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A Brief History of Genetic Therapy: Gene Therapy, Antisense Technology, and Genomics
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
Catalytic RNAs are RNA structures capable of cleaving covalent bonds in an RNA molecule. Catalytic RNAs were first described by Cech's laboratory (Zaug et al., 1980; Cech et al., 1981; Kruger et al., 1982) and Altman etal. (Guerrier-Takada et al., 1983). Cech described the catalytic removal of introns in the pre-rRNA of the ciliated protozoan, Tetrahymena thermophila. The term "ribozyme" describes RNA (ribonucleic acid) molecules with catalytic properties analogous to enzymes, as explained by Kruger et al. (1982), Because the IVS RNA is not an enzyme but has some enzyme-like characteristics, we call it a ribozyme, an RNA molecule that has the intrinsic ability to break and form covalent bonds.
The science of biotechnology
Published in Ronald P. Evens, Biotechnology, 2020
Ribozymes are RNA molecules comprising sequences of nucleic acids that possess enzymatic catalytic properties and bind to specific sites in DNA or RNA and cleave the chain. A ribozyme will have subunits responsible for the binding function and subunits responsible for enzyme function. They generally have the following desirable traits: specificity in targeting, cleavage of target RNA, small size amenable to formulation and dosing, and multiple turnover (one molecule binds and acts and then moves on to next molecule and repeats its function). However, challenges are manifold; for example, the need for cell insertion (transfection), nuclease protection in the blood, and chaperone proteins for movement in cell cytoplasm. No products have yet been approved. Aptamers are small oligonucleotide molecules that bind to proteins to disrupt disease pathogenesis. Their benefits are small molecular size, specificity toward target protein, and low immunogenicity; however, limitations are nuclease susceptibility, short systemic half-lives, and possibly limited affinity to targets. Proof of principle has been achieved as one aptamer has been approved for use, a pegylated conjugate of an oligonucleotide for wet acute macular degeneration, pegaptanib (Macugen®). The pegylation protects the molecule from lysis from nucleases, and offers a longer serum half-life and a measure of immunity.
Liposomes in the Delivery Of Antisense Oligonucleotides
Published in Danilo D. Lasic, LIPOSOMES in GENE DELIVERY, 2019
Because ribozymes can be designed to bind to specific sites of any target DNA and consequently cleave them, they can be used in human therapy and diagnostics. The sequence specificity potentially offers high specificity and reduced, if not nonexisting, toxic side effects. As with antisense oligonucleotides there is an optimal target site length, in this case of around 15 nucleotides. Shorter matching sequences may have too large nonspecificity, while longer ones may have too high binding affinity and therefore slow enzymatic kinetics.
Challenges with the discovery of RNA-based therapeutics for flaviviruses
Published in Expert Opinion on Drug Discovery, 2023
Mei-Yue Wang, Rong Zhao, Yu-Lan Wang, De-Ping Wang, Ji-Min Cao
In addition, there are some ribozyme-based strategies against flaviviruses. Ribozymes are small RNA molecules with catalytic activity and can target the particular site of RNA to cleave it. For instance, Nawtaisong et al. [36] constructed 14 hammerhead ribozymes and tested the effectiveness of these ribozymes in the suppression of DENV-2 replication in lentivirus-transduced mosquito cells. The ribozymes were expressed using pan retroviral vectors and controlled by Aedes aegypti tRNAval promoter. In lentivirus-transduced C6/36 mosquito cells, 100-fold suppression of virus replication could be observed. Another study designed the group I trans-splicing introns (a type of ribozyme) to target the conserved 5’-3’ cyclization sequence (CS) region which is common to all four DENV serotypes (DENV-1–4) [37]. The examples are presented in Table 1.
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
Ribozymes are RNAs that catalyze biochemical reactions. The first ribozyme was identified in self-splicing introns, where the RNA catalyzes both cleavage and ligation reactions that result in the excision of the intron from the transcript [38]. Subsequently, it was shown that RNA is the catalytic moiety in RNase P complexes that cleave pre-transfer (t)RNAs [39] and in ribosomes, where ribosomal RNA is responsible for catalyzing the linkage of amino acids to form proteins [40]. The most diverse group of ribozymes are the small, naturally occurring, self-cleaving ribozymes from which most ribozyme therapies have been derived [29,41]. Although these ribozymes catalyze self-cleavage reactions, they can be easily modified to cleave in trans and designed to target an RNA through complementary base pairing. An advantage of small self-cleaving ribozyme motifs is that they do not require cellular proteins to catalyze target cleavage, limiting their ability to disturb cellular physiology. Examples of trans-cleaving ribozymes based on these motifs are shown in Figure 1.
Newer therapeutic agents for retinal diseases
Published in Expert Review of Ophthalmology, 2022
Ashish Markan, Swechya Neupane, Rupesh Agrawal, Vishali Gupta
Retinitis pigmentosa (RP), a group of hereditary retinal degenerative disease, is commonly encountered inherited retinal disease in clinical practice affecting 1 in 3000 individuals [107]. Patient usually presents in the first year of life with profound blindness, roving nystagmus, variable retinal pathology and occasionally other systemic pathology. RP patients are considered to be suitable candidates for gene therapy. Ribozyme therapy has shown to effectively slow down the progress of RP successfully in animal model. Ribozyme therapy, a new technique, uses ribozymes (specialized molecules) which act as molecular scissors to target the mutant gene products and then cleaves its mutant messenger RNA to halt the production of destructive protein [108]. Liang et al studied whether adeno-associated virus (AAV) mediated delivery of gene encoding (Ciliary Neurotrophic Factor) CNTF leads to a delay in photoreceptor death in the rhodopsin knockout mouse in animal model of RP. Subretinal administration of this virus led to transduction of photoreceptors with significant photoreceptor preservation in the injected quadrant of retina, thus having an important implication in the treatment of RP [109].