Brian Chiou and James R. Connor; Pharmaceuticals 2018, 11(4), 124; doi:10.3390/ph11040124
Review
One interesting new development has been proposed in Friedreich’s Ataxia where the authors discuss the hypothesis that the mitochondrial protein frataxin may oligomerize like ferritin and perform functions redundant with mitochondrial ferritin, acting as another iron storage molecule. Loss of frataxin and this iron storage property may result in Friedreich’s Ataxia and subsequent neurodegeneration.
Sunday, November 18, 2018
Friday, November 16, 2018
Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe: methodological uncertainties
Caridad Pontes, Juan Manuel Fontanet, Roser Vives, Aranzazu Sancho, Mònica Gómez-Valent, José Ríos, Rosa Morros, Jorge Martinalbo, Martin Posch, Armin Koch, Kit Roes, Katrien Oude Rengerink, Josep Torrent-Farnell and Ferran Torres; Orphanet Journal of Rare Diseases 2018 13:206 doi:10.1186/s13023-018-0926-z
The regulatory evidence supporting OMP authorization showed substantial uncertainties, including weak protection against errors, substantial use of designs unsuited for conclusions on causality, use of intermediate variables, lack of a priorism and insufficient safety data to quantify risks of relevant magnitude. Grouping medical conditions based on clinical features and their methodological requirements may facilitate specific methodological and regulatory recommendations for the study of OMP to strengthen the evidence base.
The regulatory evidence supporting OMP authorization showed substantial uncertainties, including weak protection against errors, substantial use of designs unsuited for conclusions on causality, use of intermediate variables, lack of a priorism and insufficient safety data to quantify risks of relevant magnitude. Grouping medical conditions based on clinical features and their methodological requirements may facilitate specific methodological and regulatory recommendations for the study of OMP to strengthen the evidence base.
Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia
Zeitlberger Anna M., Thomas-Black Gilbert, Garcia-Moreno Hector, Foiani Martha, Heslegrave Amanda J., Zetterberg Henrik, Giunti Paola; Frontiers in Cellular Neuroscience 2018, 12 366, DOI=10.3389/fncel.2018.00366
This study provides the first assessment of plasma markers of neurodegeneration in FRDA, illustrating that NfL, GFAP, and UCHL1 are significantly raised in FRDA compared to aged-matched control. These observations may serve as the basis of further exploration of these brain-derived proteins as promising biomarkers in FRDA. In addition, we show for the first time in vivo an increase of GFAP reflecting astrocyte activation. This is confirmatory of in vitro studies suggesting a role of astrocytes in FRDA pathology. Finally, UCHL1 increase may reflect non-specific neuronal damage or alterations in the UPP. Future studies are needed to confirm our findings and determine whether, when applied to more heterogeneous cohorts, they serve as useful markers of disease severity.
This study provides the first assessment of plasma markers of neurodegeneration in FRDA, illustrating that NfL, GFAP, and UCHL1 are significantly raised in FRDA compared to aged-matched control. These observations may serve as the basis of further exploration of these brain-derived proteins as promising biomarkers in FRDA. In addition, we show for the first time in vivo an increase of GFAP reflecting astrocyte activation. This is confirmatory of in vitro studies suggesting a role of astrocytes in FRDA pathology. Finally, UCHL1 increase may reflect non-specific neuronal damage or alterations in the UPP. Future studies are needed to confirm our findings and determine whether, when applied to more heterogeneous cohorts, they serve as useful markers of disease severity.
Thursday, November 15, 2018
Neuromuscular diseases with hypertrophic cardiomyopathy
Cesar S.; Global Cardiology Science and Practice 2018:27 doi:10.21542/gcsp.2018.27
Patient with FA and HCM have an early onset within the first or second decades with a poor correlation with the neurological level of disability. Histologically, left ventricle cellular hypertrophy, diffuse fibrosis and focal myocardial necrosis have been described. Echocardiographic hallmark is a concentric LV hypertrophy with absence of left ventricular outflow tract obstruction, but eccentric hypertrophy might be present.
There is no specific treatment for HCM in FA patients. Management of heart failure symptoms (salt restriction, diuretic therapy), ACE inhibitors or angiotensin II receptor blockers may be beneficial in long-term treatment. Treatment of atrial arrhythmias is mandatory, because the important atrial role to LV filling and cardiac output14. The drug idebenone acts as a transporter in the electron transport chain and has been advocated for use in FA following studies showing mild diastolic improvement and reduction LVH21,22. However, further trials have shown no benefit. Cardiac transplantation is not commonly performed, due to advanced impairment of both motor skills and muscle strength.
Patient with FA and HCM have an early onset within the first or second decades with a poor correlation with the neurological level of disability. Histologically, left ventricle cellular hypertrophy, diffuse fibrosis and focal myocardial necrosis have been described. Echocardiographic hallmark is a concentric LV hypertrophy with absence of left ventricular outflow tract obstruction, but eccentric hypertrophy might be present.
There is no specific treatment for HCM in FA patients. Management of heart failure symptoms (salt restriction, diuretic therapy), ACE inhibitors or angiotensin II receptor blockers may be beneficial in long-term treatment. Treatment of atrial arrhythmias is mandatory, because the important atrial role to LV filling and cardiac output14. The drug idebenone acts as a transporter in the electron transport chain and has been advocated for use in FA following studies showing mild diastolic improvement and reduction LVH21,22. However, further trials have shown no benefit. Cardiac transplantation is not commonly performed, due to advanced impairment of both motor skills and muscle strength.
Wednesday, November 14, 2018
Longitudinal dentate nuclei iron concentration and atrophy in Friedreich ataxia: IMAGE-FRDA
Phillip Ward, Ian H Harding, Thomas G Close, Louise A Corben, Martin B Delatycki, Elsdon Storey, Nellie Georgiou-Karistianis, Gary F. Egan. bioRxiv 464537; doi: 10.1101/464537 (This article is a preprint and has not been peer-reviewed)
Progressive dentate nuclei pathology is evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a two-year period highlights the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool.
Progressive dentate nuclei pathology is evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a two-year period highlights the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool.
Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia
Lynch, D. R., Farmer, J. , Hauser, L. , Blair, I. A., Wang, Q. Q., Mesaros, C. , Snyder, N. , Boesch, S. , Chin, M. , Delatycki, M. B., Giunti, P. , Goldsberry, A. , Hoyle, C. , McBride, M. G., Nachbauer, W. , O'Grady, M. , Perlman, S. , Subramony, S. H., Wilmot, G. R., Zesiewicz, T. and Meyer, C. (2018), Ann Clin Transl Neurol. . doi:10.1002/acn3.660
Treatment of Friedreich ataxia patients with omaveloxolone at the optimal dose level of 160 mg/day appears to improve neurological function. Therefore, omaveloxolone treatment is being examined in greater detail at 150 mg/day for Friedreich ataxia.
Treatment of Friedreich ataxia patients with omaveloxolone at the optimal dose level of 160 mg/day appears to improve neurological function. Therefore, omaveloxolone treatment is being examined in greater detail at 150 mg/day for Friedreich ataxia.
Wednesday, October 31, 2018
Transcriptional profiling of isogenic Friedreich ataxia induced pluripotent stem cell-derived neurons
Jiun-I Lai, Daniel Nachun, Lina Petrosyan, Benjamin Throesch, Erica Campau, Fuying Gao, Kristin K Baldwin, Giovanni Coppola, Joel M Gottesfeld, Elisabetta Soragni; bioRxiv 457093; doi: 10.1101/457093
We find that multiple cellular pathways are commonly affected by the loss of frataxin in CNS and peripheral nervous system neurons and these changes are partially restored by HDACi treatment.
We find that multiple cellular pathways are commonly affected by the loss of frataxin in CNS and peripheral nervous system neurons and these changes are partially restored by HDACi treatment.
Emerging Regulatory Role of Nrf2 in Iron, Heme, and Hemoglobin Metabolism in Physiology and Disease.
Kasai Shuya, Mimura Junsei, Ozaki Taku, Itoh Ken. Frontiers in Veterinary Science 5,242 2018 DOI=10.3389/fvets.2018.00242
In this review article, we describe and discuss the roles of Nrf2 in various iron-mediated bioreactions and its possible coevolution with iron and oxygen. Nrf2 regulates a wide range of cytoprotective responses and protects cells against various diseases and toxicities. In this review, we will focus on the Nrf2-mediated cytoprotective response achieved by iron regulation and detoxification.
In this review article, we describe and discuss the roles of Nrf2 in various iron-mediated bioreactions and its possible coevolution with iron and oxygen. Nrf2 regulates a wide range of cytoprotective responses and protects cells against various diseases and toxicities. In this review, we will focus on the Nrf2-mediated cytoprotective response achieved by iron regulation and detoxification.
Tuesday, October 30, 2018
Patients in research: still many roadblocks
Roos Eric C. BMJ 2018; 363 :k4387 doi:10.1136/bmj.k4387
Patient involvement is receiving increasing support as it can improve speed and quality of projects. At the same time, there is still significant resistance against it among doctors, investigators, and project managers. This “mental roadblock” must be fully removed to get the projected benefits.
Patient involvement is receiving increasing support as it can improve speed and quality of projects. At the same time, there is still significant resistance against it among doctors, investigators, and project managers. This “mental roadblock” must be fully removed to get the projected benefits.
Full partnership with patients is essential to any modern research enterprise
Wicks Paul, Richards Tessa, Denegri Simon, Godlee Fiona. Patients’ roles and rights in research BMJ 2018; 362 :k3193 doi:10.1136/bmj.k3193
Patient and public involvement in research is becoming a mainstream activity thanks to recognition by everyone in the research process from funders and regulators to conference organisers and publishers that it helps them do a better job.
Including patients and the public as partners in research is accepted best practice in several Western countries, and some funders make it mandatory.
Patient and public involvement in research is becoming a mainstream activity thanks to recognition by everyone in the research process from funders and regulators to conference organisers and publishers that it helps them do a better job.
Including patients and the public as partners in research is accepted best practice in several Western countries, and some funders make it mandatory.
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