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.
Wednesday, January 30, 2019
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.
Monday, January 14, 2019
Ferroptosis as a novel therapeutic target for Friedreich's ataxia
M. Grazia Cotticelli, Shujuan Xia, Daniel Lin, Taehee Lee, Leila Terrab, Peter Wipf, Donna Huryn and Robert Wilson
Journal of Pharmacology and Experimental Therapeutics January 11, 2019, jpet.118.252759; DOI:10.1124/jpet.118.252759
Ferropotosis is a recently identified pathway of regulated, iron-dependent cell death, which is biochemically distinct from apoptosis. We evaluated whether there is evidence for ferroptotic pathway activation in cellular models of FRDA. We found that primary patient-derived fibroblasts, murine fibroblasts with FRDA-associated mutations, and murine fibroblasts in which a repeat expansion had been introduced (KIKO) were more sensitive than normal control cells to erastin, a known ferroptosis inducer. We also found that the ferroptosis inhibitors SRS11-92 and Fer-1, used at 500 nM, were efficacious in protecting human and mouse cellular models of FRDA treated with ferric ammonium citrate (FAC) and an inhibitor of glutathione synthesis (BSO), whereas caspase-3 inhibitors failed to show significant biological activity. Cells treated with FAC and BSO consistently showed decreased glutathione-dependent peroxidase activity and increased lipid peroxidation, both hallmarks of ferroptosis. Finally, the ferroptosis inhibitor SRS11-92 decreased the cell death associated with frataxin knockdown in healthy human fibroblasts. Taken together, these data suggest that ferroptosis inhibitors may have therapeutic potential in FRDA.
Journal of Pharmacology and Experimental Therapeutics January 11, 2019, jpet.118.252759; DOI:10.1124/jpet.118.252759
Ferropotosis is a recently identified pathway of regulated, iron-dependent cell death, which is biochemically distinct from apoptosis. We evaluated whether there is evidence for ferroptotic pathway activation in cellular models of FRDA. We found that primary patient-derived fibroblasts, murine fibroblasts with FRDA-associated mutations, and murine fibroblasts in which a repeat expansion had been introduced (KIKO) were more sensitive than normal control cells to erastin, a known ferroptosis inducer. We also found that the ferroptosis inhibitors SRS11-92 and Fer-1, used at 500 nM, were efficacious in protecting human and mouse cellular models of FRDA treated with ferric ammonium citrate (FAC) and an inhibitor of glutathione synthesis (BSO), whereas caspase-3 inhibitors failed to show significant biological activity. Cells treated with FAC and BSO consistently showed decreased glutathione-dependent peroxidase activity and increased lipid peroxidation, both hallmarks of ferroptosis. Finally, the ferroptosis inhibitor SRS11-92 decreased the cell death associated with frataxin knockdown in healthy human fibroblasts. Taken together, these data suggest that ferroptosis inhibitors may have therapeutic potential in FRDA.
Sunday, January 13, 2019
Longitudinal evaluation of iron concentration and atrophy in the dentate nuclei in friedreich ataxia
Phillip G. D. Ward PhD, Ian H. Harding PhD, Thomas G. Close PhD, Louise A. Corben PhD, Martin B. Delatycki MBBS, FRACP, PhD, Elsdon Storey DPhil
Nellie Georgiou‐Karistianis PhD, Gary F. Egan PhD; Movement Disorders : Official Journal of the Movement Disorder Society [09 Jan 2019] DOI: 10.1002/mds.27606
Progressive dentate nucleus abnormalities are 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 2‐year period highlight the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool
Nellie Georgiou‐Karistianis PhD, Gary F. Egan PhD; Movement Disorders : Official Journal of the Movement Disorder Society [09 Jan 2019] DOI: 10.1002/mds.27606
Progressive dentate nucleus abnormalities are 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 2‐year period highlight the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool
Saturday, January 12, 2019
Etravirine in Friedreich's ataxia: Lessons from HIV?
Lynch DR, Schadt K1, Kichula E. Mov Disord. 2019 Jan 10. doi: 10.1002/mds.27605. [Epub ahead of print]
Friday, January 11, 2019
Drug repositioning screening identifies etravirine as a potential therapeutic for friedreich's ataxia
Giulia Alfedi MSc, Riccardo Luffarelli MSc, Ivano Condò PhD, Giorgia Pedini MSc, Liliana Mannucci PhD, Damiano S. Massaro PhD, Monica Benini PhD, Nicola Toschi PhD, Giorgia Alaimo PhD, Luca Panarello MSc, Laura Pacini PhD, Silvia Fortuni PhD, Dario Serio BS, Florence Malisan PhD, Roberto Testi MD, Alessandra Rufini PhD; Movement Disorders : Official Journal of the Movement Disorder Society [09 Jan 2019] Early View. DOI: 10.1002/mds.27604
Friedreich's ataxia is an autosomal-recessive cerebellar ataxia caused by mutation of the frataxin gene, resulting in decreased frataxin expression, mitochondrial dysfunction, and oxidative stress. Currently, no treatment is available for Friedreich's ataxia patients. Given that levels of residual frataxin critically affect disease severity, the main goal of a specific therapy for Friedreich's ataxia is to increase frataxin levels. With the aim to accelerate the development of a new therapy for Friedreich's ataxia, we took a drug repositioning approach to identify market-available drugs able to increase frataxin levels. Using a cell-based reporter assay to monitor variation in frataxin amount, we performed a high-throughput screening of a library containing 853 U.S. Food and Drug Administration-approved drugs. Among the potentially interesting candidates isolated from the screening, we focused our attention on etravirine, an antiviral drug currently in use as an anti-human immunodeficiency virus therapy. Here, we show that etravirine can promote a significant increase in frataxin levels in cells derived from Friedreich's ataxia patients, by enhancing frataxin messenger RNA translation. Importantly, frataxin accumulation in treated patient cell lines is comparable to frataxin levels in unaffected carrier cells, suggesting that etravirine could be therapeutically relevant. Indeed, etravirine treatment restores the activity of the iron-sulphur cluster containing enzyme aconitase and confers resistance to oxidative stress in cells derived from Friedreich's ataxia patients. Considering its excellent safety profile along with its ability to increase frataxin levels and correct some of the disease-related defects, etravirine represents a promising candidate as a therapeutic for Friedreich's ataxia.
Friedreich's ataxia is an autosomal-recessive cerebellar ataxia caused by mutation of the frataxin gene, resulting in decreased frataxin expression, mitochondrial dysfunction, and oxidative stress. Currently, no treatment is available for Friedreich's ataxia patients. Given that levels of residual frataxin critically affect disease severity, the main goal of a specific therapy for Friedreich's ataxia is to increase frataxin levels. With the aim to accelerate the development of a new therapy for Friedreich's ataxia, we took a drug repositioning approach to identify market-available drugs able to increase frataxin levels. Using a cell-based reporter assay to monitor variation in frataxin amount, we performed a high-throughput screening of a library containing 853 U.S. Food and Drug Administration-approved drugs. Among the potentially interesting candidates isolated from the screening, we focused our attention on etravirine, an antiviral drug currently in use as an anti-human immunodeficiency virus therapy. Here, we show that etravirine can promote a significant increase in frataxin levels in cells derived from Friedreich's ataxia patients, by enhancing frataxin messenger RNA translation. Importantly, frataxin accumulation in treated patient cell lines is comparable to frataxin levels in unaffected carrier cells, suggesting that etravirine could be therapeutically relevant. Indeed, etravirine treatment restores the activity of the iron-sulphur cluster containing enzyme aconitase and confers resistance to oxidative stress in cells derived from Friedreich's ataxia patients. Considering its excellent safety profile along with its ability to increase frataxin levels and correct some of the disease-related defects, etravirine represents a promising candidate as a therapeutic for Friedreich's ataxia.
Wednesday, January 2, 2019
Differences in the determinants of right ventricular and regional left ventricular long-axis dysfunction in Friedreich ataxia
Peverill RE, Donelan L, Corben LA, Delatycki MB (2018). PLoS ONE 13(12): e0209410. doi:10.1371/journal.pone.0209410
There are generalized abnormalities of RV and LV regional long axis function in FRDA, but there are also regional differences in the association of the various LV walls long-axis TDI velocities with the small and large alleles of the FXN gene and the extent of LV structural change. Further studies are required to confirm these findings and to investigate possible mechanisms which might explain these regional LV and RV differences.
There are generalized abnormalities of RV and LV regional long axis function in FRDA, but there are also regional differences in the association of the various LV walls long-axis TDI velocities with the small and large alleles of the FXN gene and the extent of LV structural change. Further studies are required to confirm these findings and to investigate possible mechanisms which might explain these regional LV and RV differences.
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