Modeling Therapeutic Targets: β-Globin Disorders and Beyond

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. The biological foundations of $\beta$ -thalassemia and related hemoglobinopathies are reviewed, with particular emphasis on the regulatory network governing $\gamma$ - to $\beta$ -globin gene expression. 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-therapy strategies are examined through computer simulations. Model calibration and validation are performed using available qPCR and RT-qPCR data for key regulators, enabling reliable estimation of kinetic parameters 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 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.