Purroy Lledós, Rosa. Universitat de Lleida. Departament de Ciències Mèdiques Bàsiques, (03-12-2018) Tesis, Director/a: Tamarit Sumalla, Jordi; Ros Salvador, Joaquim
Friedreich Ataxia is an inherited neurodegenerative disease with cardiac alterations and without any effective therapy. It is caused by a decrease of the mitochondrial protein frataxin. Nowadays, the exact function of this protein is still under discussion but it is related to iron homeostasis and oxidative stress. To study the frataxin deficiency consequences we have used a cardiac model based on primary cultures of neonatal rat cardiomyocytess. In this work it has been detected that frataxin deficiency causes i) mitochondrial permeability transition pore (MPTP) alterations, ii) mitochondrial calcium exporter NCLX decrease and iii) activation of calcineurin/NFAT cytosolic pathway that induces hypertrophy. Moreover, oxidative stress has been also studied detecting alterations of the glutathione levels and the redox state of PDH and KGDH mitochondrial complexes. Finally, the use of compounds to revert this phenotype, such as antioxidants or MPTP inhibitors, opens a new therapeutic strategy.
L’Atàxia de Friedreich és una malaltia neurodegenerativa hereditària amb afectació cardíaca per la qual no existeix cap teràpia efectiva. És causada per una disminució de la proteïna mitocondrial frataxina. Actualment, la funció precisa d’aquesta proteïna està en discussió però s’associa amb l’homeòstasi del ferro i l’estrès oxidatiu. Per a estudiar les conseqüències de la manca de frataxina s’ha utilitzat un model cardíac basat en cultius primaris de cardiomiòcits de rates nounades. En aquest treball s’ha detectat que el dèficit de frataxina provoca i) alteració del porus de transició de permeabilitat mitocondrial (MPTP), ii) disminució dels nivells de NCLX, exportador de calci mitocondrial i iii) activació de la via citosòlica calcineurina/NFAT, inductora de la hipertròfia. També s’ha estudiat l’estrès oxidatiu detectant alteracions en els nivells de glutatió i en l’estat redox dels complexos mitocondrials PDH i KGDH. Finalment, la utilització de compostos per revertir aquest fenotip, com antioxidants o inhibidors del MPTP, obren una nova estratègia terapèutica.(CAT)
Friday, February 1, 2019
Wednesday, January 30, 2019
n $1.9B Alliance, Neurocrine to Develop Voyager Gene Therapies for Parkinson’s, Friedreich’s Ataxia
Neurocrine Biosciences will partner with Voyager Therapeutics to develop and commercialize its gene therapy programs for Parkinson’s disease and Friedreich’s ataxia, plus two other programs to be determined, through a collaboration that could generate more than $1.865 billion for Voyager, the companies said today.
Tuesday, January 29, 2019
Correction to Liquid Chromatography-High Resolution Mass Spectrometry Analysis of Platelet Frataxin as a Protein Biomarker for the Rare Disease Friedreich’s Ataxia
Guo L, Wang Q, Weng L, Hauser LA, Strawser CJ, Rocha AG, Dancis A, Mesaros C, Lynch DR, Blair IA. Anal Chem. 2019 Jan 24. doi:10.1021/acs.analchem.9b00141.
New protein biomarker for the Rare Disease Friedreich’s Ataxia.
New protein biomarker for the Rare Disease Friedreich’s Ataxia.
Sunday, January 27, 2019
Patient involvement in medical research: what patients and physicians learn from each other
Kalen Young, Dana Kaminstein, Ana Olivos, Cristina Burroughs, Celeste Castillo-Lee, Joyce Kullman, Carol McAlear, Dianne G. Shaw, Antoine Sreih, George Casey, Vasculitis Patient-Powered Research Network and Peter A. Merkel; Orphanet Journal of Rare Diseases 2019 14:21 doi:10.1186/s13023-018-0969-1
Direct engagement in research design and development by patient-partners and co-learning between investigators and patient-partners can result in a positive and productive working relationship for all members of a medical research team. This bi-directional engagement directly benefits and impacts research design, participant recruitment to studies, and study subject retention.
Direct engagement in research design and development by patient-partners and co-learning between investigators and patient-partners can result in a positive and productive working relationship for all members of a medical research team. This bi-directional engagement directly benefits and impacts research design, participant recruitment to studies, and study subject retention.
Wednesday, January 23, 2019
Rare Diseases Inform Myocardial Phenotypes for Precision Medicine
Macrae, Calum A., Journal of Cardiac Failure , Volume 24 , Issue 10 , 680 - 681
Friedreich's ataxia (FA) is an autosomal recessive “triplet repeat” disorder characterized by cerebellar degeneration, long tract neuropathy, and a generalized myopathy.1 Although neurologic symptoms typically antedate any clinical cardiac involvement, heart failure remains the dominant cause of death in FA. The genetic basis of the disorder is a dramatic expansion of a GAA repeat sequence in the first intron of the FRDA gene, which encodes an iron-binding mitochondrial protein whose function remains incompletely understood.
Friedreich's ataxia (FA) is an autosomal recessive “triplet repeat” disorder characterized by cerebellar degeneration, long tract neuropathy, and a generalized myopathy.1 Although neurologic symptoms typically antedate any clinical cardiac involvement, heart failure remains the dominant cause of death in FA. The genetic basis of the disorder is a dramatic expansion of a GAA repeat sequence in the first intron of the FRDA gene, which encodes an iron-binding mitochondrial protein whose function remains incompletely understood.
Tuesday, January 22, 2019
Modelling of Friedreich’s Ataxia and other Genetic Disorders as Defective / Noisy Genetic Information Processing
SWASTI WAGH, D.K. WAGH; Journal of Ultra Scientist of Physical Sciences - A, Voulume: 30, Issue: 12 DOI:10.22147/jusps-A/301201
Genetic disorders are due to mutation of some gene. For example, Friedreich’s Ataxia is due to mutation of frataxin gene. The mutation causes transmission error (noise) in the transmission channel. In this paper we show how this transmission error can be calculated using information theory approach.
Genetic disorders are due to mutation of some gene. For example, Friedreich’s Ataxia is due to mutation of frataxin gene. The mutation causes transmission error (noise) in the transmission channel. In this paper we show how this transmission error can be calculated using information theory approach.
Friday, January 18, 2019
Heart disease in Friedreich’s ataxia
Hanson E, Sheldon M, Pacheco B, Alkubeysi M, Raizada V.; World J Cardiol. Jan 26, 2019; 11(1): 1-12 Published online Jan 26, 2019. doi: 10.4330/wjc.v11.i1.1
The present review discusses the pathogenesis, clinical manifestations, and spectrum of cardiac disease in Friedreich’s Ataxia, and introduces gene-targeted and pathology-specific therapies, in addition to the screening guidelines that should be used to monitor cardiac disease in this mitochondrial disorder.
The present review discusses the pathogenesis, clinical manifestations, and spectrum of cardiac disease in Friedreich’s Ataxia, and introduces gene-targeted and pathology-specific therapies, in addition to the screening guidelines that should be used to monitor cardiac disease in this mitochondrial disorder.
Thursday, January 17, 2019
Estimating the clinical cost of drug development for orphan versus non-orphan drugs
Kavisha Jayasundara, Aidan Hollis, Murray Krahn, Muhammad Mamdani, Jeffrey S. Hoch and Paul Grootendorst; Orphanet Journal of Rare Diseases 201914:12 doi:10.1186/s13023-018-0990-4
Using publicly available data, we estimated the differences in trial characteristics and clinical development costs with 100 orphan and 100 non-orphan drugs. We found that the out-of-pocket clinical costs per approved orphan drug to be $166 million and $291 million (2013 USD) per non-orphan drug. The capitalized clinical costs per approved orphan drug and non-orphan drug were estimated to be $291 million and $412 million respectively. When focusing on new molecular entities only, we found that the capitalized clinical cost per approved orphan drug was half that of a non-orphan drug. More discussion is needed to better align on which cost components should be included in research and development costs for pharmaceuticals.
Using publicly available data, we estimated the differences in trial characteristics and clinical development costs with 100 orphan and 100 non-orphan drugs. We found that the out-of-pocket clinical costs per approved orphan drug to be $166 million and $291 million (2013 USD) per non-orphan drug. The capitalized clinical costs per approved orphan drug and non-orphan drug were estimated to be $291 million and $412 million respectively. When focusing on new molecular entities only, we found that the capitalized clinical cost per approved orphan drug was half that of a non-orphan drug. More discussion is needed to better align on which cost components should be included in research and development costs for pharmaceuticals.
Wednesday, January 16, 2019
Young adult with Friedreich ataxia
Milano EG, Harries IB, Bucciarelli-Ducci C, Heart Published Online First: 15 January 2019. doi: 10.1136/heartjnl-2018-314387
Clinical introduction A young adult with Friedreich ataxia complaining of exertional breathlessness underwent a cardiological evaluation. On physical examination, high blood pressure and a loud systolic murmur were noted. ECG showed sinus rhythm with voltage criteria for left ventricular hypertrophy (LVH) and T-wave changes in the inferolateral leads. Transthoracic echocardiography showed biventricular hypertrophy (maximum wall thickness of the interventricular septum 26 mm and 16 mm of the posterior wall), preserved systolic function, mild left ventricular intracavity gradient and an unremarkable mitral and aortic valve. A cardiovascular magnetic resonance (CMR) was requested for further assessment. CMR protocol, performed using a 1.5 T scanner.
Clinical introduction A young adult with Friedreich ataxia complaining of exertional breathlessness underwent a cardiological evaluation. On physical examination, high blood pressure and a loud systolic murmur were noted. ECG showed sinus rhythm with voltage criteria for left ventricular hypertrophy (LVH) and T-wave changes in the inferolateral leads. Transthoracic echocardiography showed biventricular hypertrophy (maximum wall thickness of the interventricular septum 26 mm and 16 mm of the posterior wall), preserved systolic function, mild left ventricular intracavity gradient and an unremarkable mitral and aortic valve. A cardiovascular magnetic resonance (CMR) was requested for further assessment. CMR protocol, performed using a 1.5 T scanner.
Tuesday, January 15, 2019
Revealing the Superpowers of PrimPol: rescuing replicating microsatellites
Reid, J. E., & Fischer, T. (2019). The EMBO Journal, e101298. doi:10.15252/embj.2018101298
Error‐free replication of repetitive stretches of DNA is crucial for human health, as more than 30 hereditary developmental and neurological diseases are linked to changes in length of microsatellites, where the repeating unit is < 9 nucleotides. Friedreich's ataxia (FRDA) is one such repeat expansion disease, exhibiting a large number of GAA repeats in the first intron of the FXN gene. Expansion of (GAA)n results in reduced levels of the FXN protein. Normal FXN alleles have < 12 repeats, while disease‐associated alleles often have 600–900 repeats. Therefore, it appears there is a limit to the number of (GAA)n repeats that can be present before this becomes damaging.
Error‐free replication of repetitive stretches of DNA is crucial for human health, as more than 30 hereditary developmental and neurological diseases are linked to changes in length of microsatellites, where the repeating unit is < 9 nucleotides. Friedreich's ataxia (FRDA) is one such repeat expansion disease, exhibiting a large number of GAA repeats in the first intron of the FXN gene. Expansion of (GAA)n results in reduced levels of the FXN protein. Normal FXN alleles have < 12 repeats, while disease‐associated alleles often have 600–900 repeats. Therefore, it appears there is a limit to the number of (GAA)n repeats that can be present before this becomes damaging.
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