A5082344505- Neurogenetic and Muscular Disorders Research
- RNA Research and Splicing
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Cardiac Structural Anomalies and Repair
- Pulmonary Hypertension Research and Treatments
- Congenital Anomalies and Fetal Surgery
- Congenital Heart Disease Studies
- RNA Interference and Gene Delivery
- RNA regulation and disease
- Viral Infections and Immunology Research
- MicroRNA in disease regulation
- Cardiovascular Issues in Pregnancy
- Muscle Physiology and Disorders
- Cardiovascular Conditions and Treatments
- Genetics and Neurodevelopmental Disorders
- Mechanical Circulatory Support Devices
- Cardiac Arrhythmias and Treatments
- Cancer-related gene regulation
- Infective Endocarditis Diagnosis and Management
- Infectious Aortic and Vascular Conditions
- Telomeres, Telomerase, and Senescence
- Cardiac Fibrosis and Remodeling
- Galectins and Cancer Biology
- Sphingolipid Metabolism and Signaling
Nanjing Normal University
2019-2025
Sichuan University
2016-2025
West China Second University Hospital of Sichuan University
2018-2024
Cold Spring Harbor Laboratory
2009-2020
Soochow University
2015-2020
Weatherford College
2020
Hubei University of Medicine
2019
Beijing Anzhen Hospital
2019
Monash University
2018
Second Affiliated Hospital of Soochow University
2017
To facilitate precision medicine and whole-genome annotation, we developed a machine-learning technique that scores how strongly genetic variants affect RNA splicing, whose alteration contributes to many diseases. Analysis of more than 650,000 intronic exonic revealed widespread patterns mutation-driven aberrant splicing. Intronic disease mutations are 30 nucleotides from any splice site alter splicing nine times as often common variants, missense have the least impact on protein function...
Increasing survival of motor neuron 2, centromeric (SMN2) exon 7 inclusion to express more full-length SMN protein in neurons is a promising approach treat spinal muscular atrophy (SMA), genetic neurodegenerative disease. Previously, we identified potent 2'-O-(2-methoxyethyl) (MOE) phosphorothioate-modified antisense oligonucleotide (ASO) that blocks an SMN2 intronic splicing silencer element and efficiently promotes transgenic mouse peripheral tissues after systemic administration. Here...
Central nervous system–directed antisense therapy ameliorates symptoms in a severe neuromuscular disorder mice.
Several strategies have been pursued to increase the extent of exon 7 inclusion during splicing SMN2 (survival motor neuron 2) transcripts, for eventual therapeutic use in spinal muscular atrophy (SMA), a genetic neuromuscular disease. Antisense oligonucleotides (ASOs) that target an or its flanking splice sites usually promote skipping. Here we systematically tested large number ASOs with 2'-O-methoxy-ethyl ribose (MOE) backbone hybridize different positions 7, and identified several...
Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by the loss of survival motor neuron (SMN) protein. Previously, we demonstrated that ISIS 396443, an antisense oligonucleotide (ASO) targeted to <i>SMN2</i> pre-mRNA, potent inducer exon 7 inclusion and SMN protein expression, improves function mild severe SMA mouse models. Here, demonstrate 396443 most ASO in central nervous system (CNS) tissues adult mice, compared with several other chemically modified ASOs. We...
One of the greatest thrills a biomedical researcher may experience is seeing product many years dedicated effort finally make its way to patient. As team, we have worked for past eight discover drug that could treat devastating childhood neuromuscular disease, spinal muscular atrophy (SMA). Here, describe journey has led promising based on biology underlying disease.
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...
Spinal muscular atrophy (SMA) is a neuromuscular disease caused by reduced expression of survival motor neuron (SMN), protein expressed in humans two paralogous genes, SMN1 and SMN2. These genes are nearly identical, except for 10 single-nucleotide differences 5-nucleotide insertion SMA subdivided into four main types, with type I being the most severe. SMN2 copy number key positive modifier disease, but it not always inversely correlated clinical severity. We previously reported c.859G > C...
The survival motor neuron (SMN) protein forms cytoplasmic granules when overexpressed. We report here that SMN co‐localizes with TIA‐1/R and G3BP, assemblers of stress (SGs), is co‐immunoprecipitated TIA‐1/R, suggesting are SGs. Formation precedes accumulation indicating serves as a facilitator SG formation. However, the exon 7 skipping product, SMNΔ7, largely retained in nucleus nuclear granules, critical for Our findings reveal novel function possible involvement pathogenesis spinal...
Abstract Spinal muscular atrophy (SMA) is a motor neuron disease. Nusinersen, splice-switching antisense oligonucleotide (ASO), was the first approved drug to treat SMA. Based on prior preclinical studies, both 2′-O-methoxyethyl (MOE) with phosphorothioate backbone and morpholino phosphorodiamidate backbone—with same or extended target sequence as nusinersen—displayed efficient rescue of SMA mouse models. Here, we compared therapeutic efficacy these two modification chemistries in severe...
Familial dysautonomia (FD) is a rare inherited neurodegenerative disorder caused by point mutation in the IKBKAP gene that results defective splicing of its pre-mRNA. The weakens 5′ splice site exon 20, causing this to be skipped, thereby introducing premature termination codon. Though detailed FD pathogenesis mechanisms are not yet clear, correcting defect relevant tissue(s), thus restoring normal expression levels full-length IKAP protein, could therapeutic. Splice-switching antisense...
Loss-of-function mutations in SMN1 cause spinal muscular atrophy (SMA), a leading genetic of infant mortality. The related SMN2 gene expresses suboptimal levels functional SMN protein, due to splicing defect. Many SMA patients reach adulthood, and there is also adult-onset (type IV) SMA. There currently no animal model for SMA, the tissue-specific pathogenesis post-developmental deficiency remains elusive. Here, we use an antisense oligonucleotide (ASO) exacerbate mis-splicing....
Spinal muscular atrophy (SMA) is a fatal genetic disease, mainly affecting children. A number of recent studies show, aside from lower motor neuron degeneration and skeletal muscles, widespread defects present in the central nervous system (CNS) peripheral non-neuronal cell types SMA patients mouse models, particularly severe forms. However, molecular mechanisms underlying multi-organ manifestations were hardly understood. Here, using histology, flow cytometry gene expression analysis both...
Focal atrial tachycardia (FAT) is predominant in the pediatric population. Recent research has identified cases of sustained FAT originating from interatrial septum (IAS); a subset presents unique challenge, with foci peri-patent foramen ovale (peri-PFO), requiring specialized management during catheter ablation. Here, we present rare case peri-PFO-associated that resulted tachycardia-related cardiomyopathy and propose comprehensive multipath joint strategy for successful treatment...
Spinal muscular atrophy (SMA) is a severe neurodegenerative disorder caused by deficiency of survival motor neuron (SMN). While significant progress has been made in SMA therapy rescuing SMN expression, limited knowledge about downstream genes hindered the development alternative therapies. Here, we conducted whole-transcriptome sequencing spinal cord, heart, and liver tissues mouse model at early postnatal ages to explore critical coding non-coding RNAs (ncRNAs). A large number...
Antisense oligonucleotides (ASOs) are versatile molecules that can be designed to specifically alter splicing patterns of target pre-mRNAs. Here we exploit this feature phenocopy a genetic disease. Spinal muscular atrophy (SMA) is motor neuron disease caused by loss-of-function mutations in the SMN1 gene. The related SMN2 gene expresses suboptimal levels functional SMN protein due alternative skips exon 7; correcting defect-e.g., with ASOs-is promising therapeutic approach. We describe use...
Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, characterized by progressive degeneration spinal-cord motor neurons, to skeletal muscles. However, accumulating evidence indicates that it a multi-system disorder, particularly in its severe forms. Several studies delineated structural and functional cardiac abnormalities SMA patients mouse models, yet have been primarily attributed autonomic dysfunction. Here, we show model cardiomyocytes undergo G0/G1...