Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
The thalassemias are compelling targets for therapeutic genome editing in part because monoallelic correction of a subset of hematopoietic stem cells (HSCs) would be sufficient for enduring disease amelioration. A primary challenge is the development of efficient repair strategies that are effective in HSCs. Here, we demonstrate that allelic disruption of aberrant splice sites, one of the major classes of thalassemia mutations, is a robust approach to restore gene function. We target the IVS1-110G>A mutation using Cas9 ribonucleoprotein (RNP) and the IVS2-654C>T mutation by Cas12a/Cpf1 RNP in primary CD34 hematopoietic stem and progenitor cells (HSPCs) from β-thalassemia patients. Each of these nuclease complexes achieves high efficiency and penetrance of therapeutic edits. Erythroid progeny of edited patient HSPCs show reversal of aberrant splicing and restoration of β-globin expression. This strategy could enable correction of a substantial fraction of transfusion-dependent β-thalassemia genotypes with currently available gene-editing technology.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533605 | PMC |
| http://dx.doi.org/10.1182/blood-2019-01-895094 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
enhances oligodendrocyte differentiation via nonsense-mediated mRNA decay of variant transcripts.
J Neurosci
September 2025
College of Life Sciences, Zhejiang University, Hangzhou 310058, P.R. China
Nonsense-mediated mRNA decay (NMD) is a conserved RNA surveillance mechanism that degrades transcripts with premature termination codons (PTCs) and finetunes gene expression by targeting RNA transcripts with other NMD inducing features. This study demonstrates that conditional knockout of , a key NMD component, in oligodendrocyte lineage cells disrupts the degradation of PTC-containing transcripts, including aberrant variants of the RNA-binding protein The loss of SMG5 in both sexes of mice impaired oligodendrocyte differentiation, reduced myelin gene expression, and led to thinner myelin sheaths and compromised motor function in mice. Mechanistically, HNRNPL was shown to regulate the alternative splicing of myelin-associated genes and , and promote oligodendrocyte differentiation.
View Article and Find Full Text PDFPotential molecular mechanisms explaining progressive alterations of the structural network in temporal lobe epilepsy.
Neurobiol Dis
September 2025
Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China. Electronic address:
The effect of recurrent seizures on the gradual deterioration of the white matter structural network and the potential molecular mechanisms that underlie the baseline and longitudinal changes in network topology in temporal lobe epilepsy (TLE) remain unclear. Therefore, we used diffusion tensor imaging (DTI) scans and neuropsychiatric assessments for 28 patients with unilateral TLE at baseline and follow-up, and for 28 healthy controls (HC). The topological properties of the structural network were calculated using graph theoretical analyses.
View Article and Find Full Text PDFMutant huntingtin exon 1 protein detected in mouse brain with neoepitope antibody: effects of CAG repeat expansion, MutS Homolog 3 silencing and aggregation.
Brain Commun
August 2025
Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
was identified in human and mouse Huntington's disease brain as the pathogenic exon 1 mRNA generated from aberrant splicing between exon 1 and 2 of that contributes to aggregate formation and neuronal dysfunction. Detection of the huntingtin exon 1 protein (HTT1a) has been accomplished with Meso Scale Discovery, Homogeneous Time Resolved Fluorescence and immunoprecipitation assays in Huntington's disease knock-in mice, but direct detection in homogenates by gel electrophoresis and western blot assay has been lacking. Subcellular fractions prepared from mouse and human Huntington's disease brain were separated by gel electrophoresis and probed by western blot with neoepitope monoclonal antibodies 1B12 and 11G2 directed to the C-terminal eight residues of HTT1a.
View Article and Find Full Text PDFNovel pathogenic splicing mutation in in a patient with Stickler syndrome verified by minigene splicing assay.
Front Genet
August 2025
Medical School, Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China.
Background: Stickler syndrome (STL) is a group of related connective tissue disorders characterized by heterogeneous clinical presentations with varying degrees of orofacial, ocular, skeletal, and auditory abnormalities. However, this condition is difficult to diagnose on the basis of clinical features because of phenotypic variability. Thus, expanding the variant spectrum of this disease will aid in achieving a firm definitive diagnosis of STL.
View Article and Find Full Text PDFRecursive splice sites are rare motifs postulated to facilitate splicing across massive introns and shape isoform diversity, especially for long, brain-expressed genes. The necessity of this unique mechanism remains unsubstantiated, as does the role of recursive splicing (RS) in human disease. From analyses of rare copy number variants (CNVs) from almost one million individuals, we previously identified large, heterozygous deletions eliminating an RS site (RS1) in the first intron of that conferred substantial risk for attention deficit hyperactivity disorder (ADHD) and other neurobehavioral traits.
View Article and Find Full Text PDF