A5060703300- Neurogenetic and Muscular Disorders Research
- Amyotrophic Lateral Sclerosis Research
- Genetic Syndromes and Imprinting
- Genetics and Neurodevelopmental Disorders
- RNA Interference and Gene Delivery
- Parkinson's Disease Mechanisms and Treatments
- Autophagy in Disease and Therapy
- Epigenetics and DNA Methylation
- Advanced biosensing and bioanalysis techniques
- RNA regulation and disease
- Fatty Acid Research and Health
- RNA modifications and cancer
- Pediatric Hepatobiliary Diseases and Treatments
- Cellular transport and secretion
- DNA and Nucleic Acid Chemistry
- NF-κB Signaling Pathways
- Epilepsy research and treatment
- Genomics and Rare Diseases
- Immune Response and Inflammation
- Prenatal Screening and Diagnostics
- Drug Transport and Resistance Mechanisms
- Alzheimer's disease research and treatments
- RNA Research and Splicing
- Autism Spectrum Disorder Research
- Genetic Neurodegenerative Diseases
Ionis Pharmaceuticals (United States)
2016-2023
The comprehensive structure-activity relationships of triantennary GalNAc conjugated ASOs for enhancing potency via ASGR mediated delivery to hepatocytes is reported. Seventeen clusters were assembled from six distinct scaffolds and attached ASOs. resulting ASO conjugates evaluated in binding assays, primary hepatocytes, mice. Five structurally chosen more extensive evaluation using targeting SRB-1, A1AT, FXI, TTR, ApoC III mRNAs. GalNAc-ASO exhibited excellent potencies (ED50 0.5-2 mg/kg)...
Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat wide range diseases, including neurological indications. Spinraza, an ASO that modulates splicing SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts develop ASOs for other diseases. While SMA specifically affects spinal motor neurons, diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is...
De novo variation in SCN2A can give rise to severe childhood disorders. Biophysical gain of function is seen some patients with early seizure onset developmental and epileptic encephalopathy (DEE). In these cases, targeted reduction expression could substantially improve clinical outcomes. We tested this theory by central administration a gapmer antisense oligonucleotide (ASO) targeting Scn2a mRNA mouse model DEE (Q/+ mice). Untreated Q/+ mice presented spontaneous seizures at P1 did not...
Developmental and epileptic encephalopathies (DEEs) are characterized by pharmaco-resistant seizures with concomitant intellectual disability. Epilepsy of infancy migrating focal (EIMFS) is one the most severe these syndromes. De novo variants in ion channels, including gain-of-function KCNT1, which encodes for sodium activated potassium channel protein KNa1.1, have been found to play a major role etiology EIMFS. Here, we test potential precision therapeutic approach KCNT1-associated DEE...
UBE3A encodes ubiquitin protein ligase E3A, and in neurons its expression from the paternal allele is repressed by antisense transcript (UBE3A-ATS). This leaves susceptible to loss-of-function of maternal UBE3A. Indeed, Angelman syndrome, a severe neurodevelopmental disorder, caused deficiency. A promising therapeutic approach treating syndrome reactivate intact suppressing UBE3A-ATS. Prior studies show that many neurological phenotypes Ube3a knockout mice can only be rescued reinstating...
Mutations in the endosome-associated protein CHMP2B cause frontotemporal dementia and lead to lysosomal storage pathology neurons. We here report that physiological levels of mutant causes reduced numbers significantly impaired trafficking endolysosomes within neuronal dendrites, accompanied by increased dendritic branching. Mechanistically, this is due stable incorporation onto endolysosomes, which we show renders them unable traffic dendrites. This defect inability recruit ATPase VPS4,...
Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding TDP-43, account for less than 1% all ALS cases, TDP-43-positive aggregates are present nearly patients, patients with sporadic (sALS) or carrying other familial (fALS)-causing mutations. Interestingly, TDP-43 inclusions also subsets frontotemporal dementia, Alzheimer's disease, and Parkinson's disease; therefore, methods activating...
Antisense oligonucleotides (ASOs) are widely accepted therapeutic agents that suppress RNA transcription. While the majority of ASOs well tolerated in vivo, few sequences trigger inflammatory responses absence conventional CpG motifs. In this study, we identified non-CpG oligodeoxy-nucleotide (ODN) capable triggering an response resulting B cell and macrophage activation a MyD88- TLR9-dependent manner. addition, found receptor for advance glycation end product (RAGE) to be involved...
Abstract The clinical spectrum associated with SCN2A de novo mutations (DNMs) continues to expand and includes autism disorder or without seizures, in addition early late seizure onset developmental epileptic encephalopathies (DEEs). Recent biophysical studies on variants suggest that the majority of DEE DNMs cause gain function. Gain function SCN2A, principal sodium channel excitatory pyramidal neurons, would result heightened neuronal activity is likely underlie pathology seen patients....
ABSTRACT Developmental and epileptic encephalopathies (DEE) are characterized by pharmacoresistant seizures with concomitant intellectual disability. Epilepsy of infancy migrating focal (EIMFS) is one the most severe these syndromes. De novo mutations in ion channels, including gain-of-function variants KCNT1 , have been found to play a major role etiology EIMFS. Here, we test potential precision therapeutic approach -associated DEE using gene silencing antisense oligonucleotide (ASO)...
Background and Aims: Paucity of intrahepatic bile ducts (BDs) is caused by various etiologies often leads to cholestatic liver disease. For example, in patients with Alagille syndrome (ALGS), which a genetic disease primarily mutations jagged 1 ( JAG1) , BD paucity results severe cholestasis damage. However, no mechanism-based therapy exists restore the biliary system ALGS or other diseases associated paucity. Based on previous observations, we investigated whether postnatal knockdown...
ABSTRACT Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat wide range diseases, including neurological indications. Spinraza, an ASO that modulates splicing SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing the field develop ASOs for other diseases. While SMA specifically affects spinal motor neurons, diseases affect different central nervous system (CNS) regions, neuronal, and non-neuronal cells....
Abstract Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP , encoding TDP-43, account for less than 1% all ALS cases, TDP-43-positive aggregates are present nearly patients, patients with sporadic (sALS) or carrying other familial (fALS)-causing mutations. Interestingly, TDP-43 inclusions also subsets frontotemporal dementia, Alzheimer’s disease, and Parkinson’s disease; therefore, methods...
Abstract UBE3A encodes ubiquitin protein ligase E3A, and in neurons its expression from the paternal allele is repressed by antisense transcript ( UBE3A-ATS ). This leaves susceptible to loss-of-function of maternal . Indeed, Angelman syndrome, a severe neurodevelopmental disorder, caused deficiency. A promising therapeutic approach treating syndrome reactivate intact suppressing Prior studies show that many neurological phenotypes Ube3a knockout mice can only be rescued reinstating early...