China
Africa
Explore chapters and articles related to this topic
Infiltrative Diseases
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Antisense oligonucleotides (ASOs) are short, synthetic RNAs that inhibit the translation of mRNA. Inotersen is an ASO that inhibits hepatic expression of TTR, suppressing both wild-type and mutant TTR. The NEURO-TTR trial demonstrated that, in hATTR polyneuropathy, subcutaneous injections of inotersen resulted in improvement in symptoms related to polyneuropathy.59 In a study of 22 patients with ATTR-CM, inotersen was associated with stabilization of the disease at 12 months, based on decreased left ventricular mass and improvement in 6-min walk test.60 Side effects for TTR silencers include rare infusion reactions for patisiran and glomerulonephritis, and thrombocytopenia for inotersen. FDA approved both patisiran and inotersen for hATTR polyneuropathy, with the caveat that platelets and renal function should be monitored weekly with inotersen. TTR silencers are not currently being approved for hATTR-CM without neuropathy.
Non-Viral Delivery of Genome-Editing Nucleases for Gene Therapy
Published in Yashwant Pathak, Gene Delivery, 2022
The siRNA based lipid vectors showed targeted delivery of siRNA to silence the target genes with a nanoparticle size of 200nm [64]. It was first discovered in 2005 to treat hepatitis B virus (HBV) in a mouse model HBV replication [65]. In two separate clinical trials, efficacy of LNP-based siRNA delivery has been evaluated in patients with hepatocellular carcinoma. Tekmira pharmaceuticals corporation investigated the antitumor activity of drug TKM-080301 targeted to suppress the polo-like kinase 1 (PLK1). On the other hand, Alnylam pharmaceuticals developed ALN-VSP02 to target KIF11 (which encodes kinesin spindle protein) and VEGF. In addition, ALN-TTR02 (Alnylam pharmaceuticals) based siRNA formulations are shown to have the ability of silencing the transthyretin (TTR) in TTR-mediated amyloidosis. Patisiran is a second-generation SNALP formulation ALN-TTR02, which is a DLinDMA analogue. In preclinical studies, it showed a tenfold increase in therapeutic activity [1, 66].
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Despite these problems, significant progress in the development of siRNAs for therapeutic use has been made in the last two decades, mainly by small biotech companies, the most notable being Alnylan Inc. In 2018 the FDA approved the first RNAi therapeutic, patisiran (OnpattroTM) developed by Alnylam Pharmaceuticals Inc to treat peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hATTR). Alnylam achieved further success in 2019 when the FDA approved the RNAi therapeutic givosiran (GivlaariTM) for the treatment of adults with acute hepatic porphyria (AHP), a family of rare genetic diseases caused by deficiencies in enzymes of the hem biosynthesis pathway in the liver.
Challenges with the discovery of RNA-based therapeutics for flaviviruses
Published in Expert Opinion on Drug Discovery, 2023
Mei-Yue Wang, Rong Zhao, Yu-Lan Wang, De-Ping Wang, Ji-Min Cao
RNA-based therapeutics represent a new class of antiviral therapeutics with a bright future and the potential to change the standard guidelines for disease treatment. The rapid development of RNA-based therapeutics has been propelled by technological advances in delivery, stability, and immunogenicity [101]. The first FDA-approved RNAi-based drug, patisiran, is a siRNA targeting the liver that is delivered by LNPs for the treatment of hereditary transthyretin amyloidosis with polyneuropathy. The approval of patisiran is a milestone in RNAi therapy [40]. Currently, 11 RNA-based therapeutics for various diseases, such as nusinersen for spinal muscular atrophy [102,103] and eteplirsen for Duchenne muscular dystrophy [71,104], have been approved by the FDA and/or the European Medicines Agency (EMA) [10]. Various RNA candidates are currently under development to address chronic, infectious, and genetic diseases. Thus, there is no doubt that the field of RNA therapeutics is currently undergoing a major expansion and will continue to develop rapidly over the next few years [9].
A comprehensive update of siRNA delivery design strategies for targeted and effective gene silencing in gene therapy and other applications
Published in Expert Opinion on Drug Discovery, 2023
Ahmed Khaled Abosalha, Waqar Ahmad, Jacqueline Boyajian, Paromita Islam, Merry Ghebretatios, Sabrina Schaly, Rahul Thareja, Karan Arora, Satya Prakash
Andrew Fire and Craig Mello were awarded the Nobel Prize in 2006 for their discovery of ‘RNA interference-gene silencing by a double-stranded RNA.’ This new theory represented an advanced technique of gene therapies to control numerous gene-associated diseases. The process of gene silencing describes the employment of a 21–25-nucleotide, double-stranded RNA molecule known as ‘siRNA’ to control the post-transcriptional regulation of the mRNA of the targeted gene. The siRNA duplex is composed of two strands: a sense strand (i.e. passenger) and an antisense strand (i.e. guide). The guide strand is complementary to the mRNA of the targeted gene so that this strand can easily recognize it [1,2]. Four siRNA therapies are present in the market after the approval of the FDA and regulatory agencies. Patisiran was approved in 2018 for the management of a rare genetic disorder termed ‘Hereditary Variant Transthyretin Amyloidosis’ [3]. Givosiran was authorized in 2019 for the treatment of acute hepatic porphyria [4]. In 2020, Lumasiran was the third accepted siRNA for controlling primary hyperoxaluria type 1 [5]. Recently, Inclisiran was approved for the treatment of hypercholesterolemia [6]. The delivery of these therapies was achieved by either encapsulating the siRNA into lipid nanocarriers such as liposomes (e.g. Patisiran) or through conjugation using N-acetylgalactosamine (e.g. Givosiran, Lumasiran, and Inclisiran) [7]. Currently, there are several other siRNA therapies at different phases of clinical trials including Vutrisiran, Nedosiran, Fitusiran, Cosdosiran, Tivanisiran, and Teprasiran.
Clinical pharmacology of siRNA therapeutics: current status and future prospects
Published in Expert Review of Clinical Pharmacology, 2022
Ahmed Khaled Abosalha, Jacqueline Boyajian, Waqar Ahmad, Paromita Islam, Merry Ghebretatios, Sabrina Schaly, Rahul Thareja, Karan Arora, Satya Prakash
According to patisiran full prescribing information by FDA, patisiran is administered via intravenous infusion at a dose of 0.3 mg/kg once every 3 weeks. The plasma concentration–time curve of patisiran exhibits a dose-dependent increase in the mean steady-state concentration and area under the curve (AUC), following its infusion. It takes about 6 months to reach the steady-state plasma concentration with a 3.2-fold AUC value as compared to the first dose. The estimated mean steady-state concentration and AUC are equal to 7.15 ± 2.14 µg/mL and 184 ± 159 µg.hr/mL, respectively. Patisiran is distributed principally to hepatocytes where the gene expression knockdown occurs with a volume of distribution equal to 0.26 ± 0.20 L/kg and a limited plasma protein binding (≤2.1%). It is metabolized mainly by the liver by endogenous endonucleases and shows a total body clearance of about 3.0 ± 2.5 mL/hr/kg. Less than 1% of the drug is excreted unchanged in the urine and the elimination half-life is 3.2 ± 1.8 days [119].