Strategic Transactions. Jul 2018
Executive Summary
Reata Pharmaceuticals Inc. (developing drugs targeting molecular pathways that regulate inflammation and cellular metabolism) netted $203mm through the public sale of 3mm Class A common shares at $72. Some of the funds will support ongoing development of lead candidates bardoxolone methyl (Phase II/III for chronic kidney disease caused by Alport syndrome) and omaveloxolone (Phase II for Friedreich's ataxia), and to prepare for NDA filings and future commercialization.
Saturday, July 28, 2018
Double-blind, randomized and controlled trial of EPI-743 in Friedreich's ataxia
Theresa Zesiewicz, Jason L Salemi, Susan Perlman, Kelly L Sullivan, Jessica D Shaw, Yangxin Huang, Charles Isaacs, Clifton Gooch, David R Lynch & Matthew B Klein; Neurodegenerative Disease Management [27 Jul 2018] doi:10.2217/nmt-2018-0013
Aim: To evaluate the safety and clinical effects of EPI-743 in Friedreich's ataxia patients. EPI-743 is a compound that targets oxidoreductase enzymes essential for redox control of metabolism. Methods: We conducted a multicenter trial that evaluated EPI-743 during a 6-month placebo-controlled phase, followed by an 18-month open-label phase. End points included low-contrast visual acuity and the Friedreich's Ataxia Rating Scale. Results/conclusion: EPI-743 was demonstrated to be safe and well tolerated. There were no significant improvements in key end points during the placebo phase. However, at 24 months, EPI-743 treatment was associated with a statistically significant improvement in neurological function and disease progression relative to a natural history cohort (p > 0.001).
Aim: To evaluate the safety and clinical effects of EPI-743 in Friedreich's ataxia patients. EPI-743 is a compound that targets oxidoreductase enzymes essential for redox control of metabolism. Methods: We conducted a multicenter trial that evaluated EPI-743 during a 6-month placebo-controlled phase, followed by an 18-month open-label phase. End points included low-contrast visual acuity and the Friedreich's Ataxia Rating Scale. Results/conclusion: EPI-743 was demonstrated to be safe and well tolerated. There were no significant improvements in key end points during the placebo phase. However, at 24 months, EPI-743 treatment was associated with a statistically significant improvement in neurological function and disease progression relative to a natural history cohort (p > 0.001).
Phenothiazine antioxidants increase mitochondrial biogenesis and frataxin levels in Friedreich’s Ataxia cells
Omar Khdour, Indrajit Bandyopadhyay, Nishant Visavadiya, Sandipan Roy Chowdhury, Sidney M Hecht; MedChemComm ( IF 2.342 ) Pub Date : 2018-07-26 , DOI: 10.1039/C8MD00274F
Friedreich’s ataxia (FRDA) is a progressive neurodegenerative disease that is linked to transcriptional repression of the nuclear FXN gene encoding the essential mitochondrial protein frataxin (FXN). Compounds that increase frataxin levels may enable effective therapeutic intervention for blunting disease progression. Recently, we showed that lipophilic methylene violet (MV) and methylene blue (MB) analogues both conferred benefit to cultured FRDA cells in several regards, including ROS suppression, maintenance of mitochondrial membrane potential and increased ATP production. Some of the MB analogues were also shown to promote increased frataxin levels and mitochondrial biogenesis. Presently, we report that two of the MV analogues studied previously (1 and 2) also increased frataxin levels and mitochondrial biogenesis significantly. Because the substitution pattern in the two series of compounds was not the same, we also prepared new MV derivatives having the same substitution pattern as the original MB derivatives studied to enable a more direct comparison. Two of the new MV compounds, 4b and 6b, exhibited enhanced antioxidant capability, increased frataxin levels and mitochondrial biogenesis, and improved aconitase activity. These encouraging findings demonstrated that the MV analogues had better overall activity with less cytotoxicity.
Friedreich’s ataxia (FRDA) is a progressive neurodegenerative disease that is linked to transcriptional repression of the nuclear FXN gene encoding the essential mitochondrial protein frataxin (FXN). Compounds that increase frataxin levels may enable effective therapeutic intervention for blunting disease progression. Recently, we showed that lipophilic methylene violet (MV) and methylene blue (MB) analogues both conferred benefit to cultured FRDA cells in several regards, including ROS suppression, maintenance of mitochondrial membrane potential and increased ATP production. Some of the MB analogues were also shown to promote increased frataxin levels and mitochondrial biogenesis. Presently, we report that two of the MV analogues studied previously (1 and 2) also increased frataxin levels and mitochondrial biogenesis significantly. Because the substitution pattern in the two series of compounds was not the same, we also prepared new MV derivatives having the same substitution pattern as the original MB derivatives studied to enable a more direct comparison. Two of the new MV compounds, 4b and 6b, exhibited enhanced antioxidant capability, increased frataxin levels and mitochondrial biogenesis, and improved aconitase activity. These encouraging findings demonstrated that the MV analogues had better overall activity with less cytotoxicity.
Friday, July 27, 2018
Monash plant science discovery may unlock treatment strategies for genetic diseases in humans
SOURCE Monash University
SYDNEY, July 26, 2018 /PRNewswire/ -- Monash plant scientists have discovered a new molecular mechanism of gene regulation, which could have major implications for the development of treatment strategies for Friedreich's ataxia -- a debilitating genetic disorder that causes damage to the nervous system.
"This research has major implications for our understanding of how the genetic mutation that underlies Friedreich ataxia, leads to damage of the nervous system and thus symptoms of this condition," said Professor Martin Delatycki, a clinician and researcher from Murdoch Children's Research Institute who has studied Friedreich ataxia for more than 20 years.
SYDNEY, July 26, 2018 /PRNewswire/ -- Monash plant scientists have discovered a new molecular mechanism of gene regulation, which could have major implications for the development of treatment strategies for Friedreich's ataxia -- a debilitating genetic disorder that causes damage to the nervous system.
"This research has major implications for our understanding of how the genetic mutation that underlies Friedreich ataxia, leads to damage of the nervous system and thus symptoms of this condition," said Professor Martin Delatycki, a clinician and researcher from Murdoch Children's Research Institute who has studied Friedreich ataxia for more than 20 years.
RNA-Dependent Epigenetic Silencing Directs Transcriptional Downregulation Caused by In- tronic Repeat Expansions
Hannes Eimer, Sridevi Sureshkumar, Avilash Singh Yadav, Calvin Kraupner-Taylor, Champa Bandaranayake, Andrei Seleznev, Tamblyn Thomason, Stephen J. Fletcher, Stephanie Frances Gordon, Bernard J. Carroll, Sureshkumar Balasubramanian; Cell Cell 174, 1–11 August 23, 2018, doi:10.1016/j.cell.2018.06.044
we have demonstrated that triplet expansions in transcribed regions of the genome have the potential to generate siRNAs, which in turn can target the locus harboring the repeat expansion for epigenetic gene silencing. Epigenetic changes have been implicated in several triplet expansion disorders. It has also been suggested that the repeats that undergo expansion have a distinct association with epigenetic features. Our findings reinforce the importance of epigenetic changes in establishing the disease state caused by triplet repeat expansions. It would be interesting to assess whether siRNA-mediated epigenetic silencing is of significance in triplet expansion diseases such as FRDA in the human system. Future studies should explore additional components of this pathway involving chromatin modifications that result from trinucleotide repeat expansions.
we have demonstrated that triplet expansions in transcribed regions of the genome have the potential to generate siRNAs, which in turn can target the locus harboring the repeat expansion for epigenetic gene silencing. Epigenetic changes have been implicated in several triplet expansion disorders. It has also been suggested that the repeats that undergo expansion have a distinct association with epigenetic features. Our findings reinforce the importance of epigenetic changes in establishing the disease state caused by triplet repeat expansions. It would be interesting to assess whether siRNA-mediated epigenetic silencing is of significance in triplet expansion diseases such as FRDA in the human system. Future studies should explore additional components of this pathway involving chromatin modifications that result from trinucleotide repeat expansions.
Thursday, July 26, 2018
Identification of cardioprotective drugs by medium-scale in vivo pharmacological screening on a Drosophila cardiac model of Friedreich's ataxia
Amandine Palandri, Elodie Martin, Maria Russi, Michael Rera, Hervé Tricoire, Véronique Monnier; Disease Models & Mechanisms 2018 11: dmm033811 doi: 10.1242/dmm.033811 Published 20 July 2018
This study is the first drug screening of this extent performed in vivo on a Drosophila model of cardiac disease. Thus, it also brings the proof of concept that cardiac functional imaging in adult Drosophila flies is usable for medium-scale in vivo pharmacological screening, with potent identification of cardioprotective drugs in various contexts of cardiac diseases.
This study is the first drug screening of this extent performed in vivo on a Drosophila model of cardiac disease. Thus, it also brings the proof of concept that cardiac functional imaging in adult Drosophila flies is usable for medium-scale in vivo pharmacological screening, with potent identification of cardioprotective drugs in various contexts of cardiac diseases.
Tuesday, July 24, 2018
PTC Therapeutics to Acquire Agilis Biotherapeutics
Medical Buyer Bureau. July 23, 2018. PTC Therapeutics to Acquire Agilis Biotherapeutics.
We are impressed with the clinical results shown by the AADC program and are excited with the potential to quickly bring this therapy to patients. We look forward to advancing the Friedreich ataxia and Angelman syndrome programs into the clinic in the next two years.”
We are impressed with the clinical results shown by the AADC program and are excited with the potential to quickly bring this therapy to patients. We look forward to advancing the Friedreich ataxia and Angelman syndrome programs into the clinic in the next two years.”
Monday, July 23, 2018
Zinc(II) binding on human wild-type ISCU and Met140 variants modulates NFS1 desulfurase activity
Nicholas G. Fox, Alain Martelli, Joseph F. Nabhan, Jay Janz, Oktawia Borkowska, Christine Bulawa, Wyatt W. Yue, Biochimie, 2018, doi:10.1016/j.biochi.2018.07.012.
Human de novo iron-sulfur (Fe-S) assembly complex consists of cysteine desulfurase NFS1, accessory protein ISD11, acyl carrier protein ACP, scaffold protein ISCU, and allosteric activator frataxin (FXN). FXN binds the NFS1-ISD11-ACP-ISCU complex (SDAU), to activate the desulfurase activity and Fe-S cluster biosynthesis. In the absence of FXN, the NFS1-ISD11-ACP (SDA) complex was reportedly inhibited by binding of recombinant ISCU. Recent studies also reported a substitution at position Met141 on the yeast ISCU orthologue Isu, to Ile, Leu, Val, or Cys, could bypass the requirement of FXN for Fe-S cluster biosynthesis and cell viability. Here, we show that recombinant human ISCU binds zinc(II) ion, as previously demonstrated with the E. coli orthologue IscU. Surprisingly, the relative proportion between zinc-bound and zinc-depleted forms varies among purification batches. Importantly the presence of zinc in ISCU impacts SDAU desulfurase activity. Indeed, removal of zinc(II) ion from ISCU causes a moderate but significant increase in activity compared to SDA alone, and FXN can activate both zinc-depleted and zinc-bound forms of ISCU complexed to SDA. Taking into consideration the inhibition of desulfurase activity by zinc-bound ISCU, we characterized wild type ISCU and the M140I, M140L, and M140V variants under both zinc-bound and zinc-depleted conditions, and did not observe significant differences in the biochemical and biophysical properties between wild-type and variants. Importantly, in the absence of FXN, ISCU variants behaved like wild-type and did not stimulate the desulfurase activity of the SDA complex. This study therefore identifies an important regulatory role for zinc-bound ISCU in modulation of the human Fe-S assembly system in vitro and reports no ‘FXN bypass’ effect on mutations at position Met140 in human ISCU. Furthermore, this study also calls for caution in interpreting studies involving recombinant ISCU by taking into consideration the influence of the bound zinc(II) ion on SDAU complex activity
Human de novo iron-sulfur (Fe-S) assembly complex consists of cysteine desulfurase NFS1, accessory protein ISD11, acyl carrier protein ACP, scaffold protein ISCU, and allosteric activator frataxin (FXN). FXN binds the NFS1-ISD11-ACP-ISCU complex (SDAU), to activate the desulfurase activity and Fe-S cluster biosynthesis. In the absence of FXN, the NFS1-ISD11-ACP (SDA) complex was reportedly inhibited by binding of recombinant ISCU. Recent studies also reported a substitution at position Met141 on the yeast ISCU orthologue Isu, to Ile, Leu, Val, or Cys, could bypass the requirement of FXN for Fe-S cluster biosynthesis and cell viability. Here, we show that recombinant human ISCU binds zinc(II) ion, as previously demonstrated with the E. coli orthologue IscU. Surprisingly, the relative proportion between zinc-bound and zinc-depleted forms varies among purification batches. Importantly the presence of zinc in ISCU impacts SDAU desulfurase activity. Indeed, removal of zinc(II) ion from ISCU causes a moderate but significant increase in activity compared to SDA alone, and FXN can activate both zinc-depleted and zinc-bound forms of ISCU complexed to SDA. Taking into consideration the inhibition of desulfurase activity by zinc-bound ISCU, we characterized wild type ISCU and the M140I, M140L, and M140V variants under both zinc-bound and zinc-depleted conditions, and did not observe significant differences in the biochemical and biophysical properties between wild-type and variants. Importantly, in the absence of FXN, ISCU variants behaved like wild-type and did not stimulate the desulfurase activity of the SDA complex. This study therefore identifies an important regulatory role for zinc-bound ISCU in modulation of the human Fe-S assembly system in vitro and reports no ‘FXN bypass’ effect on mutations at position Met140 in human ISCU. Furthermore, this study also calls for caution in interpreting studies involving recombinant ISCU by taking into consideration the influence of the bound zinc(II) ion on SDAU complex activity
Genome damage from CRISPR/Cas9 gene editing higher than thought
ScienceDaily, 19 July 2018. Scientists at the Wellcome Sanger Institute have discovered that CRISPR/Cas9 gene editing can cause greater genetic damage in cells than was previously thought. These results create safety implications for gene therapies using CRISPR/Cas9 in the future as the unexpected damage could lead to dangerous changes in some cells.
Journal Reference:
Michael Kosicki, Kärt Tomberg, Allan Bradley. Repair of double-strand breaks induced by CRISPR–Cas9 leads to large deletions and complex rearrangements. Nature Biotechnology, 2018; DOI: 10.1038/Nbt.4192
Journal Reference:
Michael Kosicki, Kärt Tomberg, Allan Bradley. Repair of double-strand breaks induced by CRISPR–Cas9 leads to large deletions and complex rearrangements. Nature Biotechnology, 2018; DOI: 10.1038/Nbt.4192
Inherited Cardiomyopathies and the Role of Mutations in Non-coding Regions of the Genome
Salman OF, El-Rayess HM, Abi Khalil C, Nemer G and Refaat MM (2018). Front. Cardiovasc. Med. 5:77. doi: 10.3389/fcvm.2018.00077
Although triplet repeat expansion mutations are uncommon among dilated cardiomyopathys, some diseases like Friedreich's ataxia and some muscular dystrophies are associated with DCMs.
Although triplet repeat expansion mutations are uncommon among dilated cardiomyopathys, some diseases like Friedreich's ataxia and some muscular dystrophies are associated with DCMs.
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