Search

Abstract Conductive patterned metal films bonded to compliant elastomeric substrates form meshes which enable flexible electronic interconnects for various applications. However, while bottom-up deposition of thin films by sputtering or growth is well-developed for rigid electronics, maintaining good electrical conductivity in sub-micron thin metal films upon large deformations or cyclic loading remains a significant challenge. Here, we propose a strategy to improve the electromechanical performance of nanometer-thin palladium films by in-situ synthesis of a conformal graphene coating using chemical vapor deposition (CVD). The uniform graphene coverage improves the thin film’s damage tolerance, electro-mechanical fatigue, and fracture toughness owing to the high stiffness of graphene and the conformal CVD-grown graphene-metal interface. Graphene-coated Pd thin film interconnects exhibit stable increase in electrical resistance even when strained beyond 60% and longer fatigue life up to a strain range of 20%. The effect of graphene is more significant for thinner films of < 300 nm, particularly at high strains. The experimental observations are well described by the thin film electro-fragmentation model and the Coffin-Manson relationship. These findings demonstrate the potential of CVD-grown graphene nanocomposite materials in improving the damage tolerance and electromechanical robustness of flexible electronics. The proposed approach offers opportunities for the development of reliable and high-performance ultra-conformable flexible electronic devices.

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including ATG4B, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), Atg4b depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and atg4b -/- mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore ATG4B mRNA in TARDBP knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases., (© 2024. The Author(s).)

Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by a CTG repeat expansion in the DMPK gene that generates toxic RNA with a myriad of downstream alterations in RNA metabolism. A key consequence is the sequestration of alternative splicing regulatory proteins MBNL1/2 by expanded transcripts in the affected tissues. MBNL1/2 depletion interferes with a developmental alternative splicing switch that causes the expression of fetal isoforms in adults. Boosting the endogenous expression of MBNL proteins by inhibiting the natural translational repressors miR-23b and miR-218 has previously been shown to be a promising therapeutic approach. We designed antimiRs against both miRNAs with a phosphorodiamidate morpholino oligonucleotide (PMO) chemistry conjugated to cell-penetrating peptides (CPPs) to improve delivery to affected tissues. In DM1 cells, CPP-PMOs significantly increased MBNL1 levels. In some candidates, this was achieved using concentrations less than two orders of magnitude below the median toxic concentration, with up to 5.38-fold better therapeutic window than previous antagomiRs. In HSA LR mice, intravenous injections of CPP-PMOs improve molecular, histopathological, and functional phenotypes, without signs of toxicity. Our findings place CPP-PMOs as promising antimiR candidates to overcome the treatment delivery challenge in DM1 therapy., Competing Interests: B.L. and R.A. are founders, and CEO and scientific consultant of Arthex Biotech, respectively. Arthex Biotech is developing antimiRs for use in the treatment of DM1., (© 2023 The Authors.)

Antisense oligonucleotides (ASOs) have shown great therapeutic potential in the treatment of many neuromuscular diseases including myotonic dystrophy 1 (DM1). However, systemically delivered ASOs display poor biodistribution and display limited penetration into skeletal muscle. The conjugation of cell-penetrating peptides (CPPs) to phosphorodiamidate morpholino oligonucleotides (PMOs), a class of ASOs with a modified backbone, can be used to enhance ASO skeletal muscle penetration. Peptide-PMOs (P-PMOs) have been shown to be highly effective in correcting the DM1 skeletal muscle phenotype in both murine and cellular models of DM1 and at a molecular and functional level. Here we describe the synthesis and conjugation of P-PMOs and methods for analyzing their biodistribution and toxicity in the HSA-LR DM1 mouse model and their efficacy both in vitro and in vivo using FISH and RT-PCR splicing analysis., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Myotonic dystrophy type 1 is a debilitating neuromuscular disease causing muscle weakness, myotonia, and cardiac dysfunction. The phenotypes are caused by muscleblind-like (MBNL) protein sequestration by toxic RNA in the DM1 protein kinase ( DMPK ) gene. DM1 patients exhibit a pathogenic number of repetitions in DMPK , which leads to downstream symptoms. Another disease characteristic is altered microRNA (miRNA) expression. It was previously shown that miR-23b regulates the translation of MBNL1 into protein. Antisense oligonucleotide (AON) treatment targeting this miRNA can improve disease symptoms. Here, we present a refinement of this strategy targeting a miR-23b binding site on the MBNL1 3' UTR in DM1 model cells and mice by using AONs called blockmiRs. BlockmiRs linked to novel cell-penetrating peptide chemistry showed an increase in MBNL1 protein in DM1 model cells and HSA LR mice. They also showed an increase in muscle strength and significant rescue of downstream splicing and histological phenotypes in mice without disturbing the endogenous levels of other miR-23b target transcripts., Competing Interests: We declare that R.A., B.L., and E.C.-H. are co-inventors in patent PCT/EP2017/073685, currently licensed to Arthex Biotech, of which R.A. and B.L. are co-founders and R.A. is scientific consultant., (© 2022 The Author(s).)