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Advanced therapy medicinal products (ATMPs) have a massive potential to address existing unmet medical needs. Specifically, gene therapy medicinal products (GTMPs) may potentially provide cure for several genetic diseases. In Europe, the ATMP regulation was fully implemented in 2009 and, at this point, the Committee for Advanced Therapies was created as a dedicated group of specialists to evaluate medicinal products requiring specific expertise in this area. To date, there are three authorized GTMPs, and the first one was approved in 2012. Broad research has been conducted in this field over the last few decades and different clinical applications are being investigated worldwide, using different strategies that range from direct gene replacement or addition to more complex pathways such as specific gene editing or RNA targeting. Important safety risks, limited efficacy, manufacturing hurdles, or ethical conflicts may represent challenges in the success of a candidate GTMP. During the development process, it is fundamental to take such aspects into account and establish overcoming strategies. This article reviews the current European legal framework of ATMPs, provides an overview of the clinical applications for approved and investigational GTMPs, and discusses critical challenges in the development of GTMPs.

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Herein we demonstrate for the first time that a boron promoted one-pot assembly reaction may be used to discover novel enzyme inhibitors. Inhibitors for HNE were simply assembled in excellent yields, high diastereoselectivities and IC50 up to 1.10 μM, based on components like salicylaldehyde, aryl boronic acids and amino acids. The combination of synthetic, biochemical, analytical and theoretical studies allowed the identification of the 4-methoxy or the 4-diethyl amino substituent of the salicylaldehyde as the most important recognition moiety and the imine alkylation, lactone ring opening as key events in the mechanism of inhibition.

BackgroundGene therapies have the potential to be a curative approach to a large number of genetic diseases. However, granting of a positive marketing authorisation does not equal patient access to therapy.ObjectivesThe purpose of this paper is to identify a full set of hurdles potentially preventing patient access to gene therapies based on the available literature.MethodsA review of the literature using systematic approach in two distinct databases was performed by identifying relevant, peer-reviewed publications, between 2012 and 2018.ResultsSeven major topics were identified as potential patient access hurdles, namely affordability, assessment of value, development of therapy, ethical/social factors, evidence generation, operational implementation and regulatory hurdles. From these, 25 additional subthemes were further identified. The most frequently mentioned obstacle in the literature is related to the affordability aspect especially focusing on high cost of therapy (84%) and therapy payment/reimbursement (51%). Importantly, the evidence generation focusing on limited trial outcomes (81%) seems as a strong obstacle in patient access to these therapies.ConclusionsA growing number of gene therapies are expected to be developed and made available to patients and healthcare professionals. Improvement of patient access to gene therapies can only be achieved by understanding all hurdles, in a complete and integrated fashion, so that strategies are timely established to ensure gene therapies’ benefits are provided to patients and to the society.

The therapeutic effects of human mesenchymal stromal cells (MSC) have been attributed mostly to their paracrine activity, exerted through small-secreted extracellular vesicles (EVs) rather than their engraftment into injured tissues. Currently, the production of MSC-derived EVs (MSC-EVs) is performed in laborious static culture systems with limited manufacturing capacity using serum-containing media. In this work, a serum-/xenogeneic-free microcarrier-based culture system was successfully established for bone marrow-derived MSC cultivation and MSC-EV production using a 2 L-scale controlled stirred tank reactor (STR) operated under fed-batch (FB) or fed-batch combined with continuous perfusion (FB/CP). Overall, maximal cell numbers of (3.0±0.12)×10 and (5.3±0.32)×10 were attained at days 8 and 12 for FB and FB/CP cultures, respectively, and MSC(M) expanded under both conditions retained their immunophenotype. MSC-EVs were identified in the conditioned medium collected from all STR cultures by TEM, and EV protein markers were successfully identified by WB analysis. Overall, no significant differences were observed between EVs isolated from MSC expanded in STR operated under the two feeding approaches. EV mean sizes of 163±5.27 nm and 162±4.44 nm (P>0.05) and concentrations of (2.4±0.35)x10 EVs/mL and (3.0±0.48)x10 EVs/mL (P>0.05) were estimated by nanoparticle tracking analysis for FB and FB/CP cultures, respectively. The STR-based platform optimized herein represents a major contribution towards the development of human MSC- and MSC-EV-based products as promising therapeutic agents for Regenerative Medicine settings.

MONTALBANO, F.; CAL, P. M. S. D.; CARVALHO, M. A. B. R.; GONCALVES, L. M.; LUCAS, S. D.; GUEDES, R. C.; VEIROS, L. F.; MOREIRA, R.; GOIS*, P. M. P.; Org. Biomol. Chem. 11 (2013) 27, 4465-4472, http://dx.doi.org/10.1039/c3ob40614h ; Fac. Farm., Univ. Lisboa, P-1649 Lisboa, Port.; Eng.) -U. Scheffler 43-185

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