Leading RNA Interference Therapeutics Part 2: Silencing Delta-Aminolevulinic Acid Synthase 1, with a Focus on Givosiran

Brandão, Pedro Renato de Paula; Titze‐de‐Almeida, Simoneide Souza; Titze‐de‐Almeida, Ricardo

doi:10.1007/s40291-019-00438-6

Cited by 61 publications

(48 citation statements)

References 37 publications

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“…We employed CL-qPCR to quantify the SSOs in tissues and recorded similar values to those reported using other methods (10's-100's ng/mg tissue). Whereas the PS-MOE oligonucleotide was highly stable, the conjugates were heavily metabolized in vivo, particularly the amide linkage of ORNst, which was unexpected given its common use in drug conjugates (67)(68)(69). This metabolism likely occurred after clearance from circulation, since amide cleavage was not observed in the mouse plasma assay.…”

Section: Discussionmentioning

confidence: 99%

Delivery of oligonucleotides to bone marrow to modulate ferrochelatase splicing in a mouse model of Erythropoietic Protoporphyria

Halloy

Iyer

Ćwiek

et al. 2020

Preprint

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ABSTRACTErythropoietic protoporphyria (EPP) is a rare genetic disease in which patients experience acute phototoxic reactions after sunlight exposure. It is caused by a deficiency in ferrochelatase (FECH) in the heme biosynthesis pathway. Most patients exhibit a loss-of-function mutation in trans to an allele bearing a SNP that favours aberrant splicing of transcripts. One viable strategy for EPP is to deploy splice-switching oligonucleotides (SSOs) to increase FECH synthesis, whereby an increase of a few percent would provide therapeutic benefit. However, successful application of SSOs in bone marrow cells is not described. Here, we show that SSOs comprising methoxyethyl-chemistry increase FECH levels in cells. We conjugated one SSO to three prototypical targeting groups and administered them to a mouse model of EPP in order to study their biodistribution, their metabolic stability and their FECH splice-switching ability. The SSOs exhibited distinct distribution profiles, with increased accumulation in liver, kidney, bone marrow and lung. However, they also underwent substantial metabolism, mainly at their linker groups. An SSO bearing a cholesteryl group increased levels of correctly spliced FECH transcript by 80% in the bone marrow. The results provide a promising approach to treat EPP and other disorders originating from splicing dysregulation in the bone marrow.

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Section: Discussionmentioning

confidence: 99%

Delivery of oligonucleotides to bone marrow to modulate ferrochelatase splicing in a mouse model of Erythropoietic Protoporphyria

Halloy

Iyer

Ćwiek

et al. 2020

Preprint

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“…Givosiran was developed for the treatment of acute hepatic porphyria in adults, which is a genetic disorder that results in the accumulation of the neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG) during the hemes production cycle (the hemoglobin oxygen binding site) in hepatic cells. This disorder causes severe abdominal pain, nausea, vomiting, and constipation and it can be triggered by several factors, such as certain drugs, low sugar intake due to fasting, smoking, and stress [18,19].…”

Section: Givosiran (Givlaari Tm )mentioning

confidence: 99%

“…The N-acetylgalactosamine ligand bound to the sense strand facilitates the uptake into liver cells [19]. After entering hepatocytes, it binds to and silences aminolevulinate synthase 1 (ALAS1) mRNA, thereby halting ALA production and consequently preventing the accumulation of the toxic intermediates in body tissues [18].…”

Section: Givosiran (Givlaari Tm )mentioning

confidence: 99%

“…Givosiran is administered subcutaneously and is well-tolerated. However, regular check-ups for liver and kidney function are highly recommended [19]. It was developed by Alnylam Pharmaceuticals Inc. (Cambridge, Massachusetts, United States) (the same company that developed patisiran) and approved by the FDA on 20 November 2019 [20].…”

Section: Givosiran (Givlaari Tm )mentioning

confidence: 99%

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2019 FDA TIDES (Peptides and Oligonucleotides) Harvest

et al. 2020

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2019 has been an excellent year in terms of peptides and oligonucleotides (TIDES) approved by the FDA. Despite the drop in the number of total drugs approved by the FDA in 2019 in comparison with 2018 (48 vs. 59), the total number of TIDES authorized increased (seven vs. three). Year after year, TIDES are increasingly present in therapy, as imaging agents, theragnostic and constituent moieties of other complex drugs, such as antibody drug conjugates. This means a consolidation of these kinds of drugs in the pharmaceutical arena, paving the way in the coming years for the approval of others for diverse medical indications. Here the TIDES approved in 2019 are analyzed in terms of chemical structure, medical target, mode of action, and adverse effects.

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“…RNAi is critical in this application because siRNA 10 can be designed to have selective complementarity with MMP13, obviating the enzyme selectivity 11 concerns associated with small molecule inhibitors. The clinical utility of siRNA medicines has 12 been validated by the recent clinical trial success and FDA approval of both Alnylam's 13 ONPATTRO™ (patisiran) for treatment of hereditary transthyretin-mediated amyloidosis and 14 GIVLAARI™ (givosiran) for acute hepatic porphyria (32,33). Here, we extended polymeric 15 siRNA nanopolyplexes (siNPs) recently innovated by our research group (34)(35)(36)(37) to develop the 16 first targeted form of this carrier that binds to sites of early OA cartilage damage using a collagen 17 type 2 monoclonal antibody (mAbCII).…”

mentioning

confidence: 99%

Matrix-targeted Nanoparticles for MMP13 RNA Interference Blocks Post-Traumatic Osteoarthritis

Yuan

Liu

et al. 2020

Preprint

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1Osteoarthritis (OA) is a debilitating and prevalent chronic disease, but there are no 2 approved disease modifying OA drugs (DMOADs), only pharmaceuticals for pain management. 3 OA progression, particularly for post-traumatic osteoarthritis (PTOA), is associated with 4 inflammation and enzymatic degradation of the extracellular matrix. In particular, Matrix 5Metalloproteinase 13 (MMP13) breaks down collagen type 2 (CII), a key structural component of 6 cartilage extracellular matrix, and consequently, matrix degradation fragments perpetuate 7 inflammation and a degenerative cycle that leads to progressive joint pathology. Here, we tested 8 targeted delivery of endosome-escaping, MMP13 RNA interference (RNAi) nanoparticles (NPs) 9 as a DMOAD. The new targeting approach pursued here deviates from the convention of targeting 10 specific cell types (e.g., through cell surface receptors) and instead leverages a monoclonal 11 antibody (mAbCII) that targets extracellular CII that becomes uniquely accessible at early OA 12 focal defects. Targeted mAbCII-siNPs create an in situ NP depot for retention and potent activity 13 within OA joints. The mAbCII-siNPs loaded with MMP13 siRNA (mAbCII-siNP/siMMP13) 14 potently suppressed MMP13 expression (95% silencing) in TNFa-stimulated chondrocytes in 15 vitro, and the targeted mAbCII-siNPs had higher binding to trypsin-damaged porcine cartilage 16 than untargeted control NPs. In an acute mechanical injury mouse model of PTOA, mAbCII-17 siNP/siMMP13 achieved 80% reduction in MMP13 expression (p = 0.00231), whereas a non-18 targeted control achieved only 55% silencing. In a more severe, PTOA model, weekly mAbCII-19 siNP/siMMP13 long-term treatment provided significant protection of cartilage integrity (0.45+/-20 .3 vs 1.6+/-.5 on the OARSI scale; p=0.0166), and overall joint structure (1.3+/-.6 vs 2.8+/-.2 on 21 the Degenerative Joint Disease scale; p<0.05). Intra-articular mAbCII-siNPs better protected 22 articular cartilage (OARSI score) relative to either single or weekly treatment with the clinical gold 23 Abstract Figure: PTOA targeted delivery of MMP13 siRNA to block disease progression.

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Leading RNA Interference Therapeutics Part 2: Silencing Delta-Aminolevulinic Acid Synthase 1, with a Focus on Givosiran

Cited by 61 publications

References 37 publications

Delivery of oligonucleotides to bone marrow to modulate ferrochelatase splicing in a mouse model of Erythropoietic Protoporphyria

Delivery of oligonucleotides to bone marrow to modulate ferrochelatase splicing in a mouse model of Erythropoietic Protoporphyria

2019 FDA TIDES (Peptides and Oligonucleotides) Harvest

Matrix-targeted Nanoparticles for MMP13 RNA Interference Blocks Post-Traumatic Osteoarthritis

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