Impact of biobanks on research outcomes in rare diseases: a systematic review

Monique Garcia, Jenny Downs, Alyce Russell and Wei Wang; Orphanet Journal of Rare Diseases 2018 13:202 doi:10.1186/s13023-018-0942-z

Alleviating the burden of rare diseases requires research into new diagnostic and therapeutic strategies. We undertook a systematic review to identify and compare the impact of stand-alone registries, registries with biobanks, and rare disease biobanks on research outcomes in rare diseases.

A list of the registries, and their association with BBs at the time the original article was published, can be found in this paper. There were, however, small RDBBs that had collected only 50 samples (such as the Friedrich’s Ataxia fibroblast repository). Li et al. reported that smaller RDBBs have their advantages over larger RDBB networks in the sense that they can focus on a single diseases or syndromes, or group of diseases, and can successfully accumulate significant numbers of cell lines, whilst developing an intimate understanding of the disease

OGTT is recommended for glucose homeostasis assessments in Friedreich ataxia

Azzi, A. , Cosentino, C. , Kibanda, J. , Féry, F. and Cnop, M. (2018). Ann Clin Transl Neurol. doi:10.1002/acn3.686

Diabetes is a common complication of Friedreich ataxia, requiring sensitive diagnostic methods. Here, we compared the performance of different tests that assess glucose tolerance, insulin sensitivity, and β‐cell function in Friedreich ataxia patients, heterozygous FXN mutation carriers and controls. We find that diabetes is underdiagnosed with fasting glucose alone. The oral glucose tolerance test (OGTT) provides 1.2‐ to 3.5‐fold more diagnoses of impaired glucose homeostasis and diabetes, and adequately measures insulin sensitivity, insulin secretion, and β‐cell function. Clinicians in charge of Friedreich ataxia patients and researchers should incorporate the OGTT as an accurate diagnostic and research tool.

Mining Facebook Data of People with Rare Diseases: A Content-Based and Temporal Analysis

Subirats L, Reguera N, Bañón AM, Gómez-Zúñiga B, Minguillón J, Armayones M.; Int J Environ Res Public Health. 2018;15(9):1877. Published 2018 Aug 30. doi:10.3390/ijerph15091877

This research characterized how Facebook deals with rare diseases. This characterization included a content-based and temporal analysis, and its purpose was to help users interested in rare diseases to maximize the engagement of their posts and to help rare diseases organizations to align their priorities with the interests expressed in social networks. This research used Netvizz to download Facebook data, word clouds in R for text mining, a log-likelihood measure in R to compare texts and TextBlob Python library for sentiment analysis. The Facebook analysis shows that posts with photos and positive comments have the highest engagement. We also observed that words related to diseases, attention, disability and services have a lot of presence in the decalogue of priorities (which serves for all associations to work on the same objectives and provides the lines of action to be followed by political decision makers) and little on Facebook, and words of gratitude are more present on Facebook than in the decalogue. Finally, the temporal analysis shows that there is a high variation between the polarity average and the hour of the day.

Real‐time use of audio‐biofeedback can improve postural sway in patients with degenerative ataxia

Zofia Fleszar, Sabato Mellone, Martin Giese, Carlo Tacconi, Clemens Becker, Ludger Schöls, Matthis Synofzik, Winfried Ilg; Annals of Clinical and Translational Neurology, Early View, First published: 28 November 2018 doi:10.1002/acn3.699

Our findings provide proof‐of‐principle evidence that subjects with cerebellar degeneration are still able to integrate additional sensory modalities to compensate for deficient postural control: They can use auditory cues functionally similar to vision in the absence of vision, and additive to vision in the presence of vision (in case of pronounced postural sway). These findings might inform future assistive strategies for cerebellar ataxia

Mitochondria, Nrf2 and mTOR

Gino Cortopassi. Free Radical Biology and Medicine, Volume 128, Supplement 1, 2018, Page S7, doi:10.1016/j.freeradbiomed.2018.10.382.

Abstract: Friedreich's ataxia (FA) is the most common recessive ataxia, and it's phenotype is clinically indistinguishable from AVED, a deficiency of Vitamin E transport. We were the first to show that Friedreich's patient cells are very sensitive to oxidative stress. Ultimately this defect appears to reside in a deficiency of the antioxidant pathway Nrf2, which is less active in Friedreich's patient cells, and in FA animal models. Perhaps as a result of this Nrf2 defect, there is increased inflammation in Friedreich's patient cells and mice. But as Nrf2 is not only important in antioxidant homeostasis, but also mitochondrial homeostasis, this was investigated in Friedreich's models and patients. We found that Friedreich's cells, mice, and even people have an approximately 40% mitochondrial biogenesis defect. A high-throughput screening campaign for drugs that rescued Friedreich's cells from death identified three Nrf2 inducers, which could be of benefit in human Friedreich's therapy. One of these drugs, dimethyl fumarate, was shown to dose-dependently increase mitochondrial biogenesis and function when dosed in cells, and to increase mitochondrial biogenesis in mouse and human tissues, with a mechanism that appears to require Nrf2. Thus there is an interplay between Nrf2, mitochondrial biogenesis, and antioxidant status. We observed in a particular cancer there are alterations of mitochondrial biogenesis, which appear to result from differential Nrf2 activity. These differences in mitochondrial number allow the selective killing of such cells by mitochondrial inhibitors and a novel category of mTOR inhibitors.

Heme oxygenase-1 is required for iron homeostasis and mitochondrial respiration

Jennifer Carr, Ping La, Phyllis Dennery. Free Radical Biology and Medicine, Volume 128, Supplement 1, 2018, Page S81, doi.org/10.1016/j.freeradbiomed.2018.10.182.

Heme is an essential cofactor in several enzymes of the electron transport chain (ETC) where its primary function is the coordination of iron to facilitate redox reactions. Unbound, free heme is strongly oxidative such that the cell has evolved mechanisms to prevent it from causing oxidative damage. This includes the catalytic breakdown of heme by heme oxygenase (HO-1), generating antioxidants CO and biliverdin. However the catabolism of heme also releases highly toxic free iron which seems counter productive to the antioxidant effort. We sought to explore the role of HO-1 in iron homeostasis using HO-1 knockout mouse embryonic fibroblasts and HO-1 deficient human liver cells. By Western blot these cells showed dysregulated iron handling including increased expression of transferrin receptor and decreased expression of ferritin and ferroportin compared to wild type controls. Additionally cytosolic aconitase activity was decreased in HO-1 deficient cells while the mutually exclusive mRNA binding activity of aconitase was increased. This switch is indicative of reduced FeS cluster availability. Consistent with FeS cluster deficiency we observed decreased frataxin mRNA levels, the product of which is involved in FeS cluster assembly in the mitochondria. Because FeS clusters are important in the ETC we examined mitochondrial respiration with a Seahorse Bioanalyzer (Agilent) and found it to be markedly reduced in HO-1 knockout cells. Interestingly, this was partially rescued by exogenous iron (1nM transferrin). Our findings suggest that an additional and important role of HO-1 is the maintenance of cellular iron homeostasis via the release of iron upon breakdown of heme.

Corporate Social Responsibility (CSR) of Innovative Pharmaceutical Corporations. The Case of BIOGEN

Janina Witkowska. Comparative Economic Research, Volume 21: Issue 3 45–62, First Online: 19 Sep 2018 DOI:10.2478/cer-2018-0018

The aim of a paper published in Comparative Economic Research was to discuss the common features and specificity of Corporate Social Responsibility (CSR) practices of innovative transnational corporations acting in the pharmaceutical industry, understood as their ability to make a breakthrough in the treatment of rare, incurable diseases. Traditional CSR practices include corporate philanthropy, community and neighbourhood programmes, volunteerism, etc. The author of the paper argues that the issue of CSR in the innovative pharmaceutical industry is the pricing of orphan and ultra-orphan drugs, while the case study of BIOGEN seems to show that the company is aware of the need to remove barriers to access the medicines. The author also suggests that a stronger international cooperation is needed to ensure equity of medicine access in a more efficient way.

Depression disorder in patients with cerebellar damage: Awareness of the mood state

ilvia Clausi, Michela Lupo, Giusy Olivito, Libera Siciliano, Maria Pia Contento, Fabio Aloise, Luigi Pizzamiglio, Marco Molinari, Maria Leggio. Journal of Affective Disorders, Volume 245, 2019, Pages 386-393, doi:10.1016/j.jad.2018.11.029.

Cerebellar dysfunction might slow the data integration necessary for mood state awareness, resulting in difficulty of depressed CB patients in explicitly recognizing their mood “in the here and now”.
In conclusion, cerebellar involvement in the conscious component of emotional behaviour, related to awareness of one's affective state and interpretation of one's mood, may contribute to a loss of the‘online’ self-perception of negative mood that characterizes depressive disorders in the presence of cerebellar pathology. These data may help explain why depression in cerebellar patients is often underdiagnosed.

Paradoxical disruption of Nrf2 signaling despite mitochondrial iron driven oxidative stress in Friedreich’s ataxia cardiomyopathy

Michael Huang, Amy Anzovino, Shannon Chiang, Bronwyn Brown, Clare Hawkins, Des Richardson. Free Radical Biology and Medicine, Volume 128, Supplement 1, 2018, Page S131, doi.org/10.1016/j.freeradbiomed.2018.10.346

Cardiomyopathy is the leading cause of mortality for the most prevalent inherited ataxia, Friedreich’s ataxia (FA). Deficient expression of the mitochondrial protein frataxin that is crucial for mitochondrial iron metabolism is the cause of FA, which exhibits marked mitochondrial Fe accumulation. Our studies using a conditional cardiac frataxin knockout (KO) mouse that mirrors FA cardiomyopathy have shown frataxin deletion leads to pronounced trafficking of cardiac iron from the cytosol to the mitochondrion, leading to a cytosolic iron-deficiency and mitochondrial iron accumulation in the form of non-protein-bound, biomineral iron aggregates. The ensuing oxidative stress is likely a key contributor to FA pathology. The transcription factor, nuclear factor E2-related factor 2 (Nrf2), is the master regulator of cellular antioxidant response. In the frataxin KO mouse, our studies demonstrated increased protein and GSH oxidation in the KO relative to wild-type (WT) littermates. Despite this, we found paradoxical decreases in total and nuclear Nrf2 protein and an increase in its inhibitor, Keap1, which mediates Nrf2 degradation in the cytosol. Moreover, a mechanism involving activation of the nuclear Nrf2 export/degradation machinery via Gsk3β-signaling was found in the KO heart. This is evident by: (i) increased Gsk3β activation; (ii) increased Fyn-mediated nuclear Nrf2 export; and (iii) increased expression of β-TrCP that is involved in Nrf2 degradation. Furthermore, a corresponding decrease in Nrf2-DNA-binding activity and a general decrease in Nrf2-target mRNA was observed in KO heart. Collectively, despite marked mitochondrial iron accumulation in FA cardiomyopathy, Nrf2 activity was disrupt via two mechanisms: increased Keap1 that decreases cytosolic Nrf2, and the activation of Gsk3β-signaling that decreases nuclear Nrf2.

Del deseo a la realidad: la edición genética (aún) no está preparada para tratar a pacientes

SINC, la ciencia es noticia (17 noviembre 2018). Lluís Montoliu, es investigador científico del Centro Nacional de Biotecnología (CNB-CSIC) y Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER-ISCIII), además de miembro del Comité de Ética del CSIC.

Las terapias génicas basadas en CRISPR para curar enfermedades todavía tardarán en llegar. Quizás no sea este el titular que quisiéramos leer, pero es el mensaje que hay que repetir para no generar falsas expectativas sobre esta potente herramienta de corta-pega genético.

Hoy en día se están desarrollando múltiples variantes de la técnica CRISPR, a cual más innovadora e imaginativa. Algunas de ellas son extremadamente prometedoras, como los editores de bases, una evolución de las herramientas CRISPR capaz de cambiar nucleótidos concretos del genoma sin necesidad de cortarlo. Pero todas ellas conllevan todavía riesgos inaceptables, tanto en seguridad como en eficacia, para saltar al hospital.

Son métodos sofisticados que nos permiten abordar experimentos en el laboratorio como nunca antes habíamos podido hacerlo, pero que todavía no pueden trasladarse a la clínica. Necesitan de mucho más trabajo, mucha más investigación en el laboratorio.