Protection of dystrophic muscle cells using Idebenone correlates with the interplay between calcium, oxidative stress and inflammation

Amanda Harduim Valduga, Daniela Sayuri Mizobuti, Fernanda dos Santos Rapucci Moraes, Rafael Dias Mâncio, Luis Henrique Rapucci Moraes, Túlio de Almeida Hermes, Aline Barbosa Macedo, Elaine Minatel; Int J Exp Path. 2022; 00: 1- 9. doi:10.1111/iep.12463 

The Idebenone treatment was able to reduce the levels of oxidative stress markers, such as H2O2 and 4-HNE, as well as decreasing intracellular calcium influx in the dystrophic muscle cells. Regarding Idebenone effects on the anti-oxidant defence system, an up-regulation of catalase levels, glutathione reductase (GR), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity was observed in the dystrophic muscle cells. In addition, the Idebenone treatment was also associated with reduction in inflammatory molecules, such as nuclear factor kappa-B (NF-κB) and tumour necrosis factor (TNF) in mdx muscle cells.

Astrocytic mitochondrial frataxin—A promising target for ischemic brain injury

Hazra, R, Novelli, EM, Hu, X.; CNS Neurosci Ther. 2022; 00: 1- 6. doi:10.1111/cns.14068 

In the ischemic brain, hypoxia leads to mitochondrial dysfunction, insufficient energy production, and astrocyte activation. Yet, most studies investigating mitochondrial dysfunction in cerebral ischemia have focused exclusively on neurons. This review will highlight the importance of the morphological, molecular, and functional heterogeneity of astrocytes in their role in brain injuries and explore how activated astrocytes exhibit calcium imbalance, reactive oxygen species overproduction, and apoptosis. In addition, special focus will be given to the role of the mitochondrial protein frataxin in activated astrocytes during ischemia and its putative role in the pharmacological management of cerebral ischemia.

Study traces shared and unique cellular hallmarks found in 6 neurodegenerative diseases

ScienceDaily, 21 December 2022. Arizona State University. 

In a study appearing in the current issue of Alzheimer's & Dementia: The Journal of the Alzheimer' Association, corresponding author Carol Huseby of Arizona State University and her colleagues look at cellular alterations in six distinct neurodegenerative diseases: amyotrophic lateral sclerosis or Lou Gehrig's disease, Alzheimer's disease, Friedreich's ataxia, frontotemporal dementia, Huntington's disease and Parkinson's disease. The selected RNA transcripts reveal eight common themes across the six neurodegenerative diseases: transcription regulation, degranulation (a process involved in inflammation), immune response, protein synthesis, cell death or apoptosis, cytoskeletal components, ubiquitylation/proteasome (involved in protein degradation) and mitochondrial complexes (which oversee energy usage in cells). The eight cellular dysfunctions uncovered are associated with identifiable pathologies in the brain characteristic of each disease.

Blood RNA transcripts reveal similar and differential alterations in fundamental cellular processes in Alzheimer's disease and other neurodegenerative diseases

Carol J. Huseby, Elaine Delvaux, Danielle L. Brokaw, Paul D. Coleman; Alzheimer's & Dementia, 2022; DOI: 10.1002/alz.12880 

 We report that transcripts of the blood transcriptome selected for each of the neurodegenerative diseases represent fundamental biological cell processes including transcription regulation, degranulation, immune response, protein synthesis, apoptosis, cytoskeletal components, ubiquitylation/proteasome, and mitochondrial complexes that are also affected in the brain and reveal common themes across six neurodegenerative diseases.

Efficacy and Safety of Leriglitazone in Patients With Friedreich Ataxia: A Phase 2 Double-Blind, Randomized Controlled Trial (FRAMES)

Pandolfo M, Reetz K, Darling A, Rodriguez de Rivera FJ, Henry PG, Joers J, Lenglet C, Adanyeguh I, Deelchand D, Mochel F, Pousset F, Pascual S, Van den Eede D, Martin-Ugarte I, Vilà-Brau A, Mantilla A, Pascual M, Martinell M, Meya U, Durr A.; Neurol Genet. 2022 Nov 1;8(6):e200034. doi: 10.1212/NXG.0000000000200034. 

The primary endpoint of change in spinal cord area was not met. Secondary endpoints provide evidence supporting proof of concept for leriglitazone mode of action and, with acceptable safety data, support larger studies in patients with FRDA.

Design and Delivery of SINEUP: A New Modular Tool to Increase Protein Translation

Arnoldi M, Zarantonello G, Espinoza S, Gustincich S, Di Leva F, Biagioli M.; Methods Mol Biol. 2022;2434:63-87. doi: 10.1007/978-1-0716-2010-6_4. 

Synthetic SINEUP is thus a novel molecular tool that potentially may be used for any industrial or biomedical application to enhance protein production, also as possible therapeutic strategy in haploinsufficiency-driven disorders.Here, we describe a detailed protocol to (1) design a specific BD directed to a gene of interest and (2) assemble and clone it with the ED to obtain a functional SINEUP molecule. Then, we provide guidelines to efficiently deliver SINEUP into mammalian cells and evaluate its ability to effectively upregulate target protein translation.

Recurrent repeat expansions in human cancer genomes

Erwin, G.S., Gürsoy, G., Al-Abri, R. et al.; Nature (2022). doi:10.1038/s41586-022-05515-1 

Expansions of tandem DNA repeats (TRs) are known to cause more than 50 devastating human diseases, including Huntington’s disease and fragile X syndrome1,2. TR tracts that cause human disease are typically large (more than 100 bp)1. However, identifying large TRs with short-read DNA sequencing methods is difficult because the repeat sequences are ubiquitous in the genome and many are too large—larger than the typical sequencing read length—to uniquely map to the reference genome9. Thus, many large TRs go undetected with current genomic technologies, and, despite their importance to monogenic disease, the frequency and function of recurrent repeat expansions (rREs) are unknown in complex human genetic diseases such as cancer.

Researchers may have found a new path for halting cancer cell production

Stanford Medicine; December 14, 2022; 

The project began not with cancer, but with a rare, neurodegenerative disease without a cure, Friedreich ataxia. Five years ago, Erwin, then a graduate student at the University of Wisconsin-Madison, was exploring the genetic underpinnings of Friedreich ataxia in hopes of filling the therapeutic void. Erwin knew that DNA mutations called repeat expansions cause Friedreich ataxia, along with dozens of other serious conditions, many neurological. 

Repeat expansions are stretches of DNA that erroneously repeat themselves dozens to thousands of times in the genome. 

 Testing the molecule in cells from a Friedreich ataxia patient, Erwin saw that Syn-TEF1 successfully targeted the repeat expansion, helping RNA polymerase move through it to transcribe the FXN gene, bringing frataxin to normal levels. Due to its success in cells, researchers are now testing the safety and dosage of a version of Syn-TEF1 in Friedreich ataxia patients.

Kaleibe launched by Replay to target genetic brain disorders with gene therapy

14-12-2022​. Replay, a genome writing company reprogramming biology by writing and delivering big DNA, has announced the launch of Kaleibe, a herpes simplex virus (HSV) gene therapy company targeting genetic brain disorders. It is the third product company to launch since Replay’s formation in July and will leverage its high payload capacity HSV delivery vector, synHSVTM, to target genetic brain disorders. 

The initial development programs will focus on genetic Parkinson’s disease (PD) and Friedreich’s ataxia (FRDA). These diseases have a high unmet medical need and known genetic causes. The target genes, 33kb and 135kb, respectively, far exceed the 5kb payload capacity of adeno-associated virus (AAV) vectors.

G-rich motifs within phosphorothioate-based antisense oligonucleotides (ASOs) drive activation of FXN expression through indirect effects

Feng Wang, Ezequiel Calvo-Roitberg, Julia M Rembetsy-Brown, Minggang Fang, Jacquelyn Sousa, Zachary J Kartje, Pranathi Meda Krishnamurthy, Jonathan Lee, Michael R Green, Athma A Pai, Jonathan K Watts; Nucleic Acids Research, 2022;, gkac1108, doi:10.1093/nar/gkac1108 

The phosphorodiamidate morpholino oligomer analogs of our ASOs did not activate FXN, pointing to a PS-backbone-mediated effect. Our study demonstrates the importance of multiple, detailed control experiments and target validation in oligonucleotide studies employing novel mechanisms such as gene activation.