Short G-rich oligonucleotides as a potential therapeutic for Huntington's Disease

Skogen, Michael; Roth, Jennifer A.; Yerkes, Sarah; Parekh-Olmedo, Hetal; Kmiec, Eric B.

doi:10.1186/1471-2202-7-65

Cited by 33 publications

(10 citation statements)

References 33 publications

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“…We have identified a specific set of DNA aptamers that preferentially bind to full-length huntingtin with an expanded polyglutamine tract, providing novel molecular tools that may modulate the structure and function of the mutant protein, unlike the previously reported guanine-rich oligonucleotides that bind to the exon 1-encoded short amino-terminal huntingtin fragments inhibiting their aggregation. 25 , 26 , 27 In fact, two DNA aptamers (T30923 and T40216 as clone ID) of the previously identified guanine-rich oligonucleotides 25 were included in our 3416 DNA aptamers. Interestingly, they could not be shortlisted even as tightly bound aptamers ( Figure S1 ), implying the unique specificity of our DNA aptamers toward full-length mutant huntingtin and the reliability of the microarray screening.…”

Section: Discussionmentioning

confidence: 99%

Novel DNA Aptamers that Bind to Mutant Huntingtin and Modify Its Activity

Shin

Jung

et al. 2018

Molecular Therapy - Nucleic Acids

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The CAG repeat expansion that elongates the polyglutamine tract in huntingtin is the root genetic cause of Huntington’s disease (HD), a debilitating neurodegenerative disorder. This seemingly slight change to the primary amino acid sequence alters the physical structure of the mutant protein and alters its activity. We have identified a set of G-quadruplex-forming DNA aptamers (MS1, MS2, MS3, MS4) that bind mutant huntingtin proximal to lysines K2932/K2934 in the C-terminal CTD-II domain. Aptamer binding to mutant huntingtin abrogated the enhanced polycomb repressive complex 2 (PRC2) stimulatory activity conferred by the expanded polyglutamine tract. In HD, but not normal, neuronal progenitor cells (NPCs), MS3 aptamer co-localized with endogenous mutant huntingtin and was associated with significantly decreased PRC2 activity. Furthermore, MS3 transfection protected HD NPCs against starvation-dependent stress with increased ATP. Therefore, DNA aptamers can preferentially target mutant huntingtin and modulate a gain of function endowed by the elongated polyglutamine segment. These mutant huntingtin binding aptamers provide novel molecular tools for delineating the effects of the HD mutation and encourage mutant huntingtin structure-based approaches to therapeutic development.

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Section: Discussionmentioning

confidence: 99%

Novel DNA Aptamers that Bind to Mutant Huntingtin and Modify Its Activity

Shin

Jung

et al. 2018

Molecular Therapy - Nucleic Acids

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“…The chimera aptamer consisting of the TfR aptamer and the EpCAM aptamer is reported to be delivered into the brain [109]. There are many aptamer-druggable targets for the treatment of neurodegenerative diseases, such as BACE1 [110], α-Syn [111], prion [112], and mHTT [113]. Therefore, delivering these aptamers into the brain by coupling with the TfR aptamer is an exciting research subject.…”

Section: Future Direction Of Therapeutic Aptamersmentioning

confidence: 99%

Aptamers: A Review of Their Chemical Properties and Modifications for Therapeutic Application

Adachi¹,

2019

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Aptamers are short, single-stranded oligonucleotides that bind to specific target molecules. The shape-forming feature of single-stranded oligonucleotides provides high affinity and excellent specificity toward targets. Hence, aptamers can be used as analogs of antibodies. In December 2004, the US Food and Drug Administration approved the first aptamer-based therapeutic, pegaptanib (Macugen), targeting vascular endothelial growth factor, for the treatment of age-related macular degeneration. Since then, however, no aptamer medication for public health has appeared. During these relatively silent years, many trials and improvements of aptamer therapeutics have been performed, opening multiple novel directions for the therapeutic application of aptamers. This review summarizes the basic characteristics of aptamers and the chemical modifications available for aptamer therapeutics.

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“…Aptamers can also be used as antagonists that inhibit the accumulation of misfolded proteins in the central nervous system and delay the onset of neurodegenerative diseases [136] . Currently, a variety of functional DNA and RNA aptamers are in use that inhibit the accumulation of disease‐related proteins such as β‐amyloid (Alzheimer's disease, AD), [137] Α‐Syn (Parkinson's disease, PD), [138] Prion protein (Transmissible Spongiform Encephalopathy, TSE), [139] mHTT (Huntington's disease, HD), [140] and rat myelin (multiple sclerosis) [141] . Macugen (Pegaptanib), the first aptameric nucleic acid drug, was approved by the FDA as early as 2004 for the treatment of age‐related macular degeneration [142] .…”

Section: Aptamersmentioning

confidence: 99%

Therapeutic Mechanism of Nucleic Acid Drugs

et al. 2021

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The cover picture shows an eidolon leading the way for patients, named as “Baize”. According to the Chinese myth, “Baize” is a kind of Pegasus but has the torso of a lion. It knows human language, is able to exorcise evil spirits and protects people. In this cover artwork, the nucleic acid drug is symbolized as “Baize”, flying in the sky, burning the fog away and lighting the health road for human beings via its “brilliant healthy radiance”. Similar with the “Baize” protecting humans, the nucleic acid drug is developing with enormous potential for treating or managing a wide range of diseases, what allows people to lead a healthy life. At present, nucleic acid drug includes plasmid DNA (pDNA), minicircular DNA (mcDNA), messenger RNA (mRNA), microRNA (miRNA), antisense oligonucleotides (ASOs), small interfering RNA (siRNA), aptamers, and ribozymes. Depending on its various structures, nucleic acid drug medicinal mechanism has focused on gene addition, gene knockdown, and gene correction, which offer a lot of therapeutics for us to fight diseases. By this cover artwork, readers will be more aware of the importance of nucleic acid drug and its brilliant prospects of development. More information can be found in the Review by Lianxiao Liu, Qijun Qian et al. (DOI: 10.1002/slct.202002901).

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Short G-rich oligonucleotides as a potential therapeutic for Huntington's Disease

Cited by 33 publications

References 33 publications

Novel DNA Aptamers that Bind to Mutant Huntingtin and Modify Its Activity

Novel DNA Aptamers that Bind to Mutant Huntingtin and Modify Its Activity

Aptamers: A Review of Their Chemical Properties and Modifications for Therapeutic Application

Therapeutic Mechanism of Nucleic Acid Drugs

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