A5025185243- RNA modifications and cancer
- Neurogenetic and Muscular Disorders Research
- RNA Research and Splicing
- Congenital Anomalies and Fetal Surgery
- Glioma Diagnosis and Treatment
- MicroRNA in disease regulation
- Health and Medical Research Impacts
- Advances in Oncology and Radiotherapy
- Health Sciences Research and Education
- Cancer-related molecular mechanisms research
Cold Spring Harbor Laboratory
2009-2023
Abstract Small molecule splicing modifiers have been previously described that target the general machinery and thus low specificity for individual genes. Several potent molecules correcting deficit of SMN2 (survival motor neuron 2) gene identified these are moving towards a potential therapy spinal muscular atrophy (SMA). Here by using combination RNA splicing, transcription, protein chemistry techniques, we show directly bind to two distinct sites pre-mRNA, thereby stabilizing yet...
Survival of motor neuron (SMN) deficiency causes spinal muscular atrophy (SMA), but the pathogenesis mechanisms remain elusive. Restoring SMN in neurons only partially rescues SMA mouse models, although it is thought to be therapeutically essential. Here, we address relative importance restoration central nervous system (CNS) versus peripheral tissues models using a therapeutic splice-switching antisense oligonucleotide restore and complementary decoy neutralize its effects CNS. Increasing...
Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by insufficient levels of the Survival Motor Neuron (SMN) protein. SMN expressed ubiquitously and functions in RNA processing pathways that include trafficking mRNA assembly snRNP complexes. Importantly, SMA severity correlated with decreased activity. In particular, minor spliceosomal snRNPs are affected, some U12-dependent introns have been reported to be aberrantly spliced patient cells animal models. characterized loss...
Diffuse midline gliomas (DMGs) are pediatric high-grade brain tumors in the thalamus, midbrain, or pons; latter subgroup termed diffuse intrinsic pontine (DIPG). The stem location of these limits clinical management DIPG, resulting poor outcomes for patients. A heterozygous, somatic point mutation one two genes coding noncanonical histone H3.3 is present most DIPG tumors. This dominant H3-3A gene results replacement lysine 27 with methionine (K27M) and causes a global reduction...
There is at present no cure or effective therapy for spinal muscular atrophy (SMA), a neurodegenerative disease that the leading genetic cause of infant mortality. SMA usually results from loss SMN1 (survival motor neuron 1) gene, which leads to selective degeneration. SMN2 nearly identical but has nucleotide replacement causes exon 7 skipping, resulting in truncated, unstable version protein. all patients, and correcting splicing promising approach therapy. We identified tetracycline-like...
Summary Spinal Muscular Atrophy (SMA) is a motor-neuron disease caused by loss-of-function mutations of the SMN1 gene. Humans have paralog, SMN2 , whose exon 7 predominantly skipped, and so it cannot fully compensate for lack . Nusinersen (Spinraza) splicing-correcting antisense oligonucleotide drug (ASO) approved clinical use. targets splicing silencer located in intron pre-mRNA and, blocking binding repressors hnRNPA1 A2, promotes higher E7 inclusion, increasing SMN protein levels. We show...
Spinal Muscular Atrophy (SMA) is a motor-neuron disease caused by mutations of the SMN1 gene. The human paralog SMN2, whose exon 7 (E7) predominantly skipped cannot compensate for lack SMN1. Nusinersen an antisense oligonucleotide that upregulates E7 inclusion and SMN protein levels displacing splicing repressors hnRNPA1/A2 from their target site in intron 7. We show that, promoting transcriptional elongation, histone deacetylase inhibitor VPA cooperates with nusinersen to promote inclusion....