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Infiltrative Diseases
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
TTR gene silencing, either through RNA interference or antisense oligonucleotides, is another treatment strategy for ATTR amyloidosis. Small interfering RNAs (siRNAs) are delivered to hepatocytes and target gene expression leading to the degradation of TTR mRNA. Patisiran, a siRNA, resulted in a dose-dependent reduction of serum TTR levels in patients with hATTR polyneuropathy. The phase III APOLLO study included 225 patients with hATTR polyneuropathy randomized to receive either patisiran infusions or placebo, and patisiran resulted in improvement in the neuropathy impairment score (NIS) after 18 months of therapy.57 In the pre-specified cardiac subgroup, consisting of patients with LV wall thickness ≥ 13 mm with no concomitant history of hypertension or valvular disease, patisiran resulted in an improvement in NT-proBNP, LV wall thickness, and global longitudinal strain.58
Nanomaterials in COVID-19 Drug Development
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Alaa A. A. Aljabali, Ángel Serrano-Aroca, Kenneth Lundstrom, Murtaza M. Tambuwala
Large, hydrophilic, and anionic small interfering RNA (siRNA) delivery can be improved with nanoparticles, or conjugates that actively target ligands on the cell surface, or using natural interactions with the body (e.g., serum proteins) to passively target the cell of interest because it is not easy for siRNA to cross the cell membrane alone [34]: (Figure 12.4).
The Emerging Field of RNA Nanotechnology
Published in Lajos P. Balogh, Nano-Enabled Medical Applications, 2020
Small interfering RNA [42, 44] (siRNA) is a helix with 20–25 nucleotides that interferes with gene expression through the cleavage of mRNA by a protein/RNA complex named RISC (RNA-induced silencing complex). The siRNA specifically suppresses the expression of a target protein whose mRNA includes a sequence identical to the sense strand of the siRNA. The discovery led to the award of the 2006 Nobel Prize to Andrew Fire and Craig Mello [42].
Strategies for targeting undruggable targets
Published in Expert Opinion on Drug Discovery, 2022
Gong Zhang, Juan Zhang, Yuting Gao, Yangfeng Li, Yizhou Li
For undruggable targets, another stunning approach is manipulating at genetic/transcription level rather than protein level. Small interfering RNA (siRNA) down-regulates mRNA and subsequent protein expression[46]. There have been over 50 siRNA-based clinical trials, including attempts to target mutant-specific p53 to treat kidney acute renal failure by I5NP (QPI-1002) and silence c-myc to treat solid tumor or multiple myeloma[47]. CRISPR-Cas technology is also a promising gene-editing strategy for future therapeutics (Figure 1e)[48]. These strategies are still faced with challenges, to name a few, delivery efficiency, rapid degradation, and off-target effect. These limitations might be solved by chemical modification, rational sequence design, and exquisite RNA carrier system. RNA-based therapies could be complementary to the strategies above on the therapeutic entity level to synergistically crack undruggable targets.
Layer-by-Layer technique as a versatile tool for gene delivery applications
Published in Expert Opinion on Drug Delivery, 2021
Dmitrii S. Linnik, Yana V. Tarakanchikova, Mikhail V. Zyuzin, Kirill V. Lepik, Joeri L. Aerts, Gleb Sukhorukov, Alexander S. Timin
RNA interference has a wide application as a gene silencing strategy for the treatment of genetic and acquired diseases. Small interfering RNA (siRNA) is homologous to a specific target mRNA and is able to knock down its expression using cell-intrinsic mechanisms such as Dicer and RISC, thus causing a biological effect [81]. siRNA has important limitations in biomedical applications, which can be attributed to its hydrophilic nature, low inherent stability, and degradation in the bloodstream in the presence of nucleases: inefficient cellular uptake, cytotoxicity, and stimulation of immune responses. Viral vectors have been commonly used for siRNA delivery, which overcomes the problem of low transfection. However, viral vectors have several limitations, such as the need for active cell division for gene transduction, oncogenic potential, low titers, and gene silencing [82]. Therefore, the most important challenge for siRNA-mediated in vivo silencing is the development of safe (non-viral) delivery systems to deliver siRNAs into specific tissues and organs.
The emerging role of dipeptidyl-peptidase-4 as a therapeutic target in lung disease
Published in Expert Opinion on Therapeutic Targets, 2020
Hai Zou, Ning Zhu, Shengqing Li
Small interfering RNA (siRNA), are also commonly referred to as short interfering RNA or silencing RNA. siRNA is a type of double-stranded, non-coding RNA molecule similar to micro RNA (miRNA), that operates within the RNA interference (RNAi) pathway. They are designed to impede the expression of targeted genes with complementary nucleotide sequences, by degrading mRNA after transcription, and thus inhibiting translation. Jean et al. are developing novel delivery vehicles to transfer siRNA specific to DPP-4. Moreover, positively charged nucleic acids are challenging to deliver across the cell membrane, and the therapeutic nucleic acids are vulnerable to nucleases. Novel chitosan (CS)-based nanoparticles (NP) were developed to help deliver siRNA to target cells. RT-PCR assays confirmed reduced expression the DPP-4 gene in treated cells [54]. Recent advances in research have shown the potential that DPP-4 holds in treatment of diseases, not least respiratory ones. Furthermore, its biological functions beyond metabolic disorders are slowly emerging and the molecular pathways, interactions and associations are being understood. This paves the way to innovative anti-DPP-4 therapies which are being developed and furthers its use as a drug target. It can be used in a wide spectrum of pharmaceutical approaches and different domains of the protein can be targeted. These strategies also hold the potential to reduce side effects and thus be approved for therapeutic use.