Showing papers by "Kay E. Davies published in 2021"
TL;DR: In this paper, the relative merits of cutting-edge genetic approaches, as well as the challenges that still need to be overcome before they become clinically viable for Duchenne muscular dystrophy (DMD).
Abstract: Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle-wasting disorder that is caused by a lack of functional dystrophin, a cytoplasmic protein necessary for the structural integrity of muscle As variants in the dystrophin gene lead to a disruption of the reading frame, pharmacological treatments have only limited efficacy; there is currently no effective therapy and consequently, a significant unmet clinical need for DMD Recently, novel genetic approaches have shown real promise in treating DMD, with advancements in the efficacy and tropism of exon skipping and surrogate gene therapy CRISPR-Cas9 has the potential to be a ‘one-hit’ curative treatment in the coming decade The current limitations of gene editing, such as off-target effects and immunogenicity, are in fact partly constraints of the delivery method itself, and thus research focus has shifted to improving the viral vector In order to halt the loss of ambulation, early diagnosis and treatment will be pivotal In an era where genetic sequencing is increasingly utilised in the clinic, genetic therapies will play a progressively central role in DMD therapy This review delineates the relative merits of cutting-edge genetic approaches, as well as the challenges that still need to be overcome before they become clinically viable
17 citations
TL;DR: In this article, the role of glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunit and deficits in synaptic plasticity are implicated in schizophrenia and sleep and circadian rhythm disruption.
Abstract: Dysfunction of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunit and deficits in synaptic plasticity are implicated in schizophrenia and sleep and circadian rhythm disruption. To investigate the role of GluA1 in circadian and sleep behaviour, we used wheel-running, passive-infrared, and video-based home-cage activity monitoring to assess daily rest-activity profiles of GluA1-knockout mice (Gria1-/-). We showed that these mice displayed various circadian abnormalities, including misaligned, fragmented, and more variable rest-activity patterns. In addition, they showed heightened, but transient, behavioural arousal to light→dark and dark→light transitions, as well as attenuated nocturnal-light-induced activity suppression (negative masking). In the hypothalamic suprachiasmatic nuclei (SCN), nocturnal-light-induced cFos signals (a molecular marker of neuronal activity in the preceding ~1-2 h) were attenuated, indicating reduced light sensitivity in the SCN. However, there was no change in the neuroanatomical distribution of expression levels of two neuropeptides-vasoactive intestinal peptide (VIP) and arginine vasopressin (AVP)-differentially expressed in the core (ventromedial) vs. shell (dorsolateral) SCN subregions and both are known to be important for neuronal synchronisation within the SCN and circadian rhythmicity. In the motor cortex (area M1/M2), there was increased inter-individual variability in cFos levels during the evening period, mirroring the increased inter-individual variability in locomotor activity under nocturnal light. Finally, in the spontaneous odour recognition task GluA1 knockouts' short-term memory was impaired due to enhanced attention to the recently encountered familiar odour. These abnormalities due to altered AMPA-receptor-mediated signalling resemble and may contribute to sleep and circadian rhythm disruption and attentional deficits in different modalities in schizophrenia.
8 citations
American College of Medical Genetics1, University of Leicester2, Leiden University Medical Center3, Stanford University4, University of Manchester5, Cardiff University6, American Society of Human Genetics7, University of Oxford8, University Hospitals of Leicester NHS Trust9, Saint Peter's University10, University of Alabama at Birmingham11, PLOS12, John Wiley & Sons13, Australian Institute of Tropical Health and Medicine14, Broad Institute15, Harvard University16, University of North Carolina at Chapel Hill17, Johns Hopkins University School of Medicine18
TL;DR: A committee to evaluate the feasibility of requiring authors to verify that all variants submitted for publication complied with a widely accepted standard for description found it a reasonable step toward standardizing the worldwide inventory of human variation.
Abstract: Documenting variation in our genomes is important for research and clinical care. Accuracy in the description of DNA variants is therefore essential. To address this issue, the Human Variome Project convened a committee to evaluate the feasibility of requiring authors to verify that all variants submitted for publication complied with a widely accepted standard for description. After a pilot study of two journals, the committee agreed that requiring authors to verify that variants complied with Human Genome Variation Society nomenclature is a reasonable step toward standardizing the worldwide inventory of human variation.
6 citations
TL;DR: In this paper, a novel class of utrophin modulators using an improved phenotypic screen, where reporter expression is derived from the full genomic context of the uplink promoter, is presented.
5 citations
3 citations
TL;DR: In this article, the authors investigated the role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn-/-;SMN2 and the less severe Smn2B/- SMA mice, which undergo a progressive neuromuscular decline in the first three postnatal weeks.
Abstract: Spinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle. We thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn-/-;SMN2 and the less severe Smn2B/- SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. Here, we report significantly dysregulated expression of the TWEAK/Fn14 pathway during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak-/- and Fn14-/- mice revealed dysregulated myopathy, myogenesis and glucose metabolism pathways as a common skeletal muscle feature, and providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, a pharmacological intervention (Fc-TWEAK) to upregulate the activity of the TWEAK/Fn14 pathway improved disease phenotypes in the two SMA mouse models. Our study provides novel mechanistic insights into the molecular players that contribute to muscle pathology in SMA and into the role of the TWEAK/Fn14 pathway in developing muscle.