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Diseases of Infancy and Childhood
Published in Ayşe Serap Karadağ, Lawrence Charles Parish, Jordan V. Wang, Roxburgh's Common Skin Diseases, 2022
NLE is related to the anti-Ro/SSA (Sjogren syndrome autoantigen type A-SSA) antibody in more than 90% of patients. Occasionally, patients only have anti-La/SSB (Sjogren syndrome autoantigen type B-SSB) or anti-U1RNP (small nuclear ribonucleoprotein-associated with U1 spliceosomal RNA) antibodies. The presence of these antibodies should be screened in infants with NLE. Laboratory investigations may reveal pancytopenia, thrombocytopenia, leukopenia, or elevated transaminase level.
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Other potential mechanisms have been identified, including interference with pre-mRNA processing steps either by preventing splice-directing small nuclear ribonucleoproteins (snRNP) complexes from binding to their targets at the borders of introns on a strand of pre-mRNA or by blocking the nucleophilic adenine base and preventing it from forming the splice lariat structure. They may also interfere with the binding of splice regulatory proteins such as splice silencers and splice enhancers, and have been shown to block ribozyme activity. Thus, they have been used as a starting point for experimental molecular biology reagents, and also antisense therapeutics.
Role of Epigenetics in Immunity and Immune Response to Vaccination
Published in Mesut Karahan, Synthetic Peptide Vaccine Models, 2021
Transcriptional or post-transcriptional regulation has also been suggested as a possible function for circRNAs. It has been shown that some circRNAs contain intron and are localized to the nucleus. These circRNAs can also interact with U1 small nuclear ribonucleoprotein to promote transcription (You et al. 2015).
Strategies for targeting RNA with small molecule drugs
Published in Expert Opinion on Drug Discovery, 2023
Christopher L. Haga, Donald G. Phinney
RNA splicing is a complicated key regulatory step in the generation of the diverse repertoire of human proteins from the limited protein-coding genome. The splicing process is carried out in the spliceosome, a large complex consisting of hundreds of proteins, snRNAs, and five small nuclear ribonucleoproteins (snRNP) which act in concert to bind and remove intronic sequences [63]. The vast majority of protein-coding transcripts undergo such carefully orchestrated splicing events. However, when pre-mRNA processing and splicing deviate from the norm, splicing disorders can occur. Because every intron-containing gene requires a certain level of processing and splicing, mutations falling within a canonical splice site can lead to aberrant gene translation and potentially to disease. Two such well-explored diseases concerning small molecule RNA targeting are familial dysautonomia (FD) and spinal muscular atrophy (SMA).
The discovery and development of RNA-based therapies for treatment of HIV-1 infection
Published in Expert Opinion on Drug Discovery, 2023
Michelle J Chen, Anne Gatignol, Robert J. Scarborough
U1 small nuclear RNA (U1 snRNA) interference (U1i) is a distinct gene silencing mechanism inspired by the naturally occurring eukaryotic U1 ribonucleoprotein complex that plays a role in precursor mRNA splicing [32,168]. The U1 small nuclear ribonucleoprotein (snRNP) complex consists of seven spliceosomal Smith (Sm) proteins, three U1-specific proteins, and the 164 nt U1 snRNA folded into a four stem-loop structure. This complex is important for defining the 5’ splice sites and regulating 3’-end processing on pre-mRNAs. By binding to cis-elements up- or down-stream of the polyadenylation site, U1 snRNPs can inhibit polyadenylation. Transcripts lacking the polyA tail are unstable and degraded by host cell machinery, thus preventing the maturation of pre-mRNAs. Molecular engineering of the U1 snRNA exploits this natural repression function to silence gene expression. The U1 snRNA is modified at its 5’ end to code for a ~10 nt sequence complementary to the target RNA [169]. The resulting synthetic U1i RNA is then cloned under the U1 promoter and expressed in the cell where it transits to the nucleus to recruit U1 snRNPs to the target RNA, resulting in sequence-specific post-transcriptional gene silencing (Figure 4A).
Next steps for the optimization of exon therapy for Duchenne muscular dystrophy
Published in Expert Opinion on Biological Therapy, 2023
Galina Filonova, Annemieke Aartsma-Rus
Since approved AONs have to be administered repeatedly (weekly intravenous infusions for currently approved AONs) in order to maintain steady exon skipping and expression of restored dystrophin, a technology decreasing the frequency of drug administration and keeping sufficient exon skipping and dystrophin restoration would be preferred. Previously, it was confirmed that adeno-associated viral vectors (AAV) can deliver micro-dystrophin transgenes to skeletal muscles resulting in durable expression of micro-dystrophin in animal models and DMD patients [65–67]. Thus, AAV was proposed to deliver the uridine-rich seven small nuclear RNA (U7 snRNA) gene. Normally, the U7 snRNA is a part of a small nuclear ribonucleoprotein (snRNP) complex where U7 snRNA targets histone pre-mRNA and binds proteins that induce pre-mRNA processes [68,69].