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This chapter presents a comprehensive quantitative framework for identifying and evaluating therapeutic targets for \(\beta \) -globin gene disorders through detailed modeling of the fetal-to-adult hemoglobin switch.Hemoglobin switchfetal-to-adult The biological foundations of \(\beta \) -thalassemiaDiseasebeta-thalassemia and related hemoglobinopathies are reviewed, with particular emphasis on the regulatory network governing \(\gamma \) - to \(\beta \) -globin gene expressionGenegamma-globinexpressionGenebeta-globin. A hybrid Petri net methodology is applied to capture the dynamics of transcriptional regulators, chromatin-remodeling complexes, and globin gene interactions. Both targeted drug-based and RNAi-mediated gene-therapyTherapygene strategies are examined through computer simulationsComputer simulation. Model calibrationModel calibration and validationModel validation are performed using available qPCR and RT-qPCR data for key regulators, enabling reliable estimation of kinetic parametersKinetic parameter and prediction of treatment outcomes. Comparative analyses of existing interventions identify MS-275 and ACY-957 as the most effective drug-based inducers of \(\gamma \) -globin, while CHD4-targeting RNAi emerges as the most potent among established gene therapies. The modeling framework further predicts two novel therapeutic strategies: inhibition of the erythroid transcription factor complex as a drug targetDrug target, and combined silencing of BCL11A, FOG1, and HDAC1/2 as RNAi-mediated gene-therapy approach. Both strategies produce significantly greater \(\gamma \) -globin induction than currently known treatments. Overall, the chapter demonstrates how hybrid PNs can serve as a powerful computational tool for mechanistically guided target discovery in \(\beta \) -globin disorders and related genetic diseases.

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Modeling Therapeutic Targets: \(\beta \) -Globin Disorders and Beyond

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  • 发表日期：

    2026年

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  • Rza Bashirov

摘要

This chapter presents a comprehensive quantitative framework for identifying and evaluating therapeutic targets for \(\beta \) -globin gene disorders through detailed modeling of the fetal-to-adult hemoglobin switch.Hemoglobin switchfetal-to-adult The biological foundations of \(\beta \) -thalassemiaDiseasebeta-thalassemia and related hemoglobinopathies are reviewed, with particular emphasis on the regulatory network governing \(\gamma \) - to \(\beta \) -globin gene expressionGenegamma-globinexpressionGenebeta-globin. A hybrid Petri net methodology is applied to capture the dynamics of transcriptional regulators, chromatin-remodeling complexes, and globin gene interactions. Both targeted drug-based and RNAi-mediated gene-therapyTherapygene strategies are examined through computer simulationsComputer simulation. Model calibrationModel calibration and validationModel validation are performed using available qPCR and RT-qPCR data for key regulators, enabling reliable estimation of kinetic parametersKinetic parameter and prediction of treatment outcomes. Comparative analyses of existing interventions identify MS-275 and ACY-957 as the most effective drug-based inducers of \(\gamma \) -globin, while CHD4-targeting RNAi emerges as the most potent among established gene therapies. The modeling framework further predicts two novel therapeutic strategies: inhibition of the erythroid transcription factor complex as a drug targetDrug target, and combined silencing of BCL11A, FOG1, and HDAC1/2 as RNAi-mediated gene-therapy approach. Both strategies produce significantly greater \(\gamma \) -globin induction than currently known treatments. Overall, the chapter demonstrates how hybrid PNs can serve as a powerful computational tool for mechanistically guided target discovery in \(\beta \) -globin disorders and related genetic diseases.