Inhomogeneous Diastereomeric Composition of Mongersen Antisense Phosphorothioate Oligonucleotide Preparations and Related Pharmacological Activity Impairment

Mongersen is a 21-mer antisense oligonucleotide designed to downregulate Mothers against decapentaplegic homolog 7 (SMAD7) expression to treat Crohn's disease. Mongersen was manufactured in numerous batches at different scales during several years of clinical development, which all appeared identical, using common physicochemical analytical techniques, while only phosphorous-31 nuclear magnetic resonance (P-31-NMR) in solution showed marked differences. Close-up analysis of 27 mongersen batches revealed marked differences in SMAD7 downregulation in a cell-based assay. Principal component analysis of P-31-NMR profiles showed strong correlation with SMAD7 downregulation and, therefore, with pharmacological efficacy in vitro. Mongersen contains 20 phosphorothioate (PS) linkages, whose chirality (Rp/Sp) was not controlled during manufacturing. A different diastereomeric composition throughout batches would lead to superimposable analytical data, but to distinct P-31-NMR profiles, as indeed we found. We tentatively suggest that this may be the origin of different biological activity. As similar manifolds are expected for other PS-based oligonucleotides, the protocol described here provides a general method to identify PS chirality issues and a chemometric tool to score each preparation for this elusive feature

Scenari di romanizzazione a Nora: un deposito di fondazione e un deposito votivo per la costituzione della provincia Sardinia et Corsica

Il contributo prende in esame l'eccezionale ritrovamento di 18 monete d'argento e di una maschera fittile durante lo scavo di uno degli ambienti laterali del cd. Tempio romano di Nora in Sardegna. Si tratta quasi certamente di un deposito votivo dell'ultimo quarto del III secolo interrato al momento della costituzione della Provincia di Sardinia et Corsica (225 a.C.) e poi riutilizzato al momento della ristrutturazione del complesso sacro nel corso della prima et\ue0 imperiale. Le monete sono emesse a Roma e in Italia (Magna Grecia) tra la met\ue0 del IV sec. a.C. e il 225 a.C. e costituiscono il pi\uf9 nutrito gruzzolo ad oggi recuperato in Sardegna. Nel contributo \ue8 considerata e valutata anche la presenza della maschera fittile antropomorfa, studiata dal coautore G. Falezza, che trova riferimenti e paralleli in contesti sacri medioitalici e sardi nel periodo compreso tra IV e III sec. a.C

All\u2019alba della citt\ue0 romana: il deposito votivo del Tempio romano di Nora

Abstract: The paper deals with the discovery of 18 silver coins and an anthropomorphic clay slab recovered in 2008 during the excavation of the Roman Temple of Nora by the University of Padua. The precious finds were brought to light in the layers of restructuring of the sanctuary operated in the Roman imperial age (III century AD). The same area of the discovery was already occupied by a first building of probable sacred character, built in the Archaic age, and by a second valuable building, built between 260 and 240 BC. The production of the slab is placed in the III century BC and the formation of the hoard, consisting of the most ancient Greek and Roman coins found in Sardinia, can be placed between the years 230- 225 BC. Various elements and clues lead us to hypothesize that the coins and the mask were donated in the new sacred building in these crucial years for the history of the island. Indeed the evidence generates some reflections on the possible relationship between the votive offers and the contemporary constitution of the provincia of Sardinia et Corsica, as on the role of Nora in the Roman expansionist policy in Sardinia