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Nanoparticle-Mediated Small RNA Deliveries for Molecular Therapies
Published in D. Sakthi Kumar, Aswathy Ravindran Girija, Bionanotechnology in Cancer, 2023
Ramasamy Paulmurugan, Uday Kumar Sukumar, Tarik F. Massoud
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
Published in David E. Thurston, Ilona Pysz, 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.
Liposomes in the Delivery Of Antisense Oligonucleotides
Published in Danilo D. Lasic, LIPOSOMES in GENE DELIVERY, 2019
The last two sections have shown that recent developments in liposome technology have found their way into antisense oligonucleotide delivery. The next big step is the delivery of these in vivo. For many of these applications, when targeting, stability in circulation, as well as escape from the endocytotic vacuole, are required, the field will follow the thorny path led by targeting of liposome encapsulated low-molecular -weight drugs. The most successful application to date makes use of extravasation of small, sterically stabilized liposomes in tumors and sites of infections and inflammations. This provides an opportunity to deliver antisense oligonucleotides to these sites. Because these liposomes are normally not internalized, one can use the time-dependent shedding of polymer coating to increase endocytosis. The bilayer composition can be also pH sensitive. The presence of targeting ligands and if the receptors are endocytotic can further improve delivery. Furthermore, below the unstable PEG coating other active groups can be hidden and activated after a trigger or certain time period. I believe that the use of the above mentioned options and perhaps some new developments may result in effective delivery of these specific molecules.
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%.
Epilepsy: key experimental therapeutics in early clinical development
Published in Expert Opinion on Investigational Drugs, 2020
Claude Steriade, Jacqueline French, Orrin Devinsky
Antisense oligonucleotide therapy modulates splicing of pre-mRNA transcript to bypass exon nonsense mutations. Nonsense mutations introduce a premature stop codon into a gene sequence, which then leads to a decrease in mRNA and protein production. Antisense oligonucleotide therapy can work by either 1) skipping the mutated exon and restoration of a transcript reading frame, leading to generation of a truncated but partly functional protein, or 2) binding to sequences in mRNA that target the strand for destruction, thereby increasing the production of mRNA from the normal copy of the gene. Alternative splicing can lead to functional recovery in several nonsense mutation diseases, including Duchenne muscular dystrophy [69] and cystic fibrosis [70]. Most Dravet syndrome patients carry SCN1A mutations leading to haploinsufficiency of voltage-gated sodium channels (subunit Nav1.1). One approach in development increases mRNA transcripts from the normal gene copy. Other approaches use small molecules to bypass nonsense mutations that occur in numerous genetic epileptic encephalopathies (e.g. Dravet syndrome, CDKL5 deficiency).
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.