Minoryx Therapeutics. Press Releases. Mataró, Barcelona, Spain and Charleroi, Belgium, January 9, 2020 – Minoryx Therapeutics
Leriglitazone (MIN-102), a novel, brain penetrant, orally bioavailable and selective PPARγ agonist, is currently in late-stage development for treatment of severe orphan CNS disorders, including X-ALD and Friedreich’s Ataxia. It previously received Orphan Drug Designation from EMA and FDA for both conditions
Thursday, January 9, 2020
Large-scale contractions of Friedreich’s ataxia GAA repeats in yeast occur during DNA replication due to their triplex-forming ability
Alexandra N. Khristich, Jillian F. Armenia, Robert M. Matera, Anna A. Kolchinski, and Sergei M. Mirkin; PNAS first published January 7, 2020 Doi:10.1073/pnas.1913416117
Expansions of GAA repeats cause a severe hereditary neurodegenerative disease, Friedreich’s ataxia. In this study, we characterized the mechanisms of GAA repeat contractions in a yeast experimental system. These mechanisms might, in the long run, aid development of a therapy for this currently incurable disease. We show that GAA repeats contract during DNA replication, which can explain the high level of somatic instability of this repeat in patient tissues. We also provided evidence that a triple-stranded DNA structure is at the heart of GAA repeat instability. This discovery highlights the role of triplex DNA in genome instability and human disease.
Expansions of GAA repeats cause a severe hereditary neurodegenerative disease, Friedreich’s ataxia. In this study, we characterized the mechanisms of GAA repeat contractions in a yeast experimental system. These mechanisms might, in the long run, aid development of a therapy for this currently incurable disease. We show that GAA repeats contract during DNA replication, which can explain the high level of somatic instability of this repeat in patient tissues. We also provided evidence that a triple-stranded DNA structure is at the heart of GAA repeat instability. This discovery highlights the role of triplex DNA in genome instability and human disease.
Wednesday, January 8, 2020
Multiple mechanisms underpin cerebral and cerebellar white matter deficits in Friedreich ataxia: The IMAGE‐FRDA study
Louisa P. Selvadurai Louise A. Corben Martin B. Delatycki Elsdon Storey Gary F. Egan Nellie Georgiou‐Karistianis Ian H. Harding. Hum Brain Mapp. 2020; 1– 14. doi:10.1002/hbm.24921
For the first time, we examined the relative sensitivity and relationship between multiple white matter indices in Friedreich ataxia to more richly characterize disease expression and infer possible mechanisms underlying the observed white matter abnormalities.
Multiple mechanisms likely underpin white matter abnormalities in Friedreich ataxia, with differential impacts in cerebellar and cerebral pathways.
For the first time, we examined the relative sensitivity and relationship between multiple white matter indices in Friedreich ataxia to more richly characterize disease expression and infer possible mechanisms underlying the observed white matter abnormalities.
Multiple mechanisms likely underpin white matter abnormalities in Friedreich ataxia, with differential impacts in cerebellar and cerebral pathways.
Tuesday, January 7, 2020
Heart-In-A-Jar Platform Humanizing Preclinical Research
Bio-IT World.By Deborah Borfitz, January 6, 2020.
The pumping capability was one of the more compelling features of the three-dimensional (3-D) organ construct for AstraZeneca, which is looking to screen drug candidates for treating heart failure with preserved ejection fraction—a common condition especially among the elderly and in women—with no effective therapy available, says Li. Novoheart’s cardiac tissue engineering technology, known as the MyHeart Platform, also held appeal for Pfizer, which has used it to model both electrical and mechanical defects of the heart in patients with the neurodegenerative disease Friedreich’s ataxia (FRDA).
In a study published earlier this year in Stem Cell Research & Therapy, the FRDA models demonstrated utility in evaluating novel therapeutics and disease progression. Study results highlighted the potential of small molecules or gene therapy for suppressing or reversing the cardiac symptoms of FRDA.
The pumping capability was one of the more compelling features of the three-dimensional (3-D) organ construct for AstraZeneca, which is looking to screen drug candidates for treating heart failure with preserved ejection fraction—a common condition especially among the elderly and in women—with no effective therapy available, says Li. Novoheart’s cardiac tissue engineering technology, known as the MyHeart Platform, also held appeal for Pfizer, which has used it to model both electrical and mechanical defects of the heart in patients with the neurodegenerative disease Friedreich’s ataxia (FRDA).
In a study published earlier this year in Stem Cell Research & Therapy, the FRDA models demonstrated utility in evaluating novel therapeutics and disease progression. Study results highlighted the potential of small molecules or gene therapy for suppressing or reversing the cardiac symptoms of FRDA.
Monday, January 6, 2020
Researchers suggest a pathway to reverse the genetic defect of Friedreich's ataxia
Alexandra N. Khristich el al., "Large-scale contractions of Friedreich's ataxia GAA repeats in yeast occur during DNA replication due to their triplex-forming ability," PNAS (2019). Doi:10.1073/pnas.1913416117
"While these results were uncovered in a yeast model, they do provide us with a clue into the mechanism of DNA repeat instability in Friedreich's ataxia," said Alexandra Khristich, graduate student in Mirkin's lab and first author of the study. "I hope that our discovery would become a starting point for the potential development of therapeutic strategies that tip the balance toward DNA repeat contraction in patient tissues"
"While these results were uncovered in a yeast model, they do provide us with a clue into the mechanism of DNA repeat instability in Friedreich's ataxia," said Alexandra Khristich, graduate student in Mirkin's lab and first author of the study. "I hope that our discovery would become a starting point for the potential development of therapeutic strategies that tip the balance toward DNA repeat contraction in patient tissues"
Friday, January 3, 2020
Longitudinal Increases in Cerebral Brain Activation During Working Memory Performance in Friedreich Ataxia: 24-Month Data from IMAGE-FRDA
Rosita Shishegar, Ian H. Harding, Louise A. Corben, Martin B. Delatycki, Elsdon Storey, Gary F. Egan, Nellie Georgiou-Karistianis; Cerebellum (2020). doi:10.1007/s12311-019-01094-6
These findings provide the first evidence of increased longitudinal activation over time in the cerebral cortex in FRDA, compared with controls, despite comparable working memory performance. This finding represents a possible compensatory response in the ventral attention network to help sustain working memory performance in individuals with FRDA.
These findings provide the first evidence of increased longitudinal activation over time in the cerebral cortex in FRDA, compared with controls, despite comparable working memory performance. This finding represents a possible compensatory response in the ventral attention network to help sustain working memory performance in individuals with FRDA.
Sunday, December 29, 2019
Health related quality of life in Friedreich Ataxia in a large heterogeneous cohort
Emily Xiong, Abigail E. Lynch, Louise A. Corben, Martin B. Delatycki, S.H. Subramony, Khalaf Bushara, Christopher M. Gomez, J. Chad Hoyle, Grace Yoon, Bernard Ravina, Katherine D. Mathews, George Wilmot, Theresa Zesiewicz, M. Susan Perlman, Jennifer M. Farmer, Christian Rummey, David R. Lynch; Neurological Sciences, Volume 0, Issue 0, 116642 DOI:10.1016/j.jns.2019.116642
The SF-36 and symptom specific scales capture dysfunction in FRDA in a manner that reflects disease status. HRQOL dysfunction was greatest on physically related scales; such scales correlated with disease duration, indicating that they worsen with progressing disease.
The SF-36 and symptom specific scales capture dysfunction in FRDA in a manner that reflects disease status. HRQOL dysfunction was greatest on physically related scales; such scales correlated with disease duration, indicating that they worsen with progressing disease.
Friday, December 27, 2019
Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia
Mariana Igoillo-Esteve, Ana F. Oliveira, Cristina Cosentino, Federica Fantuzzi, Céline Demarez, Sanna Toivonen, Amélie Hu, Satyan Chintawar, Miguel Lopes, Nathalie Pachera, Ying Cai, Baroj Abdulkarim, Myriam Rai, Lorella Marselli, Piero Marchetti, Mohammad Tariq, Jean-Christophe Jonas, Marina Boscolo, Massimo Pandolfo, Décio L. Eizirik, and Miriam Cnop; JCI Insight. Published December 26, 2019. doi:10.1172/jci.insight.134221.
Thursday, December 26, 2019
Antioxidant-mediated protective role of Hericium erinaceus (Bull.: Fr.) Pers. against oxidative damage in fibroblasts from Friedreich’s ataxia patient
LEW, Sze-Yuen; YOW, Yoon-Yen; LIM, Lee-Wei; WONG, Kah-Hui; SciELO journals. Dataset doi:10.6084/m9.figshare.11390835.v1
In this study, we investigated the antioxidant activities of a standardized aqueous extract from fruiting bodies of Hericium erinaceus mushroom (HESAE) and its protective effects against oxidative damage induced by L-Buthionine sulfoximine (BSO) in fibroblasts derived from FRDA patient. The lactate dehydrogenase-based viability assay showed that FRDA fibroblast was sensitive to 12.5 mM BSO with a reduction of viability to 52.51 ± 13.92% after 24 h of BSO exposure. Interestingly, co-incubation with 32 mg/mL HESAE increased the viability to 85.35 ± 3.4%. Further, 12.5 mM BSO caused a decrease in the ratio of cellular reduced glutathione (GSH) to oxidised GSH (GSSG) that leads to cell death.
FJ
In this study, we investigated the antioxidant activities of a standardized aqueous extract from fruiting bodies of Hericium erinaceus mushroom (HESAE) and its protective effects against oxidative damage induced by L-Buthionine sulfoximine (BSO) in fibroblasts derived from FRDA patient. The lactate dehydrogenase-based viability assay showed that FRDA fibroblast was sensitive to 12.5 mM BSO with a reduction of viability to 52.51 ± 13.92% after 24 h of BSO exposure. Interestingly, co-incubation with 32 mg/mL HESAE increased the viability to 85.35 ± 3.4%. Further, 12.5 mM BSO caused a decrease in the ratio of cellular reduced glutathione (GSH) to oxidised GSH (GSSG) that leads to cell death.
FJ
Tuesday, December 24, 2019
Rating scales for rare neurological diseases
Massimo Pandolfo; Neurol Genet Dec 2019, 5 (6) e380; DOI: 10.1212/NXG.0000000000000380
While only future experience will establish whether these scales are equally effective in FRDA clinical trials or if one proves superior, the point that they are both ataxia rating scales rather than comprehensive assessments of all FRDA neurologic features remains. Can we generalize this conclusion and say that rating scales assessing specific neurologic features are to be preferred to disease-specific scales in rare neurologic disorders? This is an open and controversial question. There have been and there are continuing efforts to develop and validate disease-specific scales for rare and even ultra-rare diseases, with the goal of disposing of robust, sensitive outcome measures for clinical trials, capturing as much as possible of the complexities of each of these conditions. Whether the same goal can be attained by appropriately combining general scales for neurologic impairments as weakness, spasticity, ataxia, and dystonia remains to be determined, but, in the light of our experience with a disease with as complex a neurologic picture as FRDA, this approach may be a viable and possibly even a preferable option.
While only future experience will establish whether these scales are equally effective in FRDA clinical trials or if one proves superior, the point that they are both ataxia rating scales rather than comprehensive assessments of all FRDA neurologic features remains. Can we generalize this conclusion and say that rating scales assessing specific neurologic features are to be preferred to disease-specific scales in rare neurologic disorders? This is an open and controversial question. There have been and there are continuing efforts to develop and validate disease-specific scales for rare and even ultra-rare diseases, with the goal of disposing of robust, sensitive outcome measures for clinical trials, capturing as much as possible of the complexities of each of these conditions. Whether the same goal can be attained by appropriately combining general scales for neurologic impairments as weakness, spasticity, ataxia, and dystonia remains to be determined, but, in the light of our experience with a disease with as complex a neurologic picture as FRDA, this approach may be a viable and possibly even a preferable option.
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