Accessibility
This is the culmination of 15 years of improvements in the design, stability, safety, and delivery of synthetic RNAi triggers. Pulmonary Aerosol Delivery of Let-7b microRNA Confers a Striking Inhibitory Effect on Lung Carcinogenesis through Targeting the Tumor Immune Microenvironment. 2021 May 4;6(3):e10215.
Patisiran (ALN-TTR02) is an RNAi therapeutic targeting transthyretin (TTR) in development for the treatment of TTR-mediated amyloidosis (ATTR), which is enabled by Tekmira's lipid nanoparticle (LNP) technology. In 2018, the FDA approval of Patisiran, a lipid nanoparticle (LNP) formulation. For example, we have elucidated the importance of nanoparticle elasticity on cell internalization and tumor accumulation, where we found that soft nanoparticles with a Young’s modulus of 45 kPa are able to enter cancer cells via a membrane fusion pathway that is different from the endocytotic pathway that is usually involved in nanoparticle entry into target cells. Corresponding author: Pieter R. Cullis, Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Near-complete misTTR removal from the diseased tissue is evident. Seven oligonucleotide-based drugs haven been approved (fomivirsen, mipomersen, defibrotide, eteplirsen, nusinersen, inotersen, and patisiran) for a variety of disease conditions, and many RNA drug candidates are in clinical trials [11]. 2021 Sep;8(17):e2100629. Thus, the studies with either mRNA or with LNPs suggest that lyophilization … 10 Patisiran/ONPATTRO lipid nanoparticles consist of (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino) butanoate (DLin-MC3 … Tekmira initiated a Phase I/II clinical trial of TKM-PLK1 for patients with gastrointestinal neuroendocrine tumors, adrenocortical carcinoma, and hepatocellular carcinoma.
Ionizable lipid nanoparticles (LNPs) are the most clinically advanced nano-delivery system for therapeutic nucleic acids. These developments have resulted in last year's approval of the first siRNA therapeutic, called Onpattro (patisiran), for treatment of hereditary amyloidogenic transthyretin (TTR) amyloidosis. RNA drugs can be a game changer in the crowded therapeutics space dominated by small molecules and protein biologics. Disclaimer, National Library of Medicine Found insideThe first FDA approval of an siRNA therapeutic based on an ionizable cationic lipid nanoparticle formulation (patisiran/ONPATTROTM, Alnylam Pharmaceuticals) occurred in August 2018 (Hoy 2018, Kulkarni et al. 2018). Hereditary transthyretin-mediated amyloidosis is caused by a mutation in transthyretin (TTR) gene resulting in misfolded TTR protein accumulating as amyloid fibrils. This choice likely is based more on business strategies than on scientific rationale. Each mL of concentrate contains 3.99 mg sodium. The AGO in the RISC enzymatically cleaves the target mRNA, leading to target gene knockdown. The membrane fusion pathway directly releases nucleic acid therapeutics into the cytoplasm of target cells and effectively circumvents endosomal entrapment [47]. Sallam MA, Prakash S, Kumbhojkar N, Shields CW 4th, Mitragotri S. Bioeng Transl Med. Prior clinical experiences indicate that delivery methods must balance pharmacokinetics, targeting selectivity and safety, with complexity in manufacturing and regulatory approval. ], the field of RNA has not progressed far. Nonetheless, in view of the advantage such drugs would offer to patients, I hope that in the era of personalized medicine, governments and regulatory agencies will pick up the ball and help both fund the development and facilitate the approval of unique drugs tailored to specific mutations. Starting with a slower rate of infusion over the first 15 minutes of infusion appeared to decrease the incidence of infusion reactions in the subjects.138 Transient increases in white blood cell counts, complement split products and some cytokines and chemokines were observed 24 hours after infusion in some patients but not correlated with reported adverse effects. Multiple classes of lncRNAs such as antisense RNAs (asRNAs), enhancer RNAs (eRNAs), long intergenic RNAs (lincRNAs), and pseudogenes have been identified [88]. 2021 Int. PLK1 LNP is designed to inhibit PLK1 expression, preventing the tumor cell from completing cell division, ultimately resulting in cell cycle arrest and death of the cancer cell. Recently, several therapeutic agents targeting various types of diseases have reached different stages of clinical trials (Table 2.1). Delivery strategies including cationic lipids [15], cationic liposomes [16], and cationic polymers [17] that can deliver the RNAi to cells but specifictargeting is still challenging. Epub 2018 Nov 27. About Tekmira. Found insideI Patisiran Transthyretin Lipid Transthyretin- Completed Alnylam (ALN- nanoparticle mediated amyloidosis Pharmaceuticals TTR02) NCT01559077 Patisiran (ALN- TTR02) Transthyretin Lipid nanoparticle Transthyretin- mediated amyloidosis II ... Delivering nucleic acid-based therapeutics to cells is an attractive approach to target the genetic cause of various diseases. Epub 2017 Apr 13. Review Lipid Nanoparticle Systems for Enabling Gene Therapies Pieter R. Cullis1 and Michael J. Hope2 1Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; 2Acuitas Therapeutics, Vancouver, BC V6T 1Z3, Canada Genetic drugs such as small interfering RNA (siRNA), mRNA, or plasmidDNAprovidepotential genetherapies totreatmost Although CRISPR gene editing nanomedicines are not yet in clinical use, they have shown promising therapeutic benefits in preclinical cancer gene inhibition studies [9,44,45].
In fact, inotersen and, Vita, Vita, Musumeci, Rodolico, & Messina, 2019, Special Issue: Advances in Drug Delivery Systems.
It contains several 2′ OMe modifications on the uridine nucleotides. The first-inhuman study was followed by a phase 2 study in hTTR polyneuropathy patients.138 Subjects were administered two doses of patisiran by intravenous infusions 3–4 weeks apart. 2018 Jun;28(3):146-157. doi: 10.1089/nat.2018.0721. • LNP is composed of ALN-18328, 2 novel lipid excipients (DLin-MC3-DMA and PEG2000-C-DMG) and 2 approved lipid … Patisiran/ONPATTRO is an siRNA-delivering lipid-based nanoparticle developed and marketed by Alnylam, for the silencing of a specific gene responsible for expression of transthyretin, which can cause hereditary transthyretin amyloidosis. Pharmaceutics. Patisiran in Patients With Hereditary Transthyretin-mediated Amyloidosis (hATTR Amyloidosis) Disease Progression Post-Liver Transplant. Bethesda, MD 20894, Help A randomized, double-blind placebo-controlled phase 3 study was recently completed in familial hTTR polyneuropathy patients (NCT01960348).139 Patients were infused with either 0.3 mg/kg patisiran or placebo (2:1) every 3 weeks for 18 months.
2021 Oct 4:102899. doi: 10.1016/j.jddst.2021.102899. Patisiran is a lipid nanoparticle formulation of ribonucleic acid interference (RNAi), which can reduce the production of TTR. Thus, circRNAs reduce mRNA degradation and allow the mRNAs to be translated. Furthermore, anti-miR and miRNA mimics, including miravirsen, SAR339375, cobomarsen, and MRG-201 are all currently in Phase II clinical trials (Table 1). Patisiran • Lipid nanoparticle (LNP) formulation of siRNA (ALN-18328), targeting reduction of hepatic production of wild type and mutant TTR. LNP formulations comprise several lipid components that can be adjusted to suit the specific application. Based on studies that led to givosiran, it seems that GalNAc-based siRNA delivery strategies have some important benefits over LNPs. Bookshelf These characteristics make lipid nanoparticles excellent candidates for nucleic acid delivery. 2021 Oct 8;13(10):1638. doi: 10.3390/pharmaceutics13101638. Greater than 80% reduction in plasma TTR protein was achieved at the highest dose tested (0.3 mg/kg q 3 weeks) and similar to the phase 1 experience, the effects lasted greater than 30 days after the last dose. Patisiran is an RNA interference (RNAi) therapeutic that targets both wt and mutant TTR mRNA, thereby reducing expression of all forms of TTR protein. Esmond & Chung, The Patent Landscape of siRNA Nanoparticle Delivery, 11 Nanotechnology Law & Business 15 (Spring 2014) 17 While Thermo Fisher (who acquired Dharmacon and its patent portfolio) is a prolific patent filer, they have focused their business …
M. Takahashi, ... J.J. Rossi, in Comprehensive Medicinal Chemistry III, 2017. lipid Careers. 2021 Nov;35(6):643-671. doi: 10.1007/s40259-021-00500-y. 2021 Jan;20(1):49-59. doi: 10.1016/S1474-4422(20)30368-9. The program represents the most clinically advanced application of Arbutus proprietary LNP delivery technology. PMC Patisiran is formulated in a lipid nanoparticle facilitating delivery to the liver, which is the primary site of TTR production [3, 20].
first proposed the use of genes for human genetic disease in 1972 (Friedmann & Roblin, 1972). 2020 Feb;24(1):49-59. doi: 10.1007/s40291-019-00434-w. Nucleic Acid Ther. A GalNac-conjugated, nonliposome siRNA is currently in development as a subcutaneously administered medicine.
Found inside – Page 238Unmodified siRNA is hydrophilic and needs to be transfected with cationic lipids or other types of nanoparticles to enter the cell ... Patisiran is an siRNA targeting TTR, formulated as lipid nanoparticles for delivery to hepatocytes. Patisiran in Patients With Hereditary Transthyretin-mediated Amyloidosis (hATTR Amyloidosis) Disease Progression Post-Liver Transplant. The dysregulated expression of ncRNAs (e.g., miRNAs and lncRNAs) has been linked to the development of COPD [17], and ncRNAs represent potentially novel targets for therapeutic interventions. Recent studies have also underscored the importance of circRNAs, once thought to be artefacts of aberrant RNA splicing, in various biological processes [82]. lncRNAs often exhibit tissue-specific and cell type-specific expression patterns. To facilitate hepatic drug targeting, ALN-18328 is formulated as a lipid nanoparticle (LNP) composed of four lipid excipients. Examples of currently evaluated new LNPs for siRNA clinical trial. miRNAs are small ncRNA molecules 19–25 nucleotides in size that mediate post-transcriptional silencing of multiple target genes which contain sequences usually located in the 3′ UTR complementary to the mRNA (Figure IA). Accessibility The role of helper lipids in the design of lipid nanoparticle technology for nucleic acid delivery PHOSPHOLIPID SYMPOSIUM September 14th, 2021 Dominik Witzigmann, PhD ... (patisiran) MC3 DSPC Cholesterol PEG-DMG siRNA mRNA-1273 SM-102 DSPC Cholesterol PEG-DMG 7 Schoenmaker, Witzigmann et al.
Patients were pretreated with glucocorticoids, acetaminophen, and antihistamines, and the slower initial infusion rate was utilized to minimize infusion reactions. transfection. Found inside – Page 355Patisiran consists of an siRNA encapsulated in a lipid nanoparticle. Following intravenous administration, the LNPs are opsonized by apolipoprotein E and are delivered to the liver through interaction with ApoE receptors expressed on ...
INTRODUCTION Onpattro™ (patisiran) is the first RNA interference therapeutic approved by the FDA and EMA.1, 2 The technology enabling the delivery of therapeutic short interfering RNA (siRNA) is based on lipid nanoparticles (LNP). Epub 2012 May 8. For instance, Alnylam Pharmaceuticals, Inc. teamed with Orsini Healthcare, a specialty pharmacy, in August 2018 to distribute ONPATTRO (patisiran) lipid complex injectable. While siRNA and mRNA candidates are the most abundant, dozens of other RNA therapeutic candidates have also entered clinical trials (Table 1). MesomiR-1, a TargomiR technology-based miRNA (miR)-16 mimic developed by EnGenIC, has shown encouraging results in mesothelioma and non-small cell lung cancer in multicenter Phase I trials [12]. Tekmira’s lead oncology product candidate, TKM-PLK1, targets polo-like kinase 1 (PLK1), a protein involved in tumor cell proliferation and a validated oncology target.
Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV, Tournev I, Schmidt HH, Coelho T, Berk JL, Lin KP, Vita G, Attarian S, Planté-Bordeneuve V, Mezei MM, Campistol JM, Buades J, Brannagan TH 3rd, Kim BJ, Oh J, Parman Y, Sekijima Y, Hawkins PN, Solomon SD, Polydefkis M, Dyck PJ, Gandhi PJ, Goyal S, Chen J, Strahs AL, Nochur SV, Sweetser MT, Garg PP, Vaishnaw AK, Gollob JA, Suhr OB. The primary endpoint of the study was also mNIS+7 with several secondary endpoints including quality of life, muscle strength, gait speed, nutritional status, and autonomic function. Would you like email updates of new search results? Prevention and treatment information (HHS). piRNAs are the largest class of small ncRNAs in animals, 21–31 nucleotides in size and are found in the genomic clusters comprising tens to thousands of piRNAs. ncRNAs comprise a diverse range of RNA species that vary in size, including rRNAs and tRNAs involved in mRNA translation, small nuclear (sn)RNAs and small nucleolar (sno)RNAs involved in RNA processing, and small ncRNAs (see later) involved in gene silencing [17]. In 2018, the FDA approval of Patisiran, a lipid nanoparticle (LNP) formulation. and the first small interfering RNA therapeutic to receive FDA approval, established LNPs as the premier technology for non-viral RNA delivery. During the clinical development of patisiran, the LNP delivery vehicle seemed by far the most advanced and suitable carrier for siRNA delivery in vivo. Acc Chem Res. Kristen AV, Ajroud-Driss S, Conceição I, Gorevic P, Kyriakides T, Obici L. Neurodegener Dis Manag. Additionally, miRNA also binds mRNA coding regions or intron–exon junctions to modulate target gene expression by either mRNA degradation or protein translation repression. Found inside – Page 667Finally, in 2018, the first drug based on RNAi, called patisiran, was approved by the US Food and Drug ... Medical researchers developed a lipid nanoparticle that delivers chemically synthesized small interfering RNAs (siRNAs) mainly to ... Found inside – Page 193Abraxan, is a protein nanoparticle which is used in cancer therapy with paclitaxel formulated as albumin bound ... In that respect, the lipid nanoparticles Onpattro (Patisiran) delivering siRNA for the silencing of a specific gene ... Found inside – Page 238The low surface charge due to low pKa translates to excellent tolerability of lipid nanoparticles. The ionizable lipid 1 ... This ionizable lipid excipient has a pKa of 6.44 and is used in patisiran formulation as shown in Figure 11.4. Found inside – Page 977.2 LIPID NANOSYSTEMS FOR NUCLEIC Worldwide, researchers have developed a variety of ACID DELIVERY IN CANCER non-viral delivery/vectors, including inorganic, lipid and polymer-assembled nanoparticles such as cationic lipids (Rehman, ... Found inside – Page 733From 2009, with advances made in the development of cationic lipid-based systemic nanocarrier technology, ... ALN-TTR02/patisiran and ALN-PCS are second-generation formulations of SNALP containing siRNA targeting TTR and PCSK9, ... The most common AE was mild to moderate infusion reactions which occurred in the 0.3 mg/kg dose group (~40%). Compared to the average catalytic misTTR destruction of IgMs in the blood of healthy humans, the lead IgM catabody (Cardizyme) selected by human B lymphocyte binding to an E-misTTR ETA displayed about 780-fold faster destruction rate. For efficient therapeutic siRNA delivery to hepatocytes, patisiran is critically dependent 33 on lipid nanoparticle (LNP) technology.