A Brief History of Genetic Therapy: Gene Therapy, Antisense Technology, and Genomics
Eric Wickstrom in Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
Before the advent of synthetic oligonucleotides, the phenomenon which underpins most classical antisense activity-the disruption of translation through the hybridization of a complementary oligonucleotide to a specific mRNA molecule-had been experimentally observed. Spiegelman et al. (1972), employing a phage lambda system, noted that a gene which could be bidirectionally transcribed could give rise to different gene expression patterns depending on the pattern of transcription. In the paper he noted: To measure antisense RNA, an assay based on the formation of nuclease-resistant, double-stranded RNA, specific to the cro region, was developed. These results raise the possibility that bidirectional transcription of cro has a regulatory function in phage lambda.
Nanoparticle-Mediated Small RNA Deliveries for Molecular Therapies
D. Sakthi Kumar, Aswathy Ravindran Girija in Bionanotechnology in Cancer, 2023
Stable nucleic acid lipid particles (SNALPs) are another type of nanoformulation in which nucleic acids are complexed with lipids to form stable nanoparticles for nucleic acid deliveries. SNALPs are approximately 100–150 nm in size, which facilitates efficient delivery of nucleic acids in vivo, while protecting them from nuclease-mediated degradation in the systemic circulation. SNALPs differ from lipoplexes in that the former forms physical nanostructures with certain sizes, whereas for lipoplexes, charge-based chemical composition helps them to form complexes and also facilitates transfection of loaded nucleic acids into the cells. Most SNALPs are made from cationic polymers using PEG as a base material. The bilayer lipid nanoparticles enter cells efficiently by endocytosis. Upon slow release of the loaded small RNA cargos inside the cells, efficient silencing of target genes may ensue. SNALPs were first formulated by Semple et al. for antisense oligonucleotide delivery [12]. In general, SNALPs are made from a combination of high transition temperature phospholipid, a PEGylated lipid, an ionizable cationic phospholipid (1,2-dioleyloxy-N,N-dimethyl-3-aminopropane (DODMA), and 1,2-dioleyl-3-dimethylammonium propane (DODAP)) [12]. Following the initial combination developed by Semple et al., several others have developed SNALPs by identifying various ionizable phospholipids of different saturation degrees to achieve effective fusogenic property to transfect cells efficiently [13, 14].
Nucleic Acids as Therapeutic Targets and Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
In terms of side effects associated with antisense agents, a number of reactions to the intravenous injection of backbone-modified antisense oligonucleotides have been observed. In addition, antisense drugs can accumulate in specific organs and tissues, including the liver, kidney, spleen, bone marrow, and fat cells, causing more localized toxicities. However, the most serious adverse reactions arise from so-called “off target” events that occur when an antisense oligonucleotide binds to other RNAs of similar sequence, thus leading to unpredictable side effects. Side effects such as complement activation and prolongation of blood coagulation have also been observed. Another problem with treatment is that antisense and RNAi agents are rapidly cleared from the circulation by the renal system, usually in less than one hour after dosing, and this can remove the molecules from the blood stream before they have an opportunity to interact with their target RNA.
Lipoprotein(a) in atherosclerosis: from pathophysiology to clinical relevance and treatment options
Published in Annals of Medicine, 2020
Andreja Rehberger Likozar, Mark Zavrtanik, Miran Šebeštjen
Lifestyle modifications are unlikely to have any effects on Lp(a) levels because of the primary genetic basis [24]. On the other hand, a strong genetic background has become an interesting therapeutic target. Antisense oligonucleotide therapies are gene-based therapies that use small molecules that are structurally similar to short segments of DNA. These can interface with a specific region of a gene, thus enabling the transcription and translation process of, for instance, apo(a) mRNA. ISIS-APO(a)RX (also known as IONIS-APO(a)-RX) has already been validated in this setting. In a phase I, double-blind, place-controlled clinical trial, IONIS-APO(a)RX showed dose-dependent reductions in Lp(a) levels by up to 78% (at the highest dose of 300 mg) in otherwise healthy volunteers with Lp(a) levels >100 mg/L [97]. In a phase 2 trial, the efficacy of IONIS-APO(a)RX was also confirmed in patients with higher Lp(a) levels [98]. Furthermore, the structurally modified next generation IONIS-APO(a)-RX, known as IONIS-APO(a)-LRX, is more specifically targeted to hepatocytes. Due to this higher specificity, IONIS-APO(a)-LRX achieved the same magnitude of Lp(a) reduction at one-tenth of the dose [98]. Moreover, at the highest administrated dose of 40 mg IONIS-APO(a)-LRX, the reduction in Lp(a) levels was particularly high, at 92%.
Benefits and risks of the treatment with fibrates––a comprehensive summary
Published in Expert Review of Clinical Pharmacology, 2018
Bogusław Okopień, Łukasz Bułdak, Aleksandra Bołdys
Due to economic reasons, the first gene therapy in LPL deficiency leading to severe hypertriglyceridemia has recently been withdrawn from the market [140]. Therefore, an increased effort on novel, cost-effective treatment options is warranted. There are several innovative approaches to deal with hypertriglyceridemia, which are at various steps of clinical development. The development strategies on PPAR alpha agonists will probably be focused on the selective PPAR alpha agonist (SPPARMs) and to some extent on other compounds that have dual (alpha/delta) receptor activities (e.g. elafibranor) [141]. Pemafibrate (previously known as K-877) belongs to PPARs alpha agonists and have been proven to be at least similarly effective to fenofibrate with favorable safety profile [142–144]. Nowadays, significant successes are seen in the development of antisense oligonucleotide therapies. Therefore, one may expect the advent of several new drugs that affect TG level e.g. volanesorsen against apoCIII [145] or IONIS ANGPTL3-LRx [146] against angiopoietin-like 3. These novel approaches are in fact targeted at specific pathways that have already been recognized as elements in the complex influence of PPAR alpha agonist on intracellular metabolic pathways. Safety and clinical efficacy of these strategies need to be verified in long-term clinical studies. But significant steps to effectively modify lipid profile in patients with hypertriglyceridemia and to reduce complications seem to be closer than ever.
Emerging therapeutics for the treatment of Friedreich’s ataxia
Published in Expert Opinion on Orphan Drugs, 2018
Elisabetta Indelicato, Sylvia Bösch
Currently, promising therapeutic approaches are represented by advanced therapies such as antisense oligonucleotide and gene therapy. Antisense oligonucleotides are engineered molecules which bind to specific RNA sequences thus hindering transcription or splicing. This strategy has been already proven to be effective in a fatal neuromuscular disorder, the spinal muscular atrophy (SMA). Approval of FDA for the antisense nucleotide nusinersen for the treatment of SMA has been recently achieved. In FRDA, the introduction of anti-GAA repeats oligonucleotides into patient-derived fibroblasts successfully enhanced the expression of FXN mRNA and FXN [79]. Gene therapies are based either on the permanent expression of a transgene, delivered through a viral vector, in replacement to the nonfunctional homologue, or on removal of diseased gene. Both strategies are currently explored in FRDA disease models [75,79]. To date, the delivery of a FXN human transgene in murine models completely reversed both severe cardiomyopathy [75] and sensory ataxia [76].
Related Knowledge Centers
- DNA
- DNA Profiling
- DNA Sequencing
- Genetic Testing
- Oligomer
- Polymerase Chain Reaction
- Recombinant DNA
- Rna
- Oligonucleotide Synthesis
- Artificial Gene Synthesis