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Small Interfering RNA from the Lab Discovery to Patients' Recovery Small interfering RNA from the lab discovery to patients’ recovery Marie Caillaud, Mévidette El Madani, Liliane Massaad-Massade To cite this version: Marie Caillaud, Mévidette El Madani, Liliane Massaad-Massade. Small interfering RNA from the lab discovery to patients’ recovery. Journal of Controlled Release, Elsevier, 2020, 321, pp.616-628. 10.1016/j.jconrel.2020.02.032. hal-02988620 HAL Id: hal-02988620 https://hal.archives-ouvertes.fr/hal-02988620 Submitted on 19 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 1 Small interfering RNA from the lab discovery to patients’ recovery 2 3 Marie Caillaud1, Mévidette El Madani1 and, Liliane Massaad-Massade1* 4 5 1 Université Paris-Saclay, Inserm 1195, Bâtiment Gregory Pincus, 80 rue du Général Leclerc, 6 94276 Le Kremlin-Bicêtre, France 7 8 9 1 *: Correspondance to Liliane MASSADE, PhD, Université Paris-Saclay, Inserm 1195, 10 Bâtiment Gregory Pincus, 80 rue du Général Leclerc, 94276 Le Kremlin-Bicêtre, France 11 12 13 Key words : siRNA, delivery, nanotechnology, formulation, galenic, clinical studies 14 1 1 Abstract 2 In 1998, the RNA interference discovery by Fire and Mello revolutionized the scientific and 3 therapeutic world. They showed that small double-stranded RNAs, the siRNAs, were capable 4 of selectively silencing the expression of a targeted gene by degrading its mRNA. Very quickly, 5 it appeared that the use of this natural mechanism was an excellent way to develop new 6 therapeutics, due to its specificity at low doses. However, one major hurdle lies in the delivery 7 into the targeted cells, given that the different extracellular and intracellular barriers of the 8 organism coupled with the physico-chemical characteristics of siRNA do not allow an efficient 9 and safe administration. The development of nanotechnologies has made it possible to 10 counteract these hurdles by vectorizing the siRNA in a vector composed of cationic lipids or 11 polymers, or to chemically modify it by conjugation to a molecule. This has enabled the first 12 clinical developments of siRNAs to begin very quickly after their discovery, for the treatment 13 of various acquired or hereditary pathologies. In 2018, the first siRNA-containing drug was 14 approved by the FDA and the EMA for the treatment of an inherited metabolic disease, the 15 hereditary transthyretin amyloidosis. In this review, we discuss the different barriers to the 16 siRNA after systemic administration and how vectorization or chemical modifications lead to 17 avoid it. We describe some interesting clinical developments and finally, we present the future 18 perspectives. 19 20 2 1 Table of content 2 3 Introduction ................................................................................................................................ 4 4 I. Hurdles for systemic siRNA-based therapeutics ................................................................ 4 5 A. Obstacles due to intrinsic siRNA properties ................................................................... 4 6 B. Obstacles due to administration mode ............................................................................ 6 7 II. siRNA vectorization for systemic delivery ......................................................................... 9 8 A. Physical vectorization ..................................................................................................... 9 9 a) Lipid nanoparticles (LNP) ........................................................................................... 9 10 b) Polymeric nanocarriers .............................................................................................. 14 11 c) Common limits of lipidic- and polymeric- siRNA nanocarriers ............................... 17 12 B. Chemical modification : siRNA conjugates .................................................................. 19 13 a) Conjugation to cholesterol ......................................................................................... 20 14 b) Conjugation to galactose derivative .......................................................................... 21 15 c) Conjugation to aptamer ............................................................................................. 24 16 d) Common limits of siRNA bioconjugates ................................................................... 24 17 III. Therapeutic applications – overview of some clinical trials ......................................... 26 18 A. Lipid nanoparticles ........................................................................................................ 28 19 a) Lipoplex ..................................................................................................................... 28 20 b) SNALP ....................................................................................................................... 28 21 B. Polyplex ......................................................................................................................... 30 22 C. siRNA conjugates .......................................................................................................... 31 23 IV. What is next? ................................................................................................................. 33 24 Conclusion ................................................................................................................................ 35 25 Bibliography ............................................................................................................................. 36 26 27 3 1 Introduction 2 Since the RNA interference (RNAi) discovery, a new specific therapeutic approach for severe 3 diseases has emerged and brings new hope for patients [1, 2]. In 2001, Elbashir and Tushl have 4 already mentioned the possible use of small interfering RNA (siRNA) as “a new alternative to 5 antisense or ribozyme therapeutics” [3]. The design and synthesis facilities lead to several 6 research and development of siRNA drug [4]. 7 Indeed, nine years after Elbashir and Tushl discovery, the first RNAi evidence in human was 8 done by Davis et al. [5]. The authors reported that the systemic administration of targeted 9 nanoparticles of siRNA against M2 subunit of ribonucleotide reductase (RRM2) silence 10 efficiently the targeted gene [5]. In 2018, the first-ever siRNA has been approved by the FDA 11 (Food and Drug Administration) for the treatment of a severe neuropathy, the hereditary 12 transthyretin-mediated amyloidosis [6, 7]. Very recently, a second siRNA has been marketed 13 to cure an inherited rare hepatic disease after significant results in phase III clinical trial [8]. 14 Despite the fact that siRNA are specific and efficient at low doses, their highly hydrophilicity 15 and their short plasmatic half-life constitute the main hurdles for their systemic administration. 16 Therapeutic applications of siRNA require development of nanosized delivery carriers, named 17 as nanovector or nanoparticle (NPs), to protect oligonucleotides and improve pharmacokinetic 18 parameters. In this review, we describe the siRNA hurdles that must be overcome to exert its 19 effects. Then, different vectorization approaches and their limits to counteract the siRNA 20 barriers will be presented. Finally, we depict some interesting clinical studies and the future 21 challenges of the RNAi therapy. 22 I. Hurdles for systemic siRNA-based therapeutics 23 A. Obstacles due to intrinsic siRNA properties 24 The siRNA is a double-stranded RNA composed of 19-21 base pairs with 3’-cohesive ends [3, 25 9]. Antisense strand, also called guide strand, is fully complementary to a mRNA sequence of 4 1 a targeted gene and induces its specific degradation. The synthetic siRNA bypasses through 2 Dicer cleavage and is taken directly by the RNA-Induced Silencing Complex (RISC). The RISC 3 nuclease, Ago2, unwinds siRNA strands and degrades the sense strand. The guide strand 4 anneals with its complementary mRNA leading to its degradation and the silencing of the 5 targeted gene [1, 10]. The activated RISC complex (with antisense strand included) can move 6 on, to degrade additional targeted mRNA, allowing a transient gene silencing for 3-7 days in 7 rapidly dividing cells and, for several weeks, in slowly dividing cells [11, 12]. 8 The siRNA administration aims to deliver it from the injection point to the cytosol of targeted 9 cells in enough quantities, to be able to inhibit the targeted gene expression. Unfortunately, 10 some intrinsic characteristics do not help to reach this aim. Indeed once in the blood, naked 11 siRNA are degraded by nucleases into shortened oligonucleotides then, eliminated by 12 glomerular filtration, leading to a very short blood half-life (less than 15mins) [13-15]. 13 Moreover, the siRNA is of high molecular weight (13kDa), hydrophilic and polyanionic thus 14 preventing a good cellular uptake. It can also stimulate the immune system by sequence- 15 dependent manner TLR-activation [1]. Several immune-stimulatory sequence patterns have 16
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