Informed Participation and Patient Empowerment: A Patient- Centered Approach to Improve Pediatric Clinical Research

Over the last years, a Europe-wide trend toward a patient-focused approach is developing and is influencing the decision-making process related to the clinical research. This new vision aims to draw on patient knowledge and experience in order to deliver benefits for all stakeholders of the drug development process, optimizing the clinical study design. In this context, the “patient empowerment” concept has been developed as an approach encouraging the active participation and self-determination of the patients in the caring procedure. For this reason, in 2016, European Patients’ Academy (EUPATI) launched a public consultation that ended in September 2016 with the release of the EUPATI guidance for patient involvement in the medicine research and development process. Likewise, the recommendations on the “Summaries of Clinical Trial Results for Laypersons” for the Implementation of Regulation (EU) No 536/2014 recommended a clear and comprehensible communication of the clinical trial results to the patients. However, rarely, all these attempts for the patient involvement pay attention to the pediatric population needs. An innovative approach for the patients’ involvement in pediatric clinical research is represented by the Young Persons Advisory Groups, an organization composed of youths, patients, and carers, actively participating in clinical research and advising researchers and their teams

484. Preclinical Proof of Concept of Transcriptional Silencing and Replacement Strategy for Treatment of Retinitis Pigmentosa Due To RHODOPSIN Mutations

Silencing and replacement strategy is a promising approach to overcome mutational heterogeneity of genetic defects. In autosomal dominant retinitis pigmentosa (adRP) due to rhodopsin gene (RHO) approximately 200 different mutations have been described, posing a challenge for the design of effective therapeutics.We designed a silencing and replacement strategy based on transcriptional silencing through an artificial zinc finger DNA-binding protein lacking effector domains (ZF6DBD), and tested both efficacy and safety in two animal models.In a murine model of adRP, we show that AAV-mediate retinal delivery (AAV2/8-CMV-ZF6-DBD) is associated with selective transcriptional silencing of the human mutated allele resulting in morphological and functional (Electroretinography, ERG a-wave and b-wave responses) rescue. We then tested the effect of transcriptional silencing in the porcine large pre-clinical model. Delivery of a low dose (AAV2/8-CMV-ZF6-DBD, 1×10e10 vector genomes, vg) of the ZF6 transcriptional silencer to the porcine retina resulted in robust transcriptional silencing of the endogenous porcine RHO transcript. Cell sorting of transduced photoreceptors showed an almost complete RHO transcriptional silencing effect (90% RHO transcriptional repression), underscoring the potency of the system. To determine the safety of the zinc-finger silencer we performed extensive RNA-seq analysis on treated and control retinae. The data sets generated demonstrate selective RHO gene transcriptional repression and a remarkably low number of differential expressed genes (DEGs), supporting specificity and thus, safety. The co-administration to the porcine retina of the AAV-ZF6 silencer (AAV2/8-CMV-ZF6-DBD) and the AAV-RHO replacement (5×10e11 vg, AAV2/8-GNAT1-HumanRHO) constructs resulted in a balanced silencing and replacement effect. This data support the use of zinc-finger based RHO transcriptional silencing for the development of a clinical trial for adRP patients

320 transcriptional silencing via synthetic dna binding protein lacking canonical repressor domains as a potent tool to generate therapeutics

Transcription factors (TFs) function by the combined activity of their DNA-binding domains (DBDs) and effector domains (EDs). Here we show that in vivo delivery of an engineered DNA-binding protein uncoupled from the repressor domain entails complete and gene-specific transcriptional silencing. To silence RHODOPSIN (RHO) gain-of-function mutations, we engineered a synthetic DNA-binding protein lacking canonical repressor domains and targeted to the regulatory region of the RHO gene. AAV-mediate retinal delivery at a low dose (AAV2/8-CMV-ZF6-DBD, 1×10e10 vector genomes, vg) in the porcine retina resulted in selective transcriptional silencing of RHO expression. The rod photoreceptors (the RHO expressing cells) transduced cells when isolated by FACS-sorting showed the remarkable 90% RHO transcriptional repression. To evaluate genome-wide transcriptional specificity, we analyzed the porcine retina transcriptome by RNA sequencing (RNA-Seq). The differentially expressed genes (DEGs) analysis showed that only 19 genes were perturbed. In this study, we describe a system based on a synthetic DNA binding protein enabling targeted transcriptional silencing of the RHO gene by in vivo gene transfer. The high rate of transcriptional silencing occurring in transduced cells supports applications of this regulatory genomic interference with a synthetic trans-acting factor for diseases requiring gene silencing in a large number of affected cells, including for instance a number of neurodegeneration disorders. The result support a novel mode of gene targeted silencing with a DNA-binding protein lacking intrinsic activity

Medical Device Development for Children and Young People—Reviewing the Challenges and Opportunities

Development of specific medical devices (MDs) is required to meet the healthcare needs of children and young people (CYP). In this context, MD development should address changes in growth and psychosocial maturation, physiology, and pathophysiology, and avoid inappropriate repurposing of adult technologies. Underpinning the development of MD for CYP is the need to ensure MD safety and effectiveness through pediatric MD-specific regulations. Contrary to current perceptions of limited market potential, the global pediatric healthcare market is expected to generate around USD 15,984 million by 2025. There are 1.8 billion young people in the world today; 40% of the global population is under 24, creating significant future healthcare market opportunities. This review highlights a number of technology areas that have led to successful pediatric MD, including 3D printing, advanced materials, drug delivery, and diagnostic imaging. To ensure the targeted development of MD for CYP, collaboration across multiple professional disciplines is required, facilitated by a platform to foster collaboration and drive innovation. The European Pediatric Translational Research Infrastructure (EPTRI) will be established as the European platform to support collaboration, including the life sciences industrial sector, to identify unmet needs in child health and support the development, adoption, and commercialization of pediatric MDs

EPTRI – European Paediatric Translational Research Infrastructure. Bridging the gaps of the paediatric excellence medicine

Development of age appropriate medicines for children is one of the major challenge of our century. Historically, research of new paediatric drugs has been neglected due to poor industrial interest and limited public and private investments. The ID-EPTRI project is aimed to bridge the existing gaps in the paediatric medicine that stop the progress, from the early stage drug development phases to be translated into paediatric use of medicines, through a new paediatric Research Infrastructure. To reach this goal, EPTRI has developed and disseminated a survey in order to identify the gaps and map the competences of the excellence of the paediatric research in pan-European countries that will be the potential service providers of the new Research Infrastructure. EPTRI will network all the available competences and technologies useful to the paediatric research, creating an open science space allowing top-level researchers to work together

Dietary interventions for multiple sclerosis

Clinical and experimental data suggest that certain dietary regimens, particularly those including polyunsaturated fatty acids (PUFAs) and vitamins might improve outcomes in people with multiple sclerosis (MS). Diets and dietary supplements are much used by people with MS in the belief that they might improve disease outcomes

Annali storici di Principato Citra, A. 16, n. 2.2 (2018)

A.16, n.2.2(2018): G. Guardia, Editoriale, P. 3 ; P. F. Giuliani Mazzei, Ipotesi su alcune aree insediative del centro preistorico megalitico sul Monte della Stella. ‘Vucculo re Santu Stasio’ P. 5 ; A. Capano, Roccagloriosa e il suo territorio attraverso l’analisi del catasto provvisorio del 1831, P. 42 ; P. Trotta, Documenti per la storia di Salerno. Il testamento dell’arcivescovo Bonaventura Poerio, P. 89 ; M. Cerullo, La variazione fonetica degli esiti di -LL- in Cilento: aspetti fonetici e fonomorfologici, P. 114 ; G. Lupo, La “valanga” passa a Montecorvino Rovella. L’ “Operation Avalanche” nella memoria dei Rovellesi, P. 147 ; A. Pazzanese, Il bombardamento di Roccadaspide del 15 settembre 1943, p. 169 ; P. Lucia, Luigi Cacciatore. La vita politica di un socialista, P. 200 ; R. Battista, LAssociazione “Giorgio Ambrosoli” di Salerno (AGAS), P. 219 ; F. Stella, Il RAP antidonatista di Agostino; Prudenzio fra PULP e il lirico, P. 231 ; M. Morra, Il primo eremitismo cristiano orientale tra spiritualità e contemplazione, P. 234

Intein-mediated protein trans-splicing expands adeno-associated virus transfer capacity in the retina

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