Silencing disease genes in the laboratory and the clinic

Watts, Jonathan K.; Corey, David R.

doi:10.1002/path.2993

Cited by 381 publications

(320 citation statements)

References 186 publications

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“…This technology may be used to treat various conditions including cancer, diabetes, neurodevelopmental and neurodegenerative disorders and hypertension, as well as autoimmune and cardiovascular diseases. Antisense drugs are potentially potent, selective and well-tolerated drugs and are becoming more widely accepted as potential therapeutics for various diseases (147)(148)(149).…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

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The human β-amyloid precursor protein: biomolecular and epigenetic aspects

Nguyen¹

2015

Biomolecular Concepts

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Beta-amyloid precursor protein (APP) is a membrane-spanning protein with a large extracellular domain and a much smaller intracellular domain. APP plays a central role in Alzheimer's disease (AD) pathogenesis: APP processing generates β-amyloid (Aβ) peptides, which are deposited as amyloid plaques in the brains of AD individuals; point mutations and duplications of APP are causal for a subset of early-onset familial AD (FAD) (onset age < 65 years old). However, these mutations in FAD represent a very small percentage of cases (∼1%). Approximately 99% of AD cases are nonfamilial and late-onset, i.e., sporadic AD (SAD) (onset age > 65 years old), and the pathophysiology of this disorder is not yet fully understood. APP is an extremely complex molecule that may be functionally important in its full-length configuration, as well as the source of numerous fragments with varying effects on neural function, yet the normal function of APP remains largely unknown. This article provides an overview of our current understanding of APP, including its structure, expression patterns, proteolytic processing and putative functions. Importantly, and for the first time, my recent data concerning its epigenetic regulation, especially in alternative APP pre-mRNA splicing and in the control of genomic rearrangements of the APP gene, are also reported. These findings may provide new directions for investigating the role of APP in neuropathology associated with a deficiency in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt) found in patients with Lesch-Nyhan syndrome (LNS) and its attenuated variants (LNVs). Also, these findings may be of significance for research in neurodevelopmental and neurodegenerative disorders in which the APP gene is involved in the pathogenesis of diseases such as autism, fragile X syndrome (FXS) and AD, with its diversity and complexity, SAD in particular. Accurate quantification of various APPmRNA isoforms in brain tissues is needed, and antisense drugs are potential treatments.

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Section: Discussion and Perspectivesmentioning

confidence: 99%

“…(147)(148)(149)]. Antisense drugs are a new generation of gene-silencing therapeutic agents with potential for targeted causal treatment of as yet incurable diseases.…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

The human β-amyloid precursor protein: biomolecular and epigenetic aspects

Nguyen¹

2015

Biomolecular Concepts

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“…However, when a nuclear lncRNA is to be targeted, RNAi is not efficient furthermore, although the RNAi machinery has been shown to be active in the nucleus 71, 83.…”

Section: Methods Utilized For Determination Of Lncrna Functionmentioning

confidence: 99%

State of the art technologies to explore long non‐coding RNAs in cancer

Salehi

Taheri

Azarpira

et al. 2017

J Cellular Molecular Medi

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Long non‐coding RNAs (lncRNAs) comprise a vast repertoire of RNAs playing a wide variety of crucial roles in tissue physiology in a cell‐specific manner. Despite being engaged in myriads of regulatory mechanisms, many lncRNAs have still remained to be assigned any functions. A constellation of experimental techniques including single‐molecule RNA in situ hybridization (sm‐RNA FISH), cross‐linking and immunoprecipitation (CLIP), RNA interference (RNAi), Clustered regularly interspaced short palindromic repeats (CRISPR) and so forth has been employed to shed light on lncRNA cellular localization, structure, interaction networks and functions. Here, we review these and other experimental approaches in common use for identification and characterization of lncRNAs, particularly those involved in different types of cancer, with focus on merits and demerits of each technique.

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“…Antisense and antigene technologies are powerful tools to artificially regulate target gene expression. In antisense technology, a single-stranded oligonucleotide added from outside may bind with target mRNA to form oligonucleotide-RNA duplex [1,2]. The formed duplex may inhibit ribosomemediated translation of target mRNA due to its steric hindrance, or RNaseH may cleave target mRNA in the formed duplex, which may result in reduction of expression level of target mRNA in both cases [1,2].…”

Section: Introductionmentioning

confidence: 99%