Lynch DR, Schadt K1, Kichula E. Mov Disord. 2019 Jan 10. doi: 10.1002/mds.27605. [Epub ahead of print]
Saturday, January 12, 2019
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.
Friday, December 28, 2018
GRP75 overexpression rescues frataxin deficiency and mitochondrial phenotypes in Friedreich Ataxia cellular models
Yi Na Dong Emily McMillian Elisia M Clark Hong Lin David R Lynch, Human Molecular Genetics, ddy448, doi:10.1093/hmg/ddy448 Published: 26 December 2018
We present evidence that mitochondrial molecular chaperone GRP75, also known as mortalin/mthsp70/PBP74, directly interacts with frataxin both in vivo in mouse cortex and in vitro in cortical neurons. Overexpressing GRP75 increases the levels of both wild-type frataxin and clinically relevant missense frataxin variants in HEK293 cells while clinical GRP75 variants such as R126W, A476T and P509S impair the binding of GRP75 with frataxin and the effect of GRP75 on frataxin levels. In addition, GRP75 overexpression rescues frataxin deficiency and abnormal cellular phenotypes such as the abnormal mitochondrial network and decreased ATP levels in FRDA patient-derived cells. The effect of GRP75 on frataxin might be in part mediated by the physical interaction between GRP75 and mitochondrial processing peptidase (MPP), which makes frataxin more accessible to MPP. As GRP75 levels are decreased in multiple cell types of FRDA patients, restoring GRP75 might be effective in treating both typical FRDA patients with two GAA repeat expansions and compound heterozygous patients with point mutations.
We present evidence that mitochondrial molecular chaperone GRP75, also known as mortalin/mthsp70/PBP74, directly interacts with frataxin both in vivo in mouse cortex and in vitro in cortical neurons. Overexpressing GRP75 increases the levels of both wild-type frataxin and clinically relevant missense frataxin variants in HEK293 cells while clinical GRP75 variants such as R126W, A476T and P509S impair the binding of GRP75 with frataxin and the effect of GRP75 on frataxin levels. In addition, GRP75 overexpression rescues frataxin deficiency and abnormal cellular phenotypes such as the abnormal mitochondrial network and decreased ATP levels in FRDA patient-derived cells. The effect of GRP75 on frataxin might be in part mediated by the physical interaction between GRP75 and mitochondrial processing peptidase (MPP), which makes frataxin more accessible to MPP. As GRP75 levels are decreased in multiple cell types of FRDA patients, restoring GRP75 might be effective in treating both typical FRDA patients with two GAA repeat expansions and compound heterozygous patients with point mutations.
Monday, December 17, 2018
Transcriptional profiling of isogenic Friedreich ataxia neurons and effect of an HDAC inhibitor on disease signatures
Jiun-I Lai, Daniel Nachun, Lina Petrosyan, Benjamin Throesch, Erica Campau, Fuying Gao, Kristin K Baldwin, Giovanni Coppola, Joel M. Gottesfeld, and Elisabetta Soragni; J. Biol. Chem. jbc.RA118.006515. doi:10.1074/jbc.RA118.006515
How the reduced expression of frataxin leads to neurological and other systemic symptoms in FRDA patients remains unclear. Similar to other triplet-repeat disorders, it is unknown why FRDA affects only specific cell types, primarily the large sensory neurons of the dorsal root ganglia and cardiomyocytes. The combination of iPSC technology and genome-editing techniques offers the unique possibility to address these questions in a relevant cell model of FRDA, obviating confounding effects of variable genetic backgrounds. Here, using “scarless” gene-editing methods, we created isogenic iPSC lines that differ only in the length of the GAA•TTC repeats. To uncover the gene expression signatures due to the GAA•TTC repeat expansion in FRDA neuronal cells and the effect of HDACi on these changes, we performed RNA-seq-based transcriptomic analysis of iPSC-derived central nervous system (CNS) and isogenic sensory neurons. We found that cellular pathways related to neuronal function, regulation of transcription, extracellular matrix organization and apoptosis are affected by frataxin loss in neurons of the CNS and peripheral nervous system and that these changes are partially restored by HDACi treatment.
How the reduced expression of frataxin leads to neurological and other systemic symptoms in FRDA patients remains unclear. Similar to other triplet-repeat disorders, it is unknown why FRDA affects only specific cell types, primarily the large sensory neurons of the dorsal root ganglia and cardiomyocytes. The combination of iPSC technology and genome-editing techniques offers the unique possibility to address these questions in a relevant cell model of FRDA, obviating confounding effects of variable genetic backgrounds. Here, using “scarless” gene-editing methods, we created isogenic iPSC lines that differ only in the length of the GAA•TTC repeats. To uncover the gene expression signatures due to the GAA•TTC repeat expansion in FRDA neuronal cells and the effect of HDACi on these changes, we performed RNA-seq-based transcriptomic analysis of iPSC-derived central nervous system (CNS) and isogenic sensory neurons. We found that cellular pathways related to neuronal function, regulation of transcription, extracellular matrix organization and apoptosis are affected by frataxin loss in neurons of the CNS and peripheral nervous system and that these changes are partially restored by HDACi treatment.
Saturday, December 15, 2018
Correction of half the cardiomyocytes fully rescue Friedreich Ataxia mitochondrial cardiomyopathy through cell-autonomous mechanisms
Brahim Belbellaa, Laurence Reutenauer, Laurent Monassier, Hélène Puccio; Human Molecular Genetics, , ddy427, doi:10.1093/hmg/ddy427
Correlative analysis of vector cardiac biodistribution, survival, cardiac function and biochemical hallmarks of the disease revealed that full rescue of the cardiac function was achieved when only half of the cardiomyocytes were transduced. In addition, meaningful therapeutic effect was achieved with as little as 30% transduction coverage. This therapeutic effect was mediated through cell-autonomous mechanisms for mitochondria homeostasis, although a significant increase in survival of uncorrected neighboring cells was observed.
Correlative analysis of vector cardiac biodistribution, survival, cardiac function and biochemical hallmarks of the disease revealed that full rescue of the cardiac function was achieved when only half of the cardiomyocytes were transduced. In addition, meaningful therapeutic effect was achieved with as little as 30% transduction coverage. This therapeutic effect was mediated through cell-autonomous mechanisms for mitochondria homeostasis, although a significant increase in survival of uncorrected neighboring cells was observed.
Thursday, December 13, 2018
Clinical presentation and survival of childhood hypertrophic cardiomyopathy: a retrospective study in United Kingdom
Gabrielle Norrish Ella Field Karen Mcleod Maria Ilina Graham Stuart Vinay Bhole Orhan Uzun Elspeth Brown Piers E F Daubeney Amrit Lota Katie Linter Sujeev Mathur Tara Bharucha Khoon Li Kok Satish Adwani Caroline B Jones Zdenka Reinhardt Juan Pablo Kaski. European Heart Journal, ehy798, doi:10.1093/eurheartj/ehy798
Six hundred and eighty-seven patients with HCM presented at a median age of 5.2 years (range 0–16). Aetiology was: non-syndromic (n = 433, 63%), RASopathy (n = 126, 18.3%), Friedreich’s ataxia (n = 59, 8.6%) or inborn errors of metabolism (IEM) (n = 64, 9%). In infants (n = 159, 23%) underlying aetiology was more commonly a RASopathy (42% vs. 11.2%, P < 0.0001) or IEM (18.9% vs. 6.4% P < 0.0001). In those with familial disease, median age of presentation was higher (11 years vs. 6 years, P < 0.0001), 141 (58%) presente
Six hundred and eighty-seven patients with HCM presented at a median age of 5.2 years (range 0–16). Aetiology was: non-syndromic (n = 433, 63%), RASopathy (n = 126, 18.3%), Friedreich’s ataxia (n = 59, 8.6%) or inborn errors of metabolism (IEM) (n = 64, 9%). In infants (n = 159, 23%) underlying aetiology was more commonly a RASopathy (42% vs. 11.2%, P < 0.0001) or IEM (18.9% vs. 6.4% P < 0.0001). In those with familial disease, median age of presentation was higher (11 years vs. 6 years, P < 0.0001), 141 (58%) presente
Wednesday, December 12, 2018
Be open about drug failures to speed up research
Enrica Alteri and Lorenzo Guizzaro. Nature 563, 317-319 (2018) doi: 10.1038/d41586-018-07352-7
COMMENT 13 NOVEMBER 2018
Access to evidence from disappointing drug-development programmes advances the whole scientific process, explain Enrica Alteri and Lorenzo Guizzaro.
To speed up progress, companies must be more forthcoming with their data and thinking, and regulators must find ways to help them with this. The ultimate goal is to allow broader access to data from drug-development programmes and to enable faster learning by the entire research community.
We hope that this project (Alzheimer’s treatments) leads to similar efforts in other diseases that are difficult to treat. We owe it to the public and to patients to ensure that R&D efforts continue to move towards greater transparency.
COMMENT 13 NOVEMBER 2018
Access to evidence from disappointing drug-development programmes advances the whole scientific process, explain Enrica Alteri and Lorenzo Guizzaro.
To speed up progress, companies must be more forthcoming with their data and thinking, and regulators must find ways to help them with this. The ultimate goal is to allow broader access to data from drug-development programmes and to enable faster learning by the entire research community.
We hope that this project (Alzheimer’s treatments) leads to similar efforts in other diseases that are difficult to treat. We owe it to the public and to patients to ensure that R&D efforts continue to move towards greater transparency.
Monday, December 10, 2018
From scientific discovery to treatments for rare diseases – the view from the National Center for Advancing Translational Sciences – Office of Rare Diseases Research
Petra Kaufmann, Anne R. Pariser and Christopher Austin. Orphanet Journal of Rare Diseases 2018 13:196 doi:10.1186/s13023-018-0936-x
We now live in a time of unprecedented opportunities to turn scientific discoveries into better treatments for the estimated 30 million people in the US living with rare diseases. Despite these scientific advances, more than 90% of rare diseases still lack an effective treatment. New data and genetics technologies have resulted in the first transformational new treatments for a handful of rare diseases. This challenges us as a society to accelerate progress so that no disease and no patient is, ultimately, left behind in getting access to safe and effective therapeutics.
We now live in a time of unprecedented opportunities to turn scientific discoveries into better treatments for the estimated 30 million people in the US living with rare diseases. Despite these scientific advances, more than 90% of rare diseases still lack an effective treatment. New data and genetics technologies have resulted in the first transformational new treatments for a handful of rare diseases. This challenges us as a society to accelerate progress so that no disease and no patient is, ultimately, left behind in getting access to safe and effective therapeutics.
Saturday, December 8, 2018
Large Interruptions of GAA Repeat Expansion Mutations in Friedreich Ataxia Are Very Rare
Al-Mahdawi Sahar, Ging Heather, Bayot Aurelien, Cavalcanti Francesca, La Cognata Valentina, Cavallaro Sebastiano, Giunti Paola, Pook Mark A. Front Cell Neurosci. 2018 Nov 21;12:443. doi: 10.3389/fncel.2018.00443. eCollection 2018.
Friedreich ataxia is a multi-system autosomal recessive inherited disorder primarily caused by homozygous GAA repeat expansion mutations within intron 1 of the frataxin gene. The resulting deficiency of frataxin protein leads to progressive mitochondrial dysfunction, oxidative stress and cell death, with the main affected sites being the large sensory neurons of the dorsal root ganglia and the dentate nucleus of the cerebellum. The GAA repeat expansions may be pure (GAA)n in sequence or may be interrupted with regions of non-GAA sequence. To our knowledge there has been no large-scale study of FRDA patient DNA samples to determine the frequency of large interruptions in GAA repeat expansions. Therefore, we have investigated a panel of 245 Friedreich ataxia patient and carrier DNA samples using GAA repeat PCR amplification and MboII restriction enzyme digestion. We demonstrate that the vast majority (97.8%) of Friedreich ataxia GAA repeat expansion samples do not contain significant sequence changes that would result in abnormal MboII digestion profiles, indicating that they are primarily pure GAA repeats. These results show for the first time that large interruptions in the GAA repeats are very rare.
Friedreich ataxia is a multi-system autosomal recessive inherited disorder primarily caused by homozygous GAA repeat expansion mutations within intron 1 of the frataxin gene. The resulting deficiency of frataxin protein leads to progressive mitochondrial dysfunction, oxidative stress and cell death, with the main affected sites being the large sensory neurons of the dorsal root ganglia and the dentate nucleus of the cerebellum. The GAA repeat expansions may be pure (GAA)n in sequence or may be interrupted with regions of non-GAA sequence. To our knowledge there has been no large-scale study of FRDA patient DNA samples to determine the frequency of large interruptions in GAA repeat expansions. Therefore, we have investigated a panel of 245 Friedreich ataxia patient and carrier DNA samples using GAA repeat PCR amplification and MboII restriction enzyme digestion. We demonstrate that the vast majority (97.8%) of Friedreich ataxia GAA repeat expansion samples do not contain significant sequence changes that would result in abnormal MboII digestion profiles, indicating that they are primarily pure GAA repeats. These results show for the first time that large interruptions in the GAA repeats are very rare.
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