Clinical pharmacology of siRNA therapeutics: current status and future prospects

Abosalha, Ahmed Khaled; Boyajian, Jacqueline; Ahmad, Waqar; Islam, Paromita; Ghebretatios, Merry; Schaly, Sabrina; Thareja, Rahul; Arora, Karan; Prakash, Satya

doi:10.1080/17512433.2022.2136166

Cited by 15 publications

(11 citation statements)

References 137 publications

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“…4 School of cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1Bd, UK. 5 Biocenter innsbruck (ccB), Medical University innsbruck, division of developmental immunology, innrain 80, 6020 innsbruck, Austria. 6 institute of clinical chemistry and laboratory Medicine, University hospital carl Gustav carus at the technische Universität dresden, 01307 dresden, Germany.…”

Section: Resultsmentioning

confidence: 99%

“…Small interfering RNAs (siRNAs) are widely used as tool compounds in biomedical research and recently have entered clinical trials for potential therapeutic benefit (1)(2)(3)(4). However, treatment of a cell with an siRNA markedly alters the metabolic state (5,6), and detailed mechanisms of the sensitization to cellular death and survival are understudied. Given the wide range of siRNA applications, it is surprising that even in cultured cells, changes to classical pathways of regulated cell death, such as apoptosis, necroptosis, pyroptosis, and ferroptosis, have not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis

von Mässenhausen,

Schlecht,

Beer

et al. 2024

Sci. Adv.

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Small interfering RNAs (siRNAs) are widely used in biomedical research and in clinical trials. Here, we demonstrate that siRNA treatment is commonly associated with significant sensitization to ferroptosis, independently of the target protein knockdown. Genetically targeting mitochondrial antiviral-signaling protein (MAVS) reversed the siRNA-mediated sensitizing effect, but no activation of canonical MAVS signaling, which involves phosphorylation of IkBα and interferon regulatory transcription factor 3 (IRF3), was observed. In contrast, MAVS mediated a noncanonical signal resulting in a prominent increase in mitochondrial ROS levels, and increase in the BACH1/pNRF2 transcription factor ratio and GPX4 up-regulation, which was associated with a 50% decrease in intracellular glutathione levels. We conclude that siRNAs commonly sensitize to ferroptosis and may severely compromise the conclusions drawn from silencing approaches in biomedical research. Finally, as ferroptosis contributes to a variety of pathophysiological processes, we cannot exclude side effects in human siRNA-based therapeutical concepts that should be clinically tested.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis

von Mässenhausen,

Schlecht,

Beer

et al. 2024

Sci. Adv.

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“…The siRNA-active component of Patisiran is formulated into lipid nanoparticles that protect the RNA and facilitate its delivery to target tissues. The lipid nanoparticle formulation includes buffer components, as well as the lipid components DLin-MC3-DMA, distearoylphosphatidylcholine, cholesterol, and the PEGylated slipid DMG-PEG 2000 [23,24]. A CRISPR-Cas9 in vivo gene editing approach for transthyretin amyloidosis is also being investigated in a clinical trial (funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051) [16].…”

Section: Applicationsmentioning

confidence: 99%

Biodrug Delivery Systems: Do mRNA Lipid Nanoparticles Come of Age?

Puccetti

Schoubben

Giovagnoli

et al. 2023

IJMS

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As an appealing alternative to treat and prevent diseases ranging from cancer to COVID-19, mRNA has demonstrated significant clinical effects. Nanotechnology facilitates the successful implementation of the systemic delivery of mRNA for safe human consumption. In this manuscript, we provide an overview of current mRNA therapeutic applications and discuss key biological barriers to delivery and recent advances in the development of nonviral systems. The relevant challenges that LNPs face in achieving cost-effective and widespread clinical implementation when delivering mRNA are likewise discussed.

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“…Meanwhile, small interfering RNA (siRNA) is a powerful tool for gene silencing through RNA interference (RNAi), which can inhibit the expression or transcription of specific genes. , Utilizing small interfering RNA (siRNA) targeting PD-L1 (siPD-L1) to specifically suppress the expression of PD-L1 and alter the tumor immune microenvironment is an effective immunotherapy for TNBC. However, the challenges faced by siRNA in cancer treatment include: (1) poor stability: sensitivity to endogenous nucleases and easy clearance; (2) difficulty in entry: RNA drugs, due to their negative charge and polymer properties, are difficult to enter tumor cells and exert their effects; and (3) difficulty in lysosomal escape. − Therefore, the design and synthesis of safe and effective siRNA delivery vectors are crucial for the development of siRNA-based therapeutics …”

Section: Introductionmentioning

confidence: 99%

Peptide-Modified Cyclodextrin-Based Nanosystem for Co-Delivery of Celastrol and siPD-L1 to Tumors

Wang,

Zhang,

et al. 2024

ACS Appl. Nano Mater.

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Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with high immunogenicity. In this study, we developed a peptide-modified cyclodextrin-based nanosystem for co-delivery of celastrol and siPD-L1, named H4R6RGD-carboxymethyl-β-cyclodextrin@celastrol/siPD-L1 nanoparticles (H−C@C/siPD-L1 NPs). The cyclodextrin derivative could simultaneously utilize its cavity and positively charged chain to deliver siPD-L1 and celastrol (cela) through hydrophobic and electrostatic interactions. H−C@C/siPD-L1 NPs exhibited excellent stability and dispersibility. Characterization revealed that the nanoparticles exhibited a spherical morphology, displaying smooth surfaces and an average diameter of approximately 200 nm. The H−C@C/siPD-L1 NPs demonstrated enhanced cellular uptake and efficient lysosomal escape, thereby improving drug utilization while minimizing side effects on normal tissues. Furthermore, the H−C@C/siPD-L1 NPs facilitated the delivery of siPD-L1, effectively reducing the expression of PD-L1. This, in turn, promoted tumor apoptosis and augmented the antitumor effect through the endoplasmic reticulum (ER) stress-related apoptotic pathway. Notably, this multifunctional nanodrug delivery system, designed for the combination of chemotherapy and gene therapy, not only exhibited a potent antitumor effect but also improved the immunosuppressive microenvironment of the tumor. The targeted co-delivery of cela and siPD-L1 holds significant potential in advancing the application of chemotherapeutic and genic nanomedicine for the treatment of TNBC. The materials would have good application prospects in the field of clinical drug delivery.

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Clinical pharmacology of siRNA therapeutics: current status and future prospects

Cited by 15 publications

References 137 publications

Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis

Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis

Biodrug Delivery Systems: Do mRNA Lipid Nanoparticles Come of Age?

Peptide-Modified Cyclodextrin-Based Nanosystem for Co-Delivery of Celastrol and siPD-L1 to Tumors

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