Knocking down disease: a progress report on siRNA therapeutics

Wittrup, Anders; Lieberman, Judy

doi:10.1038/nrg3978

Cited by 693 publications

(539 citation statements)

References 86 publications

(106 reference statements)

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“…Critically, during this trafficking process, significant lysosomal degradation of the gene by digestive enzymes and acidic conditions with a pH less than 4.5 occurs in lysosomes,13 thereby greatly diminishing the therapeutic efficacy. Thus, lysosomal decomposition is a critical obstacle for intracellular miRNA delivery 14. Consequently, new vectors with efficient delivery of miRNAs and perfect biocompatibility are highly desirable.…”

Section: Introductionmentioning

confidence: 99%

Rod‐Shaped Active Drug Particles Enable Efficient and Safe Gene Delivery

et al. 2017

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Efficient microRNAs (miRNA) delivery into cells is a promising strategy for disease therapy, but is a major challenge because the available conventional nonviral vectors have significant drawbacks. In particular, after these vectors are entrapped in lysosomes, the escape efficiency of genes from lysosomes into the cytosol is less than 2%. Here, a novel approach for lethal‐7a (let‐7a) replacement therapy using rod‐shaped active pure drug nanoparticles (≈130 nm in length, PNPs) with a dramatically high drug‐loading of ≈300% as vectors is reported. Importantly, unlike other vectors, the developed PNPs/let‐7a complexes (≈178 nm, CNPs) can enter cells and bypass the lysosomal route to localize to the cytosol, achieving efficient intracellular delivery of let‐7a and a 50% reduction in expression of the target protein (KRAS). Also, CNPs prolong the t 1/2 of blood circulation by ≈threefold and increase tumor accumulation by ≈1.5–2‐fold, resulting in significantly improved antitumor efficacies. Additionally, no damage to normal organs is observed following systemic injection of CNPs. In conclusion, rod‐shaped active PNPs enable efficient and safe delivery of miRNA with synergistic treatment for disease. This nanoplatform would also offer a viable strategy for the potent delivery of proteins and peptides in vitro and in vivo.

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Section: Introductionmentioning

confidence: 99%

Rod‐Shaped Active Drug Particles Enable Efficient and Safe Gene Delivery

et al. 2017

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“…This delivery system has an encouraging initial safety profile because repeated systemic administration did not affect body weight. In prior studies, performed in nonhuman primates and currently under phase III clinical trials, the LNP components that we used (except for the uninvestigated mAbs) showed satisfactory biocompatibility and little or no immune response (11,14,(16)(17)(18)24). However, more extensive toxicity studies are needed.…”

Section: Discussionmentioning

confidence: 99%

“…However, the efficient, specific and safe delivery of RNAi payloads remains a major challenge facing the application of RNAi therapeutics to most diseases (2,11). The use of RNAi for treating B-cell lymphomas has been stymied by the lack of an appropriate delivery system.…”

Section: Discussionmentioning

confidence: 99%

“…However, the clinical application of this approach is hindered by the lack of appropriate systems that could deliver RNAi payloads to MCL cells in an efficient and safe manner (10,11). RNAi therapeutics for B-cell malignancies is especially challenging because these cells are dispersed and are intrinsically resistant to transfection with nucleic acids (3,12,13).…”

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confidence: 99%

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Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies

Weinstein

Toker

Emmanuel

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tumors, systemic siRNA delivery to leukocytes remains challenging. The ability to silence gene expression in leukocytes has great potential for identifying drug targets and for RNAi-based therapy for leukocyte diseases. However, both normal and malignant leukocytes are among the most difficult targets for siRNA delivery as they are resistant to conventional transfection reagents and are dispersed in the body. We used mantle cell lymphoma (MCL) as a prototypic blood cancer for validating a novel siRNA delivery strategy. MCL is an aggressive B-cell lymphoma that overexpresses cyclin D1 with relatively poor prognosis. Downregulation of cyclin D1 using RNA interference (RNAi) is a potential therapeutic approach to this malignancy. Here, we designed lipidbased nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that are specifically taken up by human MCL cells in the bone marrow of xenografted mice. When loaded with siRNAs against cyclin D1, CD38-targeted LNPs induced gene silencing in MCL cells and prolonged survival of tumor-bearing mice with no observed adverse effects. These results highlight the therapeutic potential of cyclin D1 therapy in MCL and present a novel RNAi delivery system that opens new therapeutic opportunities for treating MCL and other B-cell malignancies.nanomedicine | siRNA | mantle cell lymphoma | cyclin D1 | CD38

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“…By interfering with the cellular pathway of disease‐related proteins, siRNA is a promising drug, e.g., against cancer 1. Moreover, siRNA has become an important tool for fundamental biological research, as it allows to knockdown gene expression in vitro.…”

Section: Introductionmentioning

confidence: 99%

Chaperonin–Dendrimer Conjugates for siRNA Delivery

et al. 2016

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The group II chaperonin thermosome (THS) is a hollow protein nanoparticle that can encapsulate macromolecular guests. Two large pores grant access to the interior of the protein cage. Poly(amidoamine) (PAMAM) is conjugated into THS to act as an anchor for small interfering RNA (siRNA), allowing to load the THS with therapeutic payload. THS–PAMAM protects siRNA from degradation by RNase A and traffics KIF11 and GAPDH siRNA into U87 cancer cells. By modification of the protein cage with the cell‐penetrating peptide TAT, RNA interference is also induced in PC‐3 cells. THS–PAMAM protein–polymer conjugates are therefore promising siRNA transfection reagents and greatly expand the scope of protein cages in drug delivery applications.

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Knocking down disease: a progress report on siRNA therapeutics

Cited by 693 publications

References 86 publications

Rod‐Shaped Active Drug Particles Enable Efficient and Safe Gene Delivery

Rod‐Shaped Active Drug Particles Enable Efficient and Safe Gene Delivery

Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies

Chaperonin–Dendrimer Conjugates for siRNA Delivery

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