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      RNA-based drugs and regulation: Toward a necessary evolution of the definitions issued from the European union legislation

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          Abstract

          Many RNA-based drugs, both vaccines and non-vaccines, are under development or even approved. They include coding mRNAs and non-coding (nc) RNAs among them antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), micro-RNAs (miRNAs), small activating RNAs (saRNAs), RNA aptamers and RNA guides. According to the European Union (EU) legislation, these products can be currently categorized into different regulatory statuses, depending, for vaccines, on their target (infectious disease or not) and, for other drugs, on how they are obtained (chemically or biologically). This classification is fundamental to the type of marketing authorization (MA), and therefore to the controls to be performed, from preclinical stages through clinical trials to pharmacovigilance, to meet the safety requirements for patients. However, the current rules raise several problems, in particular the risk, because technology is evolving, to have similar RNA drugs being covered by very different legal statuses and the lack of international harmonization. The objectives of this study are (i) to review how RNA medicinal products are currently legally categorized in the EU and especially whether they fall under the status of gene therapy medicinal products (GTMP), a regulatory status belonging to advanced therapy medicinal products (ATMP), (ii) to discuss the issues generated by this classification, with a focus on the heterogeneity of statuses of these products, the differences with the American and ICH definitions and the potential impact on the safety requirements.

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          Most cited references51

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          Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer

          T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome vaccines and implemented an RNA-based poly-neo-epitope approach to mobilize immunity against a spectrum of cancer mutations. Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient. All patients developed T cell responses against multiple vaccine neo-epitopes at up to high single-digit percentages. Vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumour cells were shown in post-vaccination resected metastases from two patients. The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival. Two of the five patients with metastatic disease experienced vaccine-related objective responses. One of these patients had a late relapse owing to outgrowth of β2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to vaccination in combination with PD-1 blockade therapy. Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalized immunotherapy for patients with cancer.
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            mRNA-based therapeutics--developing a new class of drugs.

            In vitro transcribed (IVT) mRNA has recently come into focus as a potential new drug class to deliver genetic information. Such synthetic mRNA can be engineered to transiently express proteins by structurally resembling natural mRNA. Advances in addressing the inherent challenges of this drug class, particularly related to controlling the translational efficacy and immunogenicity of the IVTmRNA, provide the basis for a broad range of potential applications. mRNA-based cancer immunotherapies and infectious disease vaccines have entered clinical development. Meanwhile, emerging novel approaches include in vivo delivery of IVT mRNA to replace or supplement proteins, IVT mRNA-based generation of pluripotent stem cells and genome engineering using IVT mRNA-encoded designer nucleases. This Review provides a comprehensive overview of the current state of mRNA-based drug technologies and their applications, and discusses the key challenges and opportunities in developing these into a new class of drugs.
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              CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

              Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR.

                Author and article information

                Contributors
                Journal
                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                2296-858X
                17 October 2022
                2022
                : 9
                : 1012497
                Affiliations
                [1] 1CREDIMI Laboratory EA 7532 and Laboratory of Excellence LipSTIC ANR-11-LABX-0021, Faculty of Health Sciences (Pharmacy), University of Burgundy , Dijon, France
                [2] 2UMR INSERM/uB/AGROSUP 1231, Team 3 HSP-Pathies, Labelled Ligue Nationale Contre le Cancer and Laboratory of Excellence LipSTIC ANR-11-LABX-0021, Faculty of Health Sciences (Pharmacy), University of Burgundy , Dijon, France
                Author notes

                Edited by: Violeta Stoyanova-Beninska, Medicines Evaluation Board, Netherlands

                Reviewed by: Marcel Hoefnagel, Medicines Evaluation Board, Netherlands; Sandor Kerpel-Fronius, Semmelweis University, Hungary

                *Correspondence: Mathieu Guerriaud, mathieu.guerriaud@ 123456u-bourgogne.fr

                These authors have contributed equally to this work

                This article was submitted to Regulatory Science, a section of the journal Frontiers in Medicine

                Article
                10.3389/fmed.2022.1012497
                9618588
                36325384
                ad835467-4237-480a-bc83-a098f7c5b87b
                Copyright © 2022 Guerriaud and Kohli.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 05 August 2022
                : 26 September 2022
                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 70, Pages: 14, Words: 8808
                Funding
                Funded by: Université de Bourgogne, doi 10.13039/501100004618;
                Categories
                Medicine
                Policy and Practice Reviews

                rna-based drugs,mrna vaccines,gene therapy medicinal products (gtmp),advanced therapy medicinal products (atmp),biological medicinal products,ema,fda,ich

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