Public offering nets $203mm for Reata

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.

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).

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.

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.

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.

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.

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.”

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

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

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.

Sodium magnetic resonance imaging in Friedreich ataxia – A preliminary study

J.S. Krahe, S. Romanzetti, I. Dogan, C. Didszun, J.B. Schulz, K. Reetz, Clinical Neurophysiology, Volume 129, Issue 8, 2018, Pages e71-e72, doi:10.1016/j.clinph.2018.04.656.

The increase of TSC in cerebellum and brainstem in FRDA patients suggests the diagnostic potential of in vivo sodium MRI to differentiate between patients and controls. Moreover, this was related to more severe ataxia, as assessed by the SARA. These preliminary results support our hypothesis that sodium MRI may be a new imaging marker that could shed new insights into the metabolic pathophysiological mechanisms of FRDA.

Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich’s Ataxia Models

Abeti R, Baccaro A, Esteras N and Giunti P (2018); Front. Cell. Neurosci. 12:188. doi: 10.3389/fncel.2018.00188

Omaveloxolone was protective to mitochondrial depolarization, promoting mitochondrial respiration and preventing cell death. Our results show that omav promotes Complex I activity and protect cells from oxidative stress. Omav could, therefore, be used as a novel therapeutic drug to ameliorate the pathophysiology of FRDA.

Activating frataxin expression by single-stranded siRNAs targeting the GAA repeat expansion

Xiulong Shen, Audrius Kilikevicius, Daniel O'Reilly, Thazha P. Prakash, Masad J. Damha, Frank Rigo, David R. Corey, Bioorganic & Medicinal Chemistry Letters 2018, doi:10.1016/j.bmcl.2018.07.033.

Agents that increase expression of FXN protein are a potential approach to therapy. We previously described anti-trinucleotide GAA duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs) that activate FXN protein expression in multiple patient derived cell lines. Here we test two distinct series of compounds for their ability to increase FXN expression. ASOs with butane linkers showed low potency, which is consistent with the low Tm values and suggesting that flexible conformation impairs activity. By contrast, single-stranded siRNAs (ss-siRNAs) that combine the strengths of dsRNA and ASO approaches had nanomolar potencies. ss-siRNAs provide an additional option for developing nucleic acid therapeutics to treat FRDA.

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

Reata Receives Orphan Drug Designation from the European Commission for Omaveloxolone for the Treatment of Friedreich’s Ataxia

IRVING, Texas, July 10, 2018 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq:RETA), a clinical-stage biopharmaceutical company, today announced that the European Commission has granted orphan drug designation for omaveloxolone for the treatment of Friedreich’s ataxia (FA), based on the positive opinion from the Committee for Orphan Medicinal Products of the European Medicines Agency (EMA).
Last year, Reata reported results from part 1 of MOXIe, a two-part, international, multi-center, randomized, double-blind, placebo-controlled Phase 2 trial studying the safety and efficacy of omaveloxolone in patients with FA. Treatment of FA patients with omaveloxolone produced dose- and time-dependent improvements in their modified Friedreich’s Ataxia Rating Scale (mFARS) scores, which are a measure of the neurologic function of FA patients. Reata is currently enrolling approximately 100 FA patients in the registrational part 2 portion of MOXIe and expects to have results in the second half of 2019.

The Cerebellum and Cognition

Jeremy D. Schmahmann, Neuroscience Letters, 2018, doi:10.1016/j.neulet.2018.07.005.

Structure function correlation studies following focal cerebellar lesions in adults and children permit a finer appreciation of the functional topography and nature of the cerebellar motor syndrome, cerebellar vestibular syndrome, and the third cornerstone of clinical ataxiology - the cerebellar cognitive affective syndrome. The ability to detect the cerebellar cognitive affective syndrome in real time in clinical neurology with a brief and validated scale should make it possible to develop a deeper understanding of the clinical consequences of cerebellar lesions in a wide range of neurological and neuropsychiatric disorders with a link to the cerebellum.

Impact of Drosophila Models in the Study and Treatment of Friedreich’s Ataxia

Monnier, V.; Llorens, J.V.; Navarro, J.A., Int. J. Mol. Sci. 2018, 19, 1989.

Drosophila melanogaster has been for over a century the model of choice of several neurobiologists to decipher the formation and development of the nervous system as well as to mirror the pathophysiological conditions of many human neurodegenerative diseases. The rare disease Friedreich’s ataxia (FRDA) is not an exception. Since the isolation of the responsible gene more than two decades ago, the analysis of the fly orthologue has proven to be an excellent avenue to understand the development and progression of the disease, to unravel pivotal mechanisms underpinning the pathology and to identify genes and molecules that might well be either disease biomarkers or promising targets for therapeutic interventions. In this review, we aim to summarize the collection of findings provided by the Drosophila models but also to go one step beyond and propose the implications of these discoveries for the study and cure of this disorder. We will present the physiological, cellular and molecular phenotypes described in the fly, highlighting those that have given insight into the pathology and we will show how the ability of Drosophila to perform genetic and pharmacological screens has provided valuable information that is not easily within reach of other cellular or mammalian models.

Architectural Features of Human Mitochondrial Cysteine Desulfurase Complexes from Crosslinking Mass Spectrometry and Small-Angle X-Ray Scattering

Kai Cai, Ronnie O. Frederick, Hesam Dashti, John L. Markley; Structure, 2018, doi:10.1016/j.str.2018.05.017.

We present a structural model for the cysteine desulfurase-ISCU-frataxin complex derived from chemical crosslinking restraints in conjunction with the recent crystal structure of the cysteine desulfurase-ISCU-zinc complex and distance constraints from nuclear magnetic resonance.

Targeting ERK signaling pathway by polyphenols as novel therapeutic strategy for neurodegeneration

Mohammad Hosein Farzaei, Devesh Tewari, Saeideh Momtaz, Sandro Argüelles, Seyed Mohammad Nabavi, Food and Chemical Toxicology, 2018, doi:10.1016/j.fct.2018.07.010.

Currently, there is remarkable interest in the beneficial effects of natural flavonoids to improve neural performance and prevent the onset and development of major neurodegenerative diseases. Natural products originated from medicinal plants, in particular antioxidants, have gained a great deal of attention due to their safe and non-toxic natures. Here, we summarized the effect of natural bioflavonoids on ERK signaling pathway and their molecular mechanism.

The Etiologies of Chronic Progressive Cerebellar Ataxia in a Korean Population

Kim JS, Kwon S, Ki CS, Youn J, Cho JW.; J Clin Neurol. 2018 Jul;14(3):374-380. Doi:10.3988/jcn.2018.14.3.374

Although the AR ataxias such as ataxia telangiectasia or FRDA are prevalent in most countries, they are extremely rare in the Korean population.26 In addition, genetic screening did not detect FRDA in the patients with undetermined ataxia. Therefore, routine screening of the FTX gene in the Korean population might not be needed unless patients show a clinical phenotype of FRDA.
FRDA is extremely rare, and to the best of our knowledge has never detected in the Korean population. In addition, phenotypes of patients in whom FRDA screening test was performed, did not correspond with FRDA.

Frataxin Restoration in the Nervous System: Possibilities for Gene Therapy

David R. Lynch, Elizabeth Kichula, and Hong Lin. Molecular Therapy, Available online 30 June 2018, ISSN 1525-0016, doi:10.1016/j.ymthe.2018.06.006

Many obstacles beyond those identified in the present study will appear in the translation of gene therapy from animal concept to human therapy. Still, the present work provides proof that gene therapy may be useful long term in FRDA, and hope for all those with this disorder.