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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
One example is the agent branaplam (Figure 5.100) which, as of July 2019, is in Phase I/II clinical trials for the treatment of children with Spinal Muscular Atrophy, branaplam is in a Phase II clinical trial SMA type 1. This molecule, based on a pyridazine building block, enhances the inclusion of exon 7, resulting in a full length and functional protein product. It represents the first example of splicing modulation using a sequence-selective small molecule and works by stabilizing the transient double-stranded RNA (dsRNA) structure formed between the SMN2 pre-mRNA and the U1 snRNP complex, a key component of the splicesome. It also increases the binding affinity of U1 snRNP to the 5’ splice site (5’ss) in a sequence-selective manner. Structure of branaplam (showing the keto-enol tautomers) which, as of July 2019, is in Phase I/II clinical trials for the treatment of children with spinal muscular atrophy (SMA).
Transcriptionally Regulatory Sequences of Phylogenetic Significance
Published in S. K. Dutta, DNA Systematics, 2019
Many mRNAs show a conserved sequence of AAUAAA in the 3' end of poly A containing mRNA. Mutation in the sequence to AAGAAA or AAUAAG produces unusually long messages, which are unstable. Thus, at least for polymerase II, the termination of transcription obeys a sequence signal in the template. This signal is reflected in the terminus of its RNA in the form of a special hairpin structure which apparently facilitates post-transcriptional cleavage. The requirement of an endonucleolytic cleavage process on a small nuclear ribonucleoprotein “snRNP” has been clearly demonstrated with histone genes.238,239 Presumably, the sequence AAUAAA and perhaps another frequently occurring sequence CApyUG56 near the poly A addition site are being recognized by a small nuclear RNA, U4, in the “snRNP”. The situation is parallel to the splicing process for mRNA maturation, in which another class of “snRNP” is involved in aligning the intron-donor-acceptor sites with its U1 RNA,240 demonstrable by specific antibody inactivation.241 In yeast, the coding sequence for Ul-like RNA constitutes a portion of the 3' acceptor site of the intron of the same gene.119
Scleroderma overlap syndromes
Published in Aparna Palit, Arun C. Inamadar, Systemic Sclerosis, 2019
Akanksha Kaushik, M. Sendhil Kumaran
Myositis may appear before, after, or simultaneously with the onset of scleroderma. The diffuse cutaneous form is the predominant form associated with myositis and association with cardiomyopathy has been reported. Gut involvement and related complications like pneumatosis intestinalis and pseudo-obstruction have been commonly reported. Studies have reported SSc/myositis overlap to be associated with specific autoantibodies like anti-PM-Scl, anti-U2 RNP, anti-Ku, and anti-U5 snRNP. Occurrence of anti-PM-Scl antibodies parallels with arthritis, and the course of interstitial lung disease (ILD) with this association is benign. Anti-Jo-1 antibodies are not commonly seen. Scleroderma/myositis overlap syndrome is considered a severe form with reported mortality rate as high as 21%.
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].
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).