Inotersen for the Treatment of Hereditary Transthyretin Amyloidosis

Mahfouz, Maria; Maruyama, Rika; Yokota, Toshifumi

doi:10.1007/978-1-0716-0771-8_6

Cited by 13 publications

(11 citation statements)

References 27 publications

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“…These mutations disrupt the TTR tetramer leading to aggregation of TTR monomers into amyloid deposits throughout the body [ 112 ]. In order to combat the buildup of TTR, inotersen targets the 3′ UTR of the TTR mRNA, preventing the production of TTR, thus inhibiting disease progression [ 113 ]. Clinical trials demonstrated the efficacy and safety of inotersen in the reduction of circulating TTR levels [ 18 ].…”

Section: Rna Therapeuticsmentioning

confidence: 99%

Current Advances in RNA Therapeutics for Human Diseases

Zogg

Singh

2022

IJMS

100

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Following the discovery of nucleic acids by Friedrich Miescher in 1868, DNA and RNA were recognized as the genetic code containing the necessary information for proper cell functioning. In the years following these discoveries, vast knowledge of the seemingly endless roles of RNA have become better understood. Additionally, many new types of RNAs were discovered that seemed to have no coding properties (non-coding RNAs), such as microRNAs (miRNAs). The discovery of these new RNAs created a new avenue for treating various human diseases. However, RNA is relatively unstable and is degraded fairly rapidly once administered; this has led to the development of novel delivery mechanisms, such as nanoparticles to increase stability as well as to prevent off-target effects of these molecules. Current advances in RNA-based therapies have substantial promise in treating and preventing many human diseases and disorders through fixing the pathology instead of merely treating the symptomology similarly to traditional therapeutics. Although many RNA therapeutics have made it to clinical trials, only a few have been FDA approved thus far. Additionally, the results of clinical trials for RNA therapeutics have been ambivalent to date, with some studies demonstrating potent efficacy, whereas others have limited effectiveness and/or toxicity. Momentum is building in the clinic for RNA therapeutics; future clinical care of human diseases will likely comprise promising RNA therapeutics. This review focuses on the current advances of RNA therapeutics and addresses current challenges with their development.

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Section: Rna Therapeuticsmentioning

confidence: 99%

Current Advances in RNA Therapeutics for Human Diseases

Zogg

Singh

2022

IJMS

100

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“…Mipomersen, a PS/2′-MOE/m 5 C modified gapmer targeting apo-B-100 mRNA, is used to treat familial hypercholesterolemia (FH) by reducing the plasma LDL-cholesterol levels [ 87 ]. Inotersen, a PS/2′-MOE 20-mer gapmer, was approved to treat hereditary Transthyretin Amyloidosis (hATTR), a fatal disease [ 88 ]. By degrading transthyretin mRNA via RNase-H degradation, it prevents the formation of deposits of transthyretin amyloid protein in the peripheral nervous system that would be toxic for the body.…”

Section: Antisense Mechanisms: Gapmers Sirnas and Splice-modulating Oligonucleotidesmentioning

confidence: 99%

From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies

Adachi

Hengesbach

et al. 2021

Biomedicines

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Therapeutic oligonucleotides interact with a target RNA via Watson-Crick complementarity, affecting RNA-processing reactions such as mRNA degradation, pre-mRNA splicing, or mRNA translation. Since they were proposed decades ago, several have been approved for clinical use to correct genetic mutations. Three types of mechanisms of action (MoA) have emerged: RNase H-dependent degradation of mRNA directed by short chimeric antisense oligonucleotides (gapmers), correction of splicing defects via splice-modulation oligonucleotides, and interference of gene expression via short interfering RNAs (siRNAs). These antisense-based mechanisms can tackle several genetic disorders in a gene-specific manner, primarily by gene downregulation (gapmers and siRNAs) or splicing defects correction (exon-skipping oligos). Still, the challenge remains for the repair at the single-nucleotide level. The emerging field of epitranscriptomics and RNA modifications shows the enormous possibilities for recoding the transcriptome and repairing genetic mutations with high specificity while harnessing endogenously expressed RNA processing machinery. Some of these techniques have been proposed as alternatives to CRISPR-based technologies, where the exogenous gene-editing machinery needs to be delivered and expressed in the human cells to generate permanent (DNA) changes with unknown consequences. Here, we review the current FDA-approved antisense MoA (emphasizing some enabling technologies that contributed to their success) and three novel modalities based on post-transcriptional RNA modifications with therapeutic potential, including ADAR (Adenosine deaminases acting on RNA)-mediated RNA editing, targeted pseudouridylation, and 2′-O-methylation.

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“…It affects different organs with the deposition of amyloid fibrils, leading primarily to peripheral nervous system impairment and cardiac involvement, formerly known as familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy (FAC) 7 . Therapeutic approaches for hATTR include (a) liver transplantation, reducing variant TTR production since most such production takes place in the liver, (b) tetramer stabilizing agents, preventing TTR fibril formation, and (c) TTR gene silencing agents, ending the production of the mutant and wild‐type forms of TTR 8–10 …”

Section: Introductionmentioning

confidence: 99%

Treatment of acquired transthyretin amyloidosis in domino liver transplantation

Tsamis

Mytilinaios²,

Heneghan

et al. 2022

Clinical Transplantation

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Background: Domino liver transplantation (DLT) has been commonly used during the last two decades to partly meet the high need for liver transplants. However, the recipients of grafts from patients with noncirrhotic inherited metabolic disorders may ultimately develop metabolic syndrome, and management is usually intricate, being complicated by the underlying initial disorder, other comorbidities, and post-transplantation conditions. Case:We report here the management and the outcome in a patient with acquired transthyretin amyloidosis after DLT and significant comorbidities. Final treatment with a transthyretin gene silencing agent, patisiran, was well tolerated and resulted in remission of the aggravating neurological deficits in a follow-up period of 2 years. Conclusions:The case presented here supports the concept that patisiran can target the hepatocytes producing the mutated transthyretin in acquired transthyretin amyloidosis, as efficiently as in hereditary transthyretin amyloidosis (hATTR), and can be used to treat patients with transthyretin amyloidosis after DLT.

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Inotersen for the Treatment of Hereditary Transthyretin Amyloidosis

Cited by 13 publications

References 27 publications

Current Advances in RNA Therapeutics for Human Diseases

Current Advances in RNA Therapeutics for Human Diseases

From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies

Treatment of acquired transthyretin amyloidosis in domino liver transplantation

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