multiple population-wide policies like social distancing, testing more people and contact tracing. To predict the course of the pandemic and come up with a strategy to control it effectively, a compartmental model has been established. The following six stages of infection are taken into consideration: susceptible (S), asymptomatic infected (A), clinically ill or symptomatic infected (I), quarantine (Q), isolation (J) and recovered (R), collectively termed as SAIQJR. The qualitative behavior of the model and the stability of biologically realistic equilibrium points are investigated in terms of the basic reproduction number. We performed sensitivity analysis with respect to the basic reproduction number and obtained that the disease transmission rate has an impact in mitigating the spread of diseases. Moreover, considering the non-pharmaceutical and pharmaceutical intervention strategies as control functions, an optimal control problem is implemented to mitigate the disease fatality. To reduce the infected individuals and to minimize the cost of the controls, an objective functional has been constructed and solved with the aid of Pontryagin's maximum principle. The implementation of optimal control strategy at the start of a pandemic tends to decrease the intensity of epidemic peaks, spreading the maximal impact of an epidemic over an extended time period. Extensive numerical simulations show that the implementation of intervention strategy has an impact in controlling the transmission dynamics of COVID-19 epidemic. Further, our numerical solutions exhibit that the combination of three controls are more influential when compared with the combination of two controls as well as single control. Therefore, the implementation of all the three control strategies may help to mitigate novel coronavirus disease transmission at this present epidemic scenario.Supplementary informationThe online version supplementary material available at 10.1007/s11071-022-07235-7.

Project description:IntroductionWe previously reported the initial results of a phase II multicenter transplant trial using haploidentical parental donors for children and aolescents with high-risk sickle cell disease achieving excellent survival with exceptionally low rates of graft-versus-host disease and resolution of sickle cell disease symptoms. To investigate human leukocyte antigen (HLA) sensitization, graft characteristics, donor chimerism, and immune reconstitution in these recipients.MethodsCD34 cells were enriched using the CliniMACS® system with a target dose of 10 x 106 CD34+ cells/kg with a peripheral blood mononuclear cell (PBMNC) addback dose of 2x105 CD3/kg in the final product. Pre-transplant HLA antibodies were characterized. Donor chimerism was monitored 1-24 months post-transplant. Comprehensive assessment of immune reconstitution included lymphocyte subsets, plasma cytokines, complement levels, anti-viral T-cell responses, activation markers, and cytokine production. Infections were monitored.ResultsHLA antibodies were detected in 7 of 11 (64%) evaluable patients but rarely were against donor antigens. Myeloid engraftment was rapid (100%) at a median of 9 days. At 30 days, donor chimerism was 93-99% and natural killer cell levels were restored. By 60 days, CD19 B cells were normal. CD8 and CD4 T-cells levels were normal by 279 and 365 days, respectively. Activated CD4 and CD8 T-cells were elevated at 100-365 days post-transplant while naïve cells remained below baseline. Tregs were elevated at 100-270 days post-transplant, returning to baseline levels at one year. At one year, C3 and C4 levels were above baseline and CH50 levels were near baseline. At one year, cytokine levels were not significantly different from baseline.DiscussionThese results suggest that haploidentical transplantation with CD34-enriched cells and peripheral blood mononuclear cell addback results in rapid engraftment, sustained donor chimerism and broad-based immune reconstitution.

Project description:Iron is a trace metal, key for the development of living organisms. Its absorption process is complex and highly regulated at the transcriptional, translational and systemic levels. Recently, the internalization of the DMT1 transporter has been proposed as an additional regulatory mechanism at the intestinal level, associated to the mucosal block phenomenon. The short-term effect of iron exposure in apical uptake and initial absorption rates was studied in Caco-2 cells at different apical iron concentrations, using both an experimental approach and a mathematical modeling framework. This is the first report of short-term studies for this system. A non-linear behavior in the apical uptake dynamics was observed, which does not follow the classic saturation dynamics of traditional biochemical models. We propose a method for developing mathematical models for complex systems, based on a genetic programming algorithm. The algorithm is aimed at obtaining models with a high predictive capacity, and considers an additional parameter fitting stage and an additional Jackknife stage for estimating the generalization error. We developed a model for the iron uptake system with a higher predictive capacity than classic biochemical models. This was observed both with the apical uptake dataset used for generating the model and with an independent initial rates dataset used to test the predictive capacity of the model. The model obtained is a function of time and the initial apical iron concentration, with a linear component that captures the global tendency of the system, and a non-linear component that can be associated to the movement of DMT1 transporters. The model presented in this paper allows the detailed analysis, interpretation of experimental data, and identification of key relevant components for this complex biological process. This general method holds great potential for application to the elucidation of biological mechanisms and their key components in other complex systems.

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Mathematical modeling of erythrocyte chimerism informs genetic intervention strategies for sickle cell disease.

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Mathematical modeling of erythrocyte chimerism informs genetic intervention strategies for sickle cell disease.

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