With advancements in gene editing technologies,our ability to make precise and efficient modifications to the genome is increasing at a remarkable rate,paving the way for scientists and clinicians to uniquely treat a ...With advancements in gene editing technologies,our ability to make precise and efficient modifications to the genome is increasing at a remarkable rate,paving the way for scientists and clinicians to uniquely treat a multitude of previously irremediable diseases.CRISPR-Cas9,short for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9,is a gene editing platform with the ability to alter the nucleotide sequence of the genome in living cells.This technology is increasing the number and pace at which new gene editing treatments for genetic disorders are moving toward the clinic.Theβ-hemoglobinopathies are a group of monogenic diseases,which despite their high prevalence and chronic debilitating nature,continue to have few therapeutic options available.In this review,we will discuss our existing comprehension of the genetics and current state of treatment forβ-hemoglobinopathies,consider potential genome editing therapeutic strategies,and provide an overview of the current state of clinical trials using CRISPR-Cas9 gene editing.展开更多
Pregnane X receptor(PXR)is a ligand-activated nuclear receptor that transcriptionally upregulates drug-metabolizing enzymes[e.g.,cytochrome P4503A4(CYP3A4)]and transporters.Although the regulation of PXR target genes ...Pregnane X receptor(PXR)is a ligand-activated nuclear receptor that transcriptionally upregulates drug-metabolizing enzymes[e.g.,cytochrome P4503A4(CYP3A4)]and transporters.Although the regulation of PXR target genes is well-characterized,less is known about the regulation of PXR protein level.By screening an RNAi library,we identified the F-box-only protein 44(FBXO44)as a novel E3ligase for PXR.PXR abundance increases upon knockdown of FBXO44,and,inversely,decreases upon overexpression of FBXO44.Further analysis revealed that FBXO44 interacts with PXR,leading to its ubiquitination and proteasomal degradation,and we determined that the F-box associated domain of FBXO44 and the ligand binding domain of PXR are required for the functional interaction.In summary,FBXO44 regulates PXR protein abundance,which has downstream consequences for CYP3A4 levels and drug-drug interactions.The results of this study provide new insight into the molecular mechanisms that regulate PXR protein level and activity and suggest the importance of considering how modulating E3ubiquitin ligase activities will affect PXR-mediated drug metabolism.展开更多
文摘With advancements in gene editing technologies,our ability to make precise and efficient modifications to the genome is increasing at a remarkable rate,paving the way for scientists and clinicians to uniquely treat a multitude of previously irremediable diseases.CRISPR-Cas9,short for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9,is a gene editing platform with the ability to alter the nucleotide sequence of the genome in living cells.This technology is increasing the number and pace at which new gene editing treatments for genetic disorders are moving toward the clinic.Theβ-hemoglobinopathies are a group of monogenic diseases,which despite their high prevalence and chronic debilitating nature,continue to have few therapeutic options available.In this review,we will discuss our existing comprehension of the genetics and current state of treatment forβ-hemoglobinopathies,consider potential genome editing therapeutic strategies,and provide an overview of the current state of clinical trials using CRISPR-Cas9 gene editing.
基金supported by the National Institutes of Health National Institute of General Medical Sciences[Grant R35GM118041]supported in part by the National Cancer Institute of the National Institutes of Health under Award Number P30 CA021765。
文摘Pregnane X receptor(PXR)is a ligand-activated nuclear receptor that transcriptionally upregulates drug-metabolizing enzymes[e.g.,cytochrome P4503A4(CYP3A4)]and transporters.Although the regulation of PXR target genes is well-characterized,less is known about the regulation of PXR protein level.By screening an RNAi library,we identified the F-box-only protein 44(FBXO44)as a novel E3ligase for PXR.PXR abundance increases upon knockdown of FBXO44,and,inversely,decreases upon overexpression of FBXO44.Further analysis revealed that FBXO44 interacts with PXR,leading to its ubiquitination and proteasomal degradation,and we determined that the F-box associated domain of FBXO44 and the ligand binding domain of PXR are required for the functional interaction.In summary,FBXO44 regulates PXR protein abundance,which has downstream consequences for CYP3A4 levels and drug-drug interactions.The results of this study provide new insight into the molecular mechanisms that regulate PXR protein level and activity and suggest the importance of considering how modulating E3ubiquitin ligase activities will affect PXR-mediated drug metabolism.
