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.