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Antisense oligonucleotides (ASO) therapeutics hold great promise for the treatment of numerous diseases, and several ASO drugs have now reached market approval, confirming the potential of this approach. However, some candidates have also failed, due to limited biodistribution/uptake and poor safety profile. In pursuit of better delivery and higher cellular uptake, ASO are being optimized, and new chemistries are developed or conjugated with various ligands. While these developments may lead to candidates with higher potency, it is important to keep the safety aspects in sight and screen for potential toxicity in early phases of preclinical development to avoid subsequent failure in clinical development. Our understanding of ASO-mediated toxicity keeps improving with increased preclinical and clinical data available. In this chapter, we will focus on the assessment of renal toxicity in mice and describe methods to measure the levels of general urinary biomarkers as well as acute kidney injury biomarkers following ASO treatment.

There is no competing financial interest in this research. This research has not received external funding from public or private entities, nor do any of its authors have a personal financial interest in them or any family member or institutional affiliation. Furthermore, none of the authors has received grants or any forms of compensation (travel funding, consultancies, board position, patents, royalty arrangement, stock share or bonds). None of the authors has been nominated for relevant employment or received remuneration for being an expert witness or providing testimony about this ongoing research. The APC was funded by PAIDI Group RNM-279 "Geografia Fisica y Territorio"., Climate change generates negative impacts on human health. However, little is known about specific impacts on eye diseases, especially in arid and semi-arid areas where increases in air temperatures are expected. Therefore, the main goals of this research are: (i) to highlight the association between common eye diseases and environmental factors; and (ii) to analyze, through the available literature, the health expenditure involved in combating these diseases and the savings from mitigating the environmental factors that aggravate them. Mixed methods were used to assess the cross-variables (environmental factors, eye diseases, health costs). Considering Southern Spain as an example, our results showed that areas with similar climatic conditions could increase eye diseases due to a sustained increase in temperatures and torrential rains, among other factors. We highlight that an increase in eye diseases in Southern Spain is conditioned by the effects of climate change by up to 36.5%; the economic burden of the main eye diseases, extrapolated to the rest of the country, would represent an annual burden of 0.7% of Spain’s Gross Domestic Product. In conclusion, the increase in eye diseases has a strong economic and social impact that could be reduced with proper management of the effects of climate change. We propose a new concept: disease sink, defined as any climate change mitigation action which reduces the incidence or morbidity of disease., PAIDI Group RNM-279

Objetivo: Describir que el ojo, ante procesos infecciosos sistémicos diversos que afectan a sus estructuras, tales como tuberculosis, infección por virus Ébola o sida (con sus infecciones oportunistas), una vez curado de su fase activa infecciosa reacciona de manera similar. Caso clínico: Presentamos el caso de una paciente que, tras ser tratada con éxito de tuberculosis ocular, desarrolló una coroiditis multifocal por hipersensibilidad retardada, de efectos potencialmente más devastadores que la propia infección activa, con inflamación coroidea y de vasos retinianos, papilitis y edema macular que, sin tratamiento, conduciría a una gran pérdida visual. Para su control, precisó corticoides sistémicos a corto plazo e inmunosupresores sistémicos de mantenimiento a largo plazo. Conclusiones: Las reacciones inflamatorias oculares por hipersensibilidad son más destructivas que la infección directa de diversos patógenos, ya que pueden generar una reacción inflamatoria basada en el reconocimiento del sistema inmunitario de restos antigénicos infecciosos en las estructuras oculares. Comprobar el control de la infección activa y posteriormente introducir corticoides sistémicos o inmunosupresores ahorradores de corticoides tiene efectos muy beneficiosos.

International audience; Scientific advance is based on reproducibility, corroboration, and availability of research results. However, large numbers of experimental results that contradict previous work do not get published and many research results are not freely available as they are hidden behind paywalls. As part of COST Action "DARTER", a network of researchers in the field of RNA therapeutics, we have performed a small survey among our members and their colleagues to assess their opinion on the subject of publishing contradictory or ambiguous results and their attitude to open access (OA) publishing. Our survey indicates that, although researchers highly value publication of "negative"results, they often do not publish their own, citing lack of time and the perception that those results may not be as highly cited. OA, on the other hand, seems to be widely accepted, but in many cases not actively sought by researchers due to higher costs associated with it.

International audience; Tricyclo-DNA (tcDNA) antisense oligonucleotides (ASOs) hold promise for therapeutic splice-switching applications and the treatment of Duchenne muscular dystrophy (DMD) in particular. We have previously reported the therapeutic potential of tcDNA-ASO in mouse models of DMD, highlighting their unique pharmaceutical properties and unprecedented uptake in many tissues after systemic delivery, including the heart and central nervous system. Following these encouraging results, we developed phosphorothioate (PS)-modified tcDNA-ASOs targeting the human dystrophin exon 51 (H51). Preliminary evaluation of H51 PS-tcDNA in mice resulted in unexpected acute toxicity following intravenous administration of the selected candidate. In vivo and in vitro assays revealed complement activation, prolonged coagulation times, and platelet activation, correlating with the observed toxicity. In this study, we identify a novel PS-tcDNA sequence-specific toxicity induced by the formation of homodimer-like structures and investigate the therapeutic potential of a detoxified PS-tcDNA targeting exon 51. Modification of the H51-PS-tcDNA sequence, while maintaining target specificity through wobble pairing, abolished the observed toxicity by preventing homodimer formation. The resulting detoxified wobble-tcDNA candidate did not affect coagulation or complement pathways any longer nor activated platelets in vitro and was well tolerated in vivo in mice, confirming the possibility to detoxify specific tcDNA-ASO candidates successfully.

Duchenne muscular dystrophy (DMD) is a fatal genetic disorder characterized by progressive muscle wasting that has currently no cure. Exon-skipping strategy represents one of the most promising therapeutic approaches that aim to restore expression of a shorter but functional dystrophin protein. The antisense field has remarkably progress over the last years with recent accelerated approval of the first antisense oligonucleotide-based therapy for DMD, Exondys 51, though the therapeutic benefit remains to be proved in patients. Despite clinical advances, the poor effective delivery to target all muscle remains the main hurdle for antisense drug therapy. This review describes the antisense-based exon-skipping approach for DMD, from proof-of-concept to first marketed drug. We discuss the main obstacles to achieve a successful exon-skipping therapy and the latest advances of the international community to develop more powerful chemistries and more sophisticated delivery systems in order to increase potency, bioavailability and safety. Finally, we highlight the importance of collaborative efforts and early dialogue between drug developers and regulatory agencies in order to overcome difficulties, find appropriate outcome markers and collect useful data.

Lo que no dice la antropología, de Sophie Caratini, fue publicado por primera vez en Francia en 2004. Más tarde, en 2012, vio la luz una edición actualizada y aumentada, que ha sido traducida al castellano por Inmaculada Jiménez Moll, y publicada en España en 2013.

Echevarria, Ferrández and Dallemagne analyse the politics of representation of two migrant minority media produced and distributed in Spain. They wonder if the alternative discourses on migrants made possible by their inclusion in the media sphere automatically implies a challenge to hegemonic discourses and structures. First, they analyse the representation of migrants as political actors. Second, they reflect on the construction of ethnic and cultural identities, and finally, they analyse gender representations. They conclude that migrant minority media bring about changes in the way the public sphere is understood and in the role migrants play in it. However, dominant regimes of representation reinforcing class, ethnic and gender structures can coexist with such innovations.

Translational accuracy depends on the correct formation of aminoacyl-tRNAs, which, in the majority of cases, are produced by specific aminoacyl-tRNA synthetases that ligate each amino acid to its cognate isoaceptor tRNA. Aminoacylation of tRNAGln, however, is performed by various mechanisms in different systems. Since no mitochondrial glutaminyl-tRNA synthetase has been identified to date in mammalian mitochondria, GlntRNAGln has to be formed by an indirect mechanism in the organelle. It has been demonstrated that human mitochondria contain a non-discriminating glutamyl-tRNA synthetase and the heterotrimeric enzyme GatCAB (where Gat is glutamyltRNAGln amidotransferase), which are able to catalyse the formation of Gln-tRNAGln in vitro. In the present paper we demonstrate that mgatA (mouse GatA) interference inmouse cells produces a strong defect in mitochondrial translation without affecting the stability of the newly synthesized proteins. As a result, interfered cells present an impairment of the oxidative phosphorylation system and a significant increase in ROS (reactive oxygen species) levels. MS analysis of mitochondrial proteins revealed no glutamic acid found in the position of glutamines, strongly suggesting that misaminoacylated GlutRNAGln is rejected from the translational apparatus to maintain the fidelity of mitochondrial protein synthesis in mammals., This work was supported by the Center for Biomedical Research on Rare Diseases (CIBERER), the Instituto de Salud Carlos III [grant numbers PI 07/0167 and PI 10/0703 (to R.G.)] and the Comunidad de Madrid [grant number S2010/BMD-2402 (to R.G.)]. L.E. was funded by the Ministerio de Ciencia e Innovación (Spain) and P.C. by the Comunidad de Madrid.

Cytochrome c oxidase (COX) or complex IV of the mitochondrial respiratory chain plays a fundamental role in energy production of aerobic cells. In humans, COX deficiency is the most frequent cause of mitochondrial encephalomyopathies. Human COX is composed of 13 subunits of dual genetic origin, whose assembly requires an increasing number of nuclear-encoded accessory proteins known as assembly factors. Here, we have identified and characterized human CCDC56, an 11.7-kDa mitochondrial transmembrane protein, as a new factor essential for COX biogenesis. CCDC56 shares sequence similarity with the yeast COX assembly factor Coa3 and was termed hCOA3. hCOA3-silenced cells display a severe COX functional alteration owing to a decreased stability of newly synthesized COX1 and an impairment in the holoenzyme assembly process. We show that hCOA3 physically interacts with both the mitochondrial translation machinery and COX structural subunits. We conclude that hCOA3 stabilizes COX1 co-translationally and promotes its assembly with COX partner subunits. Finally, our results identify hCOA3 as a new candidate when screening for genes responsible for mitochondrial diseases associated with COX deficiency.

ResumenPresentamos el caso de un ex toxicómano de 50 años que acudió a consulta de oftalmología con visión borrosa bilateral. En la anamnesis refería su desintoxicación 20 años atrás, con abstinencia total desde entonces y buena reinserción social. Su historia clínica reflejaba serología de hepatitis B+ y C+, pero VIH− y recientemente comenzó con esclerosis múltiple, controlada con interferón beta. Señalaba haber padecido últimamente un resfriado invernal prolongado.En la exploración oftalmológica se apreciaba una uveítis bilateral con precipitados queráticos. En funduscopia del ojo derecho destacaban múltiples granulomas coroideos y zonas de vasculitis periférica, activas y cicatriciales. La funduscopia del ojo izquierdo era normal.Tras diversas pruebas diagnósticas, como radiografía torácica y TAC pulmonar, se detectaron varios nódulos pulmonares. Asimismo, se realizó una prueba de Mantoux que resultó fuertemente positiva. La analítica mostraba neutropenia y linfopenia importantes. Por todo ello se hizo un diagnóstico de presunción de panuveítis secundaria a tuberculosis sistémica.Se administraron fármacos antituberculosos y corticoides sistémicos, con buena respuesta clínica sistémica y ocular.El interferón beta 1b es un inmunomodulador apropiado para la esclerosis múltiple, pero sus principales efectos secundarios son alteraciones analíticas como leucopenia, linfocitopenia y trombocitopenia.Los linfocitos CD4+ T, leucocitos, macrófagos y granulocitos, con la producción de sus mediadores interferón gamma, IL-12 o TNF-α son fundamentales para controlar al Mycobacterium tuberculosis. Por ello, antes de introducir Interferón beta 1b, convendría realizar técnicas de screening, como la prueba de Mantoux o el interferon gamma release assay–(quantiferon-TB) para detectar posibles tuberculosis latentes potencialmente activables.AbstractAn ex-drug addict 50 years-old man came to our hospital with bilateral blurred vision. The anamnesis revealed his detoxification 20 years ago, with complete drug abstinence since then and a good social reinsertion. His medical history showed a serology for Hepatitis B+ and C+ viruses, but it showed VIH−. Recently, he began to suffer multiple sclerosis disease, but it was well-controlled with interferon-beta. He also mentioned to have suffered a recent, prolonged winter cold.The ophthalmologic examination enables identification of bilateral uveitis with keratic precipitates. The right eye funduscopy revealed several choroidal granulomas, besides healed and actives peripheral vasculitis zones. The left eye funduscopy was normal.After several diagnostic tests as chest x-ray and pulmonary CAT scan, several pulmonary nodules were found. Also, it was carried out a Mantoux-test that was strongly positive. The blood analysis showed neutropenia and lymphopenia. Consequently, we proposed a presumptive diagnosis of panuveitis related to systemic tuberculosis.Anti-tuberculosis drugs and systemic corticoids were given, with a good clinical and ocular response.Interferon-beta 1b is a suitable immunomodulator for multiple sclerosis treatment, but its main secondary effects are blood abnormalities as leukopenia, lymphocytopenia and thrombocytopenia.CD4+ T lymphocytes, leukocytes, macrophages and granulocytes, furthermore the production of its mediators: interferon gamma, IL-12 or TNF-α, are essential to control Mycobacterium tuberculosis. Thus, before introduction of interferon-beta 1b, it would be advisable to attempt screening techniques, as Mantoux-test or interferon gamma release assay (quantiferon-TB) to detect probably latent tuberculosis, potentially likely to be active again.

ResumenLa retinosis pigmentaria unilateral es una patología relativamente infrecuente, no habiendo sido recogidos más de un centenar de casos en la bibliografía científica desde 1865. Por tanto, la asociación con foseta papilar es todavía más infrecuente, no quedando descartado un mecanismo intrínseco común.Presentamos el caso de una paciente de 66 años de edad, seguida desde el año 2000 en nuestro servicio, con una coincidencia de foseta papilar y retinosis pigmentaria unilateral en el mismo ojo. Como consecuencia de la foseta papilar desarrolló un proceso de desprendimiento seroso macular que no se reabsorbió espontáneamente y que acabó produciendo un agujero lamelar macular.Este tipo de complicaciones actualmente son en algunos casos tratadas con vitrectomía; sólo que la coincidencia en el mismo ojo de retinosis pigmentaria y foseta papilar hizo que se modificara la indicación terapéutica por la enorme degeneración y atrofia de la retina periférica de dicho ojo. Así, se optó finalmente por una fotocoagulación con láser de argón en el borde de la foseta papilar, consiguiendo una importante ganancia visual y evitando las variaciones visuales que a lo largo del día experimentaba la paciente, por haberse acumulado líquido en la mácula a lo largo de la noche, frenando el proceso de deterioro macular.AbstractUnilateral retinitis pigmentosa is a relatively rare disease: scientific research has not found more than one hundred cases since 1865. Therefore, this pathology in association with optic disc pit is increasingly rare; in this association it is possible to understand a common intrinsic mechanism.We show a 66-years-old woman monitored since 2000 by our service, with a unilateral retinitis pigmentosa and optic disc pit coincidence in the same eye. As a result of the optic disc pit she developed a serous macular detachment which was not naturally reabsorbed and which caused a lamellar macular hole.These complications are actually treated with vitrectomy in some cases; but the unilateral retinitis pigmentosa and optic disc pit coincidence in the same eye forced us to modify the therapeutic indication because of a wide degeneration and the atrophy of peripheral retina of that eye. Thus, we finally chose to apply argon laser photocoagulation in peripheral area of optic disc pit, achieving an important visual improvement and saving the patient from visual variation she used to suffer throughout the day because of a liquid accumulation in macula during the night. so her macular damage process stopped.