
Karen AnthonyUniversity of Northampton | UN · Faculty of Arts Science and Technology
Karen Anthony
PhD, FHEA
About
46
Publications
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Introduction
Karen is a leading researcher on RNA processing and RNA-based therapeutics. Karen has worked on a number of drug and disease targets including tau for Alzheimer's and frontotemporal dementia. Her pioneering and ongoing work currently focuses on neuromuscular disorders and the pre-clinical and clinical development of exon skipping as a therapeutic approach for Duchenne muscular dystrophy.
Additional affiliations
August 2020 - present
September 2017 - August 2020
September 2015 - September 2017
Education
October 2005 - March 2009
October 2001 - June 2005
Publications
Publications (46)
RNA-based therapeutics have entered the mainstream with seemingly limitless possibilities to treat all categories of neurological disease. Here, common RNA-based drug modalities such as antisense oligonucleotides, small interfering RNAs, RNA aptamers, RNA-based vaccines and mRNA drugs are reviewed highlighting their current and potential applicatio...
Duchenne muscular dystrophy (DMD) is caused by the lack of dystrophin, but many patients have rare revertant fibres that express dystrophin. The skeletal muscle pathology of DMD patients includes immune cell infiltration and inflammatory cascades. There are several strategies to restore dystrophin in skeletal muscles of patients, including exon ski...
Duchenne muscular dystrophy is caused by a lack of dystrophin. Several strategies exist to restore dystrophin production, including exon skipping and gene therapy. However, dystrophin epitopes, expressed in revertant fibres in non-treated patients, may elicit a T cell-mediated immune response, which could reduce the efficacy of therapies designed t...
Alterations in the expression of the Duchenne muscular dystrophy (DMD) gene have been associated with the development, progression and survival outcomes of numerous cancers including tumours of the central nervous system. We undertook a detailed bioinformatic analysis of low‑grade glioma (LGG) bulk RNAseq data to characterise the association betwee...
Machine learning approaches are powerful techniques commonly employed for developing cancer prediction models using associated gene expression and mutation data. This manuscript provides a comprehensive review of recent cancer studies that have employed gene expression data from several cancer types (breast, lung, kidney, ovarian, liver, central ne...
Background: Mutation of the Duchenne muscular dystrophy (DMD) gene causes Duchenne and Becker muscular dystrophy, degenerative neuromuscular disorders that primarily affect voluntary muscles. However, increasing evidence implicates DMD in the development of all major cancer types. DMD is a large gene with 79 exons that codes for the essential muscl...
Duchenne muscular dystrophy (DMD) is caused by frameshift mutations in the DMD gene that prevent the body-wide translation of its protein product, dystrophin. Besides a severe muscle phenotype, cognitive impairment and neuropsychiatric symptoms are prevalent. Dystrophin protein 71 (Dp71) is the major DMD gene product expressed in the brain and muta...
Background
Duchenne muscular dystrophy is a lethal disease caused by lack of dystrophin. Skipping of exons adjacent to out-of-frame deletions has proven to restore dystrophin expression in Duchenne patients. Exon 51 has been the most studied target in both preclinical and clinical settings and the availability of standardized procedures to quantify...
Exon skipping levels of DMDΔ48–50 and DMDΔ52 cells obtained by qPCR (1st transfection experiment).
Error bars represent standard deviation.
(TIF)
Examples of raw data to determine exon skipping levels by ddPCR (A), bioanalyzer (B) and densitometry (C) of Δ48–50 cells treated with an AON to skip exon 51. A. The 1D amplitude plot shows positive (blue) and negative dots (grey) for the skipped and the non-skipped assays. B. Results of the electrophoresis run of the high sensitivity DNA assay sho...
Intra-laboratory variation of exon 51 skipping levels in DMDΔ48–50 (A-C) and DMDΔ52 cells (D-E). Three different protocols were repeated by the same operator (n = 2/3). Error bars represent standard deviation.
(TIF)
Sequences of primers, probes and AON used.
FAM = 6-carboxyfluorescein label, 2’OMePS = 2'-O-methyl-modified bases on a phosphorothioate backbone.
(DOCX)
Exon 51 skipping percentages obtained by the different laboratories for the different technologies.
Three biological replicates of each sample were measured. SD = standard deviation.
(DOCX)
Detailed description of cell culture conditions, transfection and RNA purification.
(DOCX)
Photo cross-linking of proteins with short RNA oligomers is a classical method to study RNA–protein interactions that are implicated in many aspects of RNA metabolism and function. Most commonly, this involves the use of [γ-32P]-labeled RNA probes. Although very sensitive, these procedures are complicated by the safety issues associated with the us...
Duchenne muscular dystrophy is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. Restoration of the open reading frame and dystrophin production can be achieved by exon skipping using antisense oligonucleotides targeted to splicing elements. This approach aim...
Multicenter quantification of dystrophin exon 51 skipping
Becker (BMD) and Duchenne muscular dystrophy (DMD) are allelic disorders arising from mutations in the dystrophin gene. In-frame mutations lead to the milder BMD while out-of-frame mutations disrupt the reading frame and lead to the severe DMD with lack of dystrophin. A therapeutic strategy for skipping specific exons in dystrophin and restoring th...
Objective:
We formed a multi-institution collaboration in order to compare dystrophin quantification methods, reach a consensus on the most reliable method, and report its biological significance in the context of clinical trials.
Methods:
Five laboratories with expertise in dystrophin quantification performed a data-driven comparative analysis...
The microtubule-associated protein tau is predominantly localized in the axonal compartment over the entire length of the axon in neurons. The mechanisms responsible for the localization of tau in axons at long distance from the cell body are not properly understood. Using fluorescence in situ hybridization, we show that tau mRNA is present in the...
Importance:
In Duchenne muscular dystrophy (DMD), the reading frame of an out-of-frame DMD deletion can be repaired by antisense oligonucleotide (AO)-mediated exon skipping. This creates a shorter dystrophin protein, similar to those expressed in the milder Becker muscular dystrophy (BMD). The skipping of some exons may be more efficacious than ot...
The pre-symptomatic induction of inflammatory cascades and invasion of muscle by immune cells in dystrophin deficient muscle contributes to the pathology of Duchenne muscular dystrophy (DMD). Traditional and RNA-based gene therapy approaches for DMD are progressing through clinical development. Whilst in one study a post-treatment reduction in infl...
In the search of the most efficacious antisense oligonucleotides (AO) aimed at inducing SMN2 exon 7 inclusion, we systematically assessed three AOs, PMO25 (-10, -34), PMO18 (-10, -27) and PMO20 (-10, -29), complementary to SMN2 intron 7 splicing silencer (ISS-N1). PMO25 was the most efficacious in augmenting exon7 inclusion in vitro in spinal muscu...
Restoration of the open reading frame of the DMD gene and dystrophin protein production in Duchenne muscular dystrophy (DMD) can be achieved by exon skipping using antisense oligomers (AOs) targeted to splicing elements. Several such RNA-based gene therapy approaches are in clinical development where to date, all studies have assessed AO efficacy b...
Exon skipping using antisense oligonucleotides (AONs) is a promising therapy for Duchenne muscular dystrophy (DMD) which aims to genocopy the milder Becker muscular dystrophy (BMD) by restoring the reading frame of an out-of-frame deletion. The less severe phenotype of BMD patients suggests that internally truncated dystrophin retains some function...
Duchenne muscular dystrophy (DMD) is the most common childhood neuromuscular disorder. It is caused by mutations in the DMD gene that disrupt the open reading frame (ORF) preventing the production of functional dystrophin protein. The loss of dystrophin ultimately leads to the degeneration of muscle fibres, progressive weakness and premature death....
Duchenne muscular dystrophy is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. Restoration of the open reading frame and dystrophin production can be achieved by exon skipping using antisense oligonucleotides targeted to splicing elements. This approach aim...
We previously conducted a proof of principle; dose escalation study in Duchenne muscular dystrophy (DMD) patients using the morpholino splice-switching oligonucleotide AVI-4658 (eteplirsen) that induces skipping of dystrophin exon 51 in patients with relevant deletions, restores the open reading frame and induces dystrophin protein expression after...
We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne muscular dystrophy.
We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) in ambulant patients with Duch...
The importance of aberrant RNA processing in neurodegeneration is becoming increasingly clear; a recent example being the identification of the splicing factor TDP-43 as the major component of inclusions characteristic of a number of neurodegenerative conditions including amyotrophic lateral sclerosis (ALS). Due to the enormous diversity generated...
Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is caused by mutations in the MAPT gene, encoding the tau protein that accumulates in intraneuronal lesions in a number of neurodegenerative diseases. Several FTDP-17 mutations affect alternative splicing and result in excess exon 10 (E10) inclusion in tau mRNA. RNA reprogr...
Elucidating the mechanisms of alternative splicing in the brain is a prerequisite to the understanding of the pathogenesis of major neurological diseases linked to impairment of pre-mRNA alternative splicing. The gene trinucleotide repeat-containing 4 (TNRC4) is predicted to encode a member of the CELF (CUG-BP- and ETR-3-like factors) family of RNA...