Cellular Stress-Modulating Drugs Can Potentially Be Identified by in Silico Screening with Connectivity Map (CMap)

Gao Y, Sungwoo Kim, Lee YI, Lee J; International Journal of Molecular Sciences, 09 Nov 2019, 20(22) DOI: 10.3390/ijms20225601

A target-based drug discovery method currently being used widely (reverse pharmacology) may not be adequate to uncover novel drugs targeting cellular stresses and related diseases. The connectivity map (CMap) is an online pharmacogenomic database cataloging gene expression data from cultured cells treated individually with various chemicals, including a variety of phytochemicals. Moreover, by querying through CMap, researchers may screen registered chemicals in silico and obtain the likelihood of drugs showing a similar gene expression profile with desired and chemopreventive conditions. Thus, CMap is an effective genome-based tool to discover novel chemopreventive drugs.

Functional characterization of frataxin isoforms and mechanisms of regulation of frataxin expression

Autores: Mauro Agrò. Directores de la Tesis: Javier Díaz Nido (dir. tes.), Alfredo Giménez-Cassina Sendón (codir. tes.). Lectura: En la Universidad Autónoma de Madrid ( España ) en 2019. Idioma: español.


The regulation of frataxin gene expression is another issue of major interest for its possible therapeutic relevance. Several factors including Erythropoietin and some Epo-mimetic molecules have been reported to increase frataxin levels. There are some drawbacks, since canonical Epo can cause hematocrit problems, while some of the derivative peptides described are known to be highly unstable, with a very low half-life in the organism. For this reason, we decided to focus on a retro-enantiomeric version of a HBSP-based peptide, called EPO2. We described in this work the positive regulatory effects on frataxin of this synthetic epomimetic peptide, both in vitro in several cell models and in vivo in the cerebellum of wild type mice.
Finally, we reported the effects of spontaneous physical activity in wild type mouse cerebellum on frataxin expression. Frataxin levels appeared positively modulated after exercise, suggesting a post-transcriptional regulation mechanism. We investigated for possible mediators of this beneficial effect by qPCRs and through a cytokine array which highlighted the upregulation of several factors, including the neurotrophin NT-3, SHH protein, MIP-1α and IFN-γ, pointing the way to a multi-layered regulatory complex behind frataxin modulation set up by physical exercise.

Iron Hack - A symposium/hackathon focused on porphyrias, Friedreich’s ataxia, and other rare iron-related diseases

Ferreira GC, Oberstaller J, Fonseca R et al. Iron Hack; F1000Research 2019, 8:1135 [version 1; peer review: 2 approved] doi:10.12688/f1000research.19140.1

MassiveSeq’s implementation of HISAT2 and StringTie identified novel-isoform transcripts in various samples. We focused our analyses on the FXN gene, as trinucleotide GAA-repeats at this locus are causative of FRDA. We identified multiple novel-isoform transcripts within 1kb up and downstream of FXN in affected, unaffected and carrier-patients (Table 2). We were able to visualize the truncation of the FXN transcripts from the above samples using IGV. Shallow read-coverage of the whole transcriptome from this particular study made it difficult to confirm the reliability of the identified transcript truncation.

Common questions in the community about hackathons include whether they can focus on specific diseases and how clinical personnel can interact more effectively with data scientists. We found that it was indeed possible to focus on a given disease while developing generalized tools in a hackathon. In fact, we found it helpful to have cases to use in our analyses from a specific disease. Finally, we found it was to the benefit of everyone to have clinical personnel involved, especially in the later stages of the event.

Neurochemical profiles in hereditary ataxias: A meta-analysis of Magnetic Resonance Spectroscopy studies

Janna Krahe, Ferdinand Binkofski, Jörg B. Schulz, Kathrin Reetz, Sandro Romanzetti,; Neuroscience & Biobehavioral Reviews, 2019, doi:10.1016/j.neubiorev.2019.12.019.

Magnetic resonance spectroscopy (MRS) is applied to investigate the neurochemical profiles of degenerative hereditary ataxias. This meta-analysis provides a quantitative review and reappraisal of MRS findings in spinocerebellar ataxias (SCA) and Friedreich ataxia (FA) available to date. From each study, changes in N-acetyl aspartate (NAA), choline-containing compounds (Cho) and myo-Inositol (mI) ratios to total creatine (Cr) were calculated for groups of patients (1499 patients in total: SCA1 = 223, SCA2 = 298, SCA3 = 711, SCA6 = 165, and FA = 102) relative to their own control group, mostly in cerebellum and pons. SCA1, 2, 3, 6, and FA patients showed overall decreased NAA/Cr compared to controls. Decreased Cho/Cr was visible in SCA1, 2, and 3 and elevated mI/Cr in SCA2 patients in cerebellum. In SCA6 and FA Cho/Cr and mI/Cr did not differ with respect to controls but SCA6 patients indicated higher Cho/Cr compared to SCA1 patients in cerebellum. SCA2 subjects showed the lowest NAA/Cr and Cho/Cr in cerebellum and the highest mI/Cr compared to controls and other genotypes, and therefore the most promising results for a potential biomarker.

An analysis of orphan medicine expenditure in Europe: is it sustainable?

Jorge Mestre-Ferrandiz, Christina Palaska, Tom Kelly, Adam Hutchings & Adam Parnaby; Orphanet J Rare Dis 14, 287 (2019) doi:10.1186/s13023-019-1246-7

Orphan medicinal product (OMP) prices are considered by some to be a challenge to the sustainability of healthcare expenditure. These concerns are compounded by the increasing number of OMPs receiving marketing authorisation (MA) annually. The aim of this study was to explore the sustainability of OMP expenditure within the context of total European pharmaceutical expenditure.
The EU regulation on OMPs has had success in fostering R&D addressing unmet needs for treatments for rare diseases, with approximately 150 OMPs being approved since its introduction. However, despite the success of the regulation in supporting the development of medicines for rare diseases, the findings from this analysis suggest that the resultant impact on OMP expenditure could be deemed sustainable when seen in the context of total pharmaceutical expenditure.