The growth of siRNA-based therapeutics: Updated clinical studies

Zhang, M. May; Bahal, Raman; Rasmussen, Theodore P.; Manautou, José E.; Zhong, Xiao‐bo

doi:10.1016/j.bcp.2021.114432

Cited by 313 publications

(278 citation statements)

References 102 publications

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“…siRNAs formulated as a lipid complex or covalently linked to specific ligands enabled FDA approval of ONPATTRO ® (patisiran) for treatment of polyneuropathy in patients with hereditary transthyretin-mediated amyloidosis and GIVLAARI™ (givosiran) used for treatment of acute hepatic porphyria (AHP) [ 64 , 65 ]. However, developing specific delivery of siRNAs to malignant cells is greatly needed.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Silencing of BCL-2 Using NK Cell-Derived Exosomes as a Novel Therapeutic Approach in Breast Cancer

Kaban

Hinterleitner

Zhou

et al. 2021

Cancers

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Overexpression of the anti-apoptotic protein BCL-2 is frequently observed in multiple malignancies, including about 85% of patients with estrogen receptor positive (ER+) breast cancer. Besides being studied as a prognostic marker, BCL-2 is investigated as a therapeutic target in ER+ breast cancer. Here, we introduce a new exosome-based strategy to target BCL-2 using genetically modified natural killer (NK) cells. The NK cell line NK92MI was lentivirally transduced to express and load BCL-2 siRNAs (siBCL-2) into exosomes (NKExos) and then evaluated for its potential to treat ER+ breast cancer. Transfected NK92MI cells produced substantial levels of BCL-2 siRNAs, without substantially affecting NK cell viability or effector function and led to loading of siBCL-2 in NKExos. Remarkably, targeting BCL-2 via siBCL-2 NKExos led to enhanced intrinsic apoptosis in breast cancer cells, without affecting non-malignant cells. Together, our prototypical results for BCL-2 in breast cancer provide proof of concept for a novel strategy to utilize NKExos as a natural delivery vector for siRNA targeting of oncogenes.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Silencing of BCL-2 Using NK Cell-Derived Exosomes as a Novel Therapeutic Approach in Breast Cancer

Kaban

Hinterleitner

Zhou

et al. 2021

Cancers

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“…For instance, nedosiran is developed to treat primary hyperoxaluria, vutrisiran for the treatment of hATTR like patisiran, teprasiran for the prevention of acute kidney injury after transplant or cardiovascular surgery, fitusiran, for hemophilia A and B, tivanisiran to treat ocular pain and dry eye disease, and cosdosiran to treat nonarteritic anterior ischemic optic neuropathy. Also, siRNA therapy was expanded from orphan and rare diseases to more prevalent conditions, such as inclisiran for hypercholesterolemia 56 . Most of these drug candidates are GalNAc conjugates, except teprasiran, cosdosiran, and tivanisiran, which were not delivered with a carrier or conjugated to a targeting ligand.…”

Section: Sirnas As Promising Therapeutics For Ali/ardsmentioning

confidence: 99%

Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome

Zoulikha

Xiao

Boafo

et al. 2022

Acta Pharmaceutica Sinica B

142

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The use of small interfering RNAs (siRNAs) has been under investigation for the treatment of several unmet medical needs, including acute lung injury/acute respiratory distress syndrome (ALI/ARDS) wherein siRNA may be implemented to modify the expression of pro-inflammatory cytokines and chemokines at the mRNA level. The clear anatomy, accessibility, and relatively low enzyme activity make the lung a good target for local siRNA therapy. However, the clinical translation of siRNA is hampered by the inefficient delivery of siRNA therapeutics to the target cells due to the properties of naked siRNA. Thus, this review will focus on the various delivery systems that can be used and the different barriers that need to be surmounted for the development of stable inhalable siRNA formulations for human use before siRNA therapeutics for ALI/ARDS become available in the clinic.

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“…Small interfering RNAs (siRNAs) inhibit the expression of mRNAs bearing complementary sequences (1). The first siRNA therapeutic, patisiran, was approved by the FDA in 2018, and the second siRNA therapeutic, givosiran, was approved the following year (2). Several studies have focused on RNA therapy, especially siRNA-based therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Effect of using amino acids in the freeze‑drying of siRNA lipoplexes on gene knockdown in cells after reverse transfection

Tang

Hattori

2021

Biomed Rep

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Recently, small interfering RNA (siRNA)/cationic liposome complexes (siRNA lipoplexes) have become a crucial research tool for studying gene function. Easy and reliable siRNA transfection with a large set of siRNAs is required for the successful screening of gene function. Reverse (Rev)-transfection with freeze-dried siRNA lipoplexes is validated for siRNA transfection with a large set of siRNAs in a multi-well plate. In our previous study, it was shown that Rev-transfection with siRNA lipoplexes freeze-dried in disaccharides or trisaccharides resulted in long-term stability with a high level of gene-knockdown activity. In the present study, the effects of amino acids used as cryoprotectants in the freeze-drying of siRNA lipoplexes on gene knockdown via Rev-transfection were assessed. A total of 15 types of amino acids were used to prepare freeze-dried siRNA lipoplexes, and it was found that the freeze-drying of siRNA lipoplexes with amino acid concentrations >100 mM strongly suppressed targeted gene expression regardless of the amino acid type; however, some amino acids strongly upregulated or downregulated gene expression in the cells transfected with negative control siRNA. Amongst the amino acids tested, the presence of asparagine showed specific gene-knockdown activity, forming large cakes after freeze-drying and retaining a favorable siRNA lipoplex size after rehydration. These findings provide valuable information regarding amino acids as cryoprotectants for Rev-transfection using freeze-dried siRNA lipoplexes for the efficient delivery of siRNA into cells.

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The growth of siRNA-based therapeutics: Updated clinical studies

Cited by 313 publications

References 102 publications

Therapeutic Silencing of BCL-2 Using NK Cell-Derived Exosomes as a Novel Therapeutic Approach in Breast Cancer

Therapeutic Silencing of BCL-2 Using NK Cell-Derived Exosomes as a Novel Therapeutic Approach in Breast Cancer

Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome

Effect of using amino acids in the freeze‑drying of siRNA lipoplexes on gene knockdown in cells after reverse transfection

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