An evaluation of oligonucleotide-based therapeutic strategies for polyQ diseases

<p>Abstract</p> <p>Background</p> <p>RNA interference (RNAi) and antisense strategies provide experimental therapeutic agents for numerous diseases, including polyglutamine (polyQ) disorders caused by CAG repeat expansion. We compared the potential of different oligonucleotide-based strategies for silencing the genes responsible for several polyQ diseases, including Huntington's disease and two spinocerebellar ataxias, type 1 and type 3. The strategies included nonallele-selective gene silencing, gene replacement, allele-selective SNP targeting and CAG repeat targeting.</p> <p>Results</p> <p>Using the patient-derived cell culture models of polyQ diseases, we tested various siRNAs, and antisense reagents and assessed their silencing efficiency and allele selectivity. We showed considerable allele discrimination by several SNP targeting siRNAs based on a weak G-G or G-U pairing with normal allele and strong G-C pairing with mutant allele at the site of RISC-induced cleavage. Among the CAG repeat targeting reagents the strongest allele discrimination is achieved by miRNA-like functioning reagents that bind to their targets and inhibit their translation without substantial target cleavage. Also, morpholino analog performs well in mutant and normal allele discrimination but its efficient delivery to cells at low effective concentration still remains a challenge.</p> <p>Conclusions</p> <p>Using three cellular models of polyQ diseases and the same experimental setup we directly compared the performance of different oligonucleotide-based treatment strategies that are currently under development. Based on the results obtained by us and others we discussed the advantages and drawbacks of these strategies considering them from several different perspectives. The strategy aimed at nonallele-selective inhibiting of causative gene expression by targeting specific sequence of the implicated gene is the easiest to implement but relevant benefits are still uncertain. The gene replacement strategy that combines the nonallele-selective gene silencing with the expression of the exogenous normal allele is a logical extension of the former and it deserves to be explored further. Both allele-selective RNAi approaches challenge cellular RNA interference machinery to show its ability to discriminate between similar sequences differing in either single base substitutions or repeated sequence length. Although both approaches perform well in allele discrimination most of our efforts are focused on repeat targeting due to its potentially higher universality.</p

Using TRAILER tool for Managing Informal Learning in academic and professional contexts: the learners’ perspective

Viegas, C., Marques, A., Alves, G., Zangrando, V., Galanis, N., Brouns, F., Janssen, J., Waszkiewicz, E., Mykowska, A., Gonzalez, M., Holgado, A., & García-Peñalvo, F. (2013). Using TRAILER tool for Managing Informal Learning in academic and professional contexts: the learners’ perspective. In F. J. García-Peñalvo (Ed.) Proceedings of the 2013 Conference on Technological Ecosystems for Enhancing Multiculturality. (pp. 529-534). November, 14-15, 2013, Salamanca, Spain.Informal Learning plays an important role in everyone's life and yet we often are unaware of it. The need to keep track of the knowledge acquired through informal learning is increasing as its sources become increasingly diverse. This paper presents a study on a tool developed to help keeping track of learners’ informal learning, both within academic and professional contexts, This tool, developed within the European Commission funded TRAILER project, will further integrate the improvements suggested by users during the piloting phase. The two studied contexts were similar regarding the importance and perception of Informal Learning, but differed concerning tool usage. The overall idea of managing one’s informal learning was well accepted and welcomed, which validated the emerging need for a tool with this purpose.Tagging, Recognition and Acknowledgment of Informal Learning ExpeRiences project (TRAILER) that is funded by the European Commission's Lifelong Learning Programme. Ref. 519141-LLP-1-2011-1-ES-KA3-KA3MP [http://www.trailerproject.eu]. This publication reflects the views only of the author, and the Commission cannot be held responsible for any use which may be made of the information contained therein

TRAILER project overview: tagging, recognition and acknowledgment of informal learning experiences

The evolution of new technology and its increasing use, have for some years been making the existence of informal learning more and more transparent, especially among young and older adults in both Higher Education and workplace contexts. However, the nature of formal and non-formal, coursebased, approaches to learning has made it hard to accommodate these informal processes satisfactorily, and although technology bring us near to the solution, it has not yet achieved. TRAILER project aims to address this problem by developing a tool for the management of competences and skills acquired through informal learning experiences, both from the perspective of the user and the institution or company. This paper describes the research and development main lines of this project.Peer ReviewedPostprint (published version

TRAILER: A Tool for Managing Informal Learning

Even though informal learning plays an important role in everyone’s life, not everyone is aware of its importance. These informal activities contribute to the development of self-regulated learning that can help productivity in different environments. As this kind of apprentices grow, the need to keep track of this developed knowledge is becoming vital. This paper presents a study on the perception and usage of a tool that would help keeping track of learners’ informal learning. This study was conducted both within academic and professional contexts and was developed within the European Commission funded TRAILER project. The contexts were similar regarding the importance and perception of informal learning, but differed concerning tool usage and the usefulness of such a platform. The overall idea of managing one’s informal learning was well accepted and welcomed, which validated the emerging need for a tool with this purpose

Inhibition of mutant huntingtin expression by RNA duplex targeting expanded CAG repeats

The specific silencing of the gene of interest is the major objective of RNA interference technology; therefore, unique sequences but not abundant sequence repeats are targeted by silencing reagents. Here, we describe the targeting of expanded CAG repeats that occur in transcripts derived from the mutant allele of the gene implicated in Huntington’s disease (HD) in the presence of the normal allele and other human mRNAs containing CAG and CUG repeat tracts. We show that a high degree of silencing selectivity may be achieved between the repeated sequences. We demonstrate preferential suppression of the mutant huntingtin allele and concomitant activation of the normal huntingtin allele in cell lines derived from HD patients that were transfected with short RNA duplexes composed of CAG and CUG repeats containing mutations at specific positions. These effects may lead to promising therapeutic modalities for HD, a condition for which no therapy presently exists

Enhancing informal learning recognition through TRAILER project

Conde, M. A., García-Peñalvo, F. J., Zangrando, V., García-Holgado, A., Seoane-Pardo, A. M., Alier, M., Galanis, N., Griffiths, D., Johnson, M., Janssen, J., Brouns, F., Vogten, H., Finders, A., Sloep, P. B., Marques, M. A., Viegas, M. C., Alves, G. R., Waszkiewicz, E., Mykowska, A., Minovic, M., & Milovanovic, M. (2013). Enhancing informal learning recognition through TRAILER project. In F. J. García-Peñalvo, M. Á. Conde, & D. Griffiths (Eds.), Proceedings of the Workshop on Solutions that Enhance Informal Learning Recognition (WEILER 2013) (pp. 21-30). September, 18, 2013, Paphos, Cyprus. http://ceur-ws.org/Vol-1039/The evolution of new technology and its increasing use, has for some years been making the existence of informal learning more and more transparent, especially among young and older adults in both Higher Education and workplace contexts. However, the nature of formal and non-formal, coursebased, approaches to learning has made it hard to accommodate these informal processes satisfactorily. The project aims to facilitate first the identification by the learner (as the last responsible of the learning process), and then the recognition by the institution, in dialogue with the learner, of this learning. To do so a methodology and a technological framework to support it have been implemented. This project has been tested in several contexts showing that an informal learning dialogue between learners and people in charge of the institutions is possible.Tagging, Recognition and Acknowledgment of Informal Learning ExpeRiences project (TRAILER) that is funded by the European Commission's Lifelong Learning Programme. Ref. 519141-LLP-1-2011-1-ES-KA3-KA3MP [http:// trailerproject.eu]. This publication reflects the views only of the author, and the Commission cannot be held responsible for any use which may be made of the information contained therein

Tagging, Recognition, Acknowledgment of Informal Learning experiences (TRAILER)

[EN] Learners do not only learn in the institutions, they learn during their live in different contexts, with different resources and from the interaction with different persons. This kind of learning that is not always intentionally carried out is known as informal learning. The application of Information and Communication Technologies to learning and teaching processes facilitates making visible such kind of learning for the institutions. However the nature of formal and non-formal, coursebased, approaches to learning has made it hard to accommodate these informal processes satisfactorily. The project aims to facilitate first the identification by the learner (as the last responsible of the learning process), and then the recognition by the institution, in dialogue with the learner, of this learning. To do so a methodology and a technological framework to support it have been implemented and tested