FDA approves patisiran to treat hereditary transthyretin amyloidosis

Wood, Heather

doi:10.1038/s41582-018-0065-0

Cited by 95 publications

(90 citation statements)

References 2 publications

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“…From the initiation of the first clinical trials of siRNA‐based therapeutics in 2004, it took 14 years for the first siRNA‐based therapeutic to be approved. This trajectory aligns closely with the history of antibody‐based therapeutics, which started in 1975 and received their first approval (for a monoclonal antibody) in 1986 …”

Section: Future Prospectivesupporting

confidence: 66%

“…Indeed, LNP formulations have completed multiple clinical trials for delivery of siRNA, such as those against PLK‐1 (TKM‐080301) for the treatment of neuroendocrine tumors (NET), adrenocortical carcinoma (ACC), and primary/secondary liver cancer . With the substantial achievements in siRNA loading, lipid design, and lipid composition, lipid‐based nanoparticles have enjoyed the greatest success in translation from benchtop development to clinical trials, which led to the first FDA‐approved siRNA‐based LNP therapeutic, Patisiran …”

Section: Protective Carriers For Sirna Deliverymentioning

confidence: 99%

“…However, Alnylam made a breakthrough only two years later with another formulation for the same disease; Patisiran demonstrated significant therapeutic outcome in patients and became the first FDA‐approved RNAi/siRNA therapeutic in 2018. This pioneering achievement signals that we may be only at the beginning of the RNAi therapy story.…”

Section: Future Prospectivementioning

confidence: 99%

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Rekindling RNAi Therapy: Materials Design Requirements for In Vivo siRNA Delivery

2019

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The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adma.201903637.With the recent FDA approval of the first siRNA-derived therapeutic, RNA interference (RNAi)-mediated gene therapy is undergoing a transition from research to the clinical space. The primary obstacle to realization of RNAi therapy has been the delivery of oligonucleotide payloads. Therefore, the main aims is to identify and describe key design features needed for nanoscale vehicles to achieve effective delivery of siRNA-mediated gene silencing agents in vivo. The problem is broken into three elements: 1) protection of siRNA from degradation and clearance; 2) selective homing to target cell types; and 3) cytoplasmic release of the siRNA payload by escaping or bypassing endocytic uptake. The in vitro and in vivo gene silencing efficiency values that have been reported in publications over the past decade are quantitatively summarized by material type (lipid, polymer, metal, mesoporous silica, and porous silicon), and the overall trends in research publication and in clinical translation are discussed to reflect on the direction of the RNAi therapeutics field.

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Section: Future Prospectivesupporting

confidence: 66%

Section: Protective Carriers For Sirna Deliverymentioning

confidence: 99%

Section: Future Prospectivementioning

confidence: 99%

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Rekindling RNAi Therapy: Materials Design Requirements for In Vivo siRNA Delivery

2019

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“…The APOLLO phase 3 trial proved that patisiran was beneficial to patients with hereditary transthyretin amyloidosis. The approval of patisiran may finally lead to the development of RNAi drugs . Nanoparticle‐mediated siRNA treatment is expected to be an alternative to chemotherapy for lung cancers.…”

Section: Introductionmentioning

confidence: 99%

“…The approval of patisiran may finally lead to the development of RNAi drugs. [13][14][15] Nanoparticlemediated siRNA treatment is expected to be an alternative to chemotherapy for lung cancers. Many kinds of small interfering RNA (siRNA) therapy have been promoted, including VEGF, EPHA2, and PKN3.…”

Section: Introductionmentioning

confidence: 99%

Localized RNA interference therapy to eliminate residual lung cancer after incomplete microwave ablation

et al. 2019

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Background This study evaluated the safety and efficacy of localized injection of polyethylene glycol (PEG)‐hyperbranched polyethyleneimine (PEI)‐EGFR‐small interfering RNA (siRNA) nanocomposites as a treatment for residual lung cancer after incomplete microwave ablation (MWA). Methods Human lung cancer cell lines with high and low EGFR expression were selected for the study. The effects of PEG‐PEI‐EGFR‐siRNA nanocomposite transfection on the proliferation, migration, and apoptosis of lung cancer cells were verified. Sixteen healthy ICR mice were injected into the lung to test the biological safety of the nanocomposites. In addition, 24 subcutaneous xenograft BALB/C nude mice with high EGFR expression were separated into four groups and then treated with an intratumoral injection of PEG‐PEI‐EGFR‐siRNA, PEG‐PEI‐normal control (NC)‐siRNA, PEG‐PEI‐EGFR‐siRNA after MWA, or PEG‐PEI‐NC‐siRNA after MWA. Tumor growth, pathological changes, and EGFR expression in each group were observed. Results PEG‐PEI‐EGFR‐siRNA nanocomposites were transfected to HCC 827 cells showing high EGFR expression and to H23 cells showing low EGFR expression. In HCC827 cells, downregulation of EGFR gene expression reduced cell proliferation, invasion, and migration, whereas cell apoptosis increased. In contrast, in H23 cells, no significant differences in those parameters were detected. No acute toxicity occurred in the ICR mice during the biosafety test. Localized injection of PEG‐PEI‐EGFR‐siRNA nanocomposites significantly inhibited the growth of human lung xenografts in mice and the growth of residual tumors after MWA. Conclusion PEG‐PEI‐EGFR‐siRNA nanocomposites may be a supplemental therapy strategy to treat residual lung cancer after incomplete MWA.

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Securing the Payload, Finding the Cell, and Avoiding the Endosome: Peptide‐Targeted, Fusogenic Porous Silicon Nanoparticles for Delivery of siRNA

et al. 2019

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in the development of siRNA-based therapeutics over more than 15 years, substantial challenges have limited their clinical translation. The first siRNA-based drug was approved only in the last year, and that only for treatment of a rare hereditary disease; [2] there is currently no approved cancer therapeutic based on siRNA. A primary obstacle in this endeavor has been the lack of delivery vehicles that can overcome in vivo clearance and cellular degradation via endocytosis. [3,4] One of the early proposed solutions to the problem of endocytotic sequestration and subsequent lysosomal degradation of siRNA was delivery via fusogenic liposomes. [5] Fusogenic liposomes directly fuse with the cell membrane, bypassing endocytotic uptake pathways. [6] While they have shown promise as delivery vehicles for ribonucleic acid interference (RNAi) therapeutics, [7] liposomes suffer from a generally low carrying capacity for nucleic acid therapeutics [8] and leakage of their payloads either during storage or in vivo. [9] We recently demonstrated a delivery system that harnessed together a fusogenic lipid and a solid porous silicon nanoparticle (pSiNP) core. The system capitalized on the relatively high loading of Despite the promise of ribonucleic acid interference therapeutics, the delivery of oligonucleotides selectively to diseased tissues in the body, and specifically to the cellular location in the tissues needed to provide optimal therapeutic outcome, remains a significant challenge. Here, key material properties and biological mechanisms for delivery of short interfering RNAs (siRNAs) to effectively silence target-specific cells in vivo are identified. Using porous silicon nanoparticles as the siRNA host, tumor-targeting peptides for selective tissue homing, and fusogenic lipid coatings to induce fusion with the plasma membrane, it is shown that the uptake mechanism can be engineered to be independent of common receptor-mediated endocytosis pathways. Two examples of the potential broad clinical applicability of this concept in a mouse xenograft model of ovarian cancer peritoneal carcinomatosis are provided: silencing the Rev3l subunit of polymerase Pol ζ to impair DNA repair in combination with cisplatin; and reprogramming tumor-associated macrophages into a proinflammatory state. RNAi TherapyOf the ≈100 FDA-approved anticancer drugs, about 40% are cytotoxic agents and 60% are inhibitors of oncogenic pathways. [1] As the discovery of key oncogenic markers and pathways has progressed, short interfering RNAs (siRNAs) have emerged as a promising class of drugs to transiently silence oncogenic mutations. Despite the worldwide effort expended

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FDA approves patisiran to treat hereditary transthyretin amyloidosis

Cited by 95 publications

References 2 publications

Rekindling RNAi Therapy: Materials Design Requirements for In Vivo siRNA Delivery

Rekindling RNAi Therapy: Materials Design Requirements for In Vivo siRNA Delivery

Localized RNA interference therapy to eliminate residual lung cancer after incomplete microwave ablation

Securing the Payload, Finding the Cell, and Avoiding the Endosome: Peptide‐Targeted, Fusogenic Porous Silicon Nanoparticles for Delivery of siRNA

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