Chemically Modified, α-Amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) Receptor RNA Aptamers Designed for <i>in Vivo</i> Use

Huang, Zhen; Wen, Wei; Wu, Andrew; Niu, Li

doi:10.1021/acschemneuro.7b00211

Cited by 7 publications

(20 citation statements)

References 52 publications

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“…The RNA sequence of M1040 is identical to that of FN1040, but M1040 contains regular NTPs. As shown in Figure 6A, unmodified RNA control (M1040) had a t 1/2 of ∼1 min at 37 • C. Under identical condition, FN1040, however, showed a t 1/2 of ∼3.5 days in the medium ( Figure 6B) and ∼2.5 days in the rat CSF ( Figure 6C), respectively [88]. These data demonstrate replacing 2 -OH group with 2 -F atom on all A, C and U positions is sufficient to improve the stability of the RNA aptamer.…”

Section: Challenges Of Translating Rna Aptamers Into Clinical Drugsmentioning

confidence: 92%

“…We have recently developed a chemically modified RNA aptamer against AMPA receptors, which we termed FN1040 [88]. FN1040 is modified in that the 2 -OH group in all of the C, A and U positions is replaced with 2 -F NTPs (i.e., 'N' in the 'NTP' stands for ATP, CTP and UTP), whereas all the G positions in this aptamer are unmodified.…”

Section: Challenges Of Translating Rna Aptamers Into Clinical Drugsmentioning

confidence: 99%

“…If a direct, sequence-based replacement method is used, and the chemically modified RNA loses its biological activity significantly, a chemically modified library can be used to run or rerun SELEX, known as pre-SELEX modification. In fact, FN1040 has been selected using SELEX but with a 2 -fluoro modified library [88].…”

Section: Challenges Of Translating Rna Aptamers Into Clinical Drugsmentioning

confidence: 99%

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Developing RNA Aptamers for Potential Treatment of Neurological Diseases

Huang

Niu

2019

Future Med. Chem.

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AMPA receptor antagonists are drug candidates for potential treatment of a number of CNS diseases that involve excessive receptor activation. To date, small-molecule compounds are the dominating drug candidates in the field. However, lower potency, cross activity and poor water solubility are generally associated with these compounds. Here we show the potential of RNA-based antagonists or RNA aptamers as drug candidates and some strategies to discover these aptamers from a random sequence library (∼10 14 sequences). As an alternative to small molecule compounds, our aptamers exhibit higher potency and selectivity toward AMPA receptors. Because aptamers are RNA molecules, they are naturally water soluble. We also discuss the major challenges of translating RNA aptamers as lead molecules into drugs/treatment options.

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Section: Challenges Of Translating Rna Aptamers Into Clinical Drugsmentioning

confidence: 92%

Section: Challenges Of Translating Rna Aptamers Into Clinical Drugsmentioning

confidence: 99%

Section: Challenges Of Translating Rna Aptamers Into Clinical Drugsmentioning

confidence: 99%

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Developing RNA Aptamers for Potential Treatment of Neurological Diseases

Huang

Niu

2019

Future Med. Chem.

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“…Since its inception [ 10 , 12 , 87 ], many variations of SELEX have been developed and used, achieving targeted and specific outcomes [ 119 , 120 ], and SELEX has been optimized and extended to isolation of RNA, single-stranded DNA, or modified versions thereof.…”

Section: Aptamers and Systematic Evolution Of Ligands By Exponentimentioning

confidence: 99%

Aptamers Selected for Recognizing Amyloid β-Protein—A Case for Cautious Optimism

Rahimi

2018

IJMS

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Aptamers are versatile oligonucleotide ligands used for molecular recognition of diverse targets. However, application of aptamers to the field of amyloid β-protein (Aβ) has been limited so far. Aβ is an intrinsically disordered protein that exists in a dynamic conformational equilibrium, presenting time-dependent ensembles of short-lived, metastable structures and assemblies that have been generally difficult to isolate and characterize. Moreover, despite understanding of potential physiological roles of Aβ, this peptide has been linked to the pathogenesis of Alzheimer disease, and its pathogenic roles remain controversial. Accumulated scientific evidence thus far highlights undesirable or nonspecific interactions between selected aptamers and different Aβ assemblies likely due to the metastable nature of Aβ or inherent affinity of RNA oligonucleotides to β-sheet-rich fibrillar structures of amyloidogenic proteins. Accordingly, lessons drawn from Aβ–aptamer studies emphasize that purity and uniformity of the protein target and rigorous characterization of aptamers’ specificity are important for realizing and garnering the full potential of aptamers selected for recognizing Aβ or other intrinsically disordered proteins. This review summarizes studies of aptamers selected for recognizing different Aβ assemblies and highlights controversies, difficulties, and limitations of such studies.

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“…The water solubility of these compounds is thus limited. We have previously isolated a group of RNA aptamers targeting AMPA receptors ( Huang et al, 2010 ; Huang et al, 2017 ) using an in vitro evolution process known as systematic evolution of ligands by exponential enrichment (SELEX) ( Ellington & Szostak, 1990 ; Tuerk & Gold, 1990 ). As antagonists, the RNA aptamers we have isolated show higher potency and selectivity, as compared with traditional, small-molecule compounds, and they are water soluble by nature.…”

Section: Introductionmentioning

confidence: 99%

Testing of the therapeutic efficacy and safety of AMPA receptor RNA aptamers in an ALS mouse model

et al. 2022

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In motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients, the RNA editing at the glutamine/arginine site of the GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors is defective or incomplete. As a result, AMPA receptors containing the abnormally expressed, unedited isoform of GluA2 are highly Ca2+-permeable, and are responsible for mediating abnormal Ca2+ influx, thereby triggering motor neuron degeneration and cell death. Thus, blocking the AMPA receptor–mediated, abnormal Ca2+ influx is a potential therapeutic strategy for treatment of sporadic ALS. Here, we report a study of the efficacy and safety of two RNA aptamers targeting AMPA receptors on the ALS phenotype of AR2 mice. A 12-wk continuous, intracerebroventricular infusion of aptamers to AR2 mice reduced the progression of motor dysfunction, normalized TDP-43 mislocalization, and prevented death of motor neurons. Our results demonstrate that the use of AMPA receptor aptamers as a novel class of AMPA receptor antagonists is a promising strategy for developing an ALS treatment approach.

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Chemically Modified, α-Amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) Receptor RNA Aptamers Designed for in Vivo Use

Cited by 7 publications

References 52 publications

Developing RNA Aptamers for Potential Treatment of Neurological Diseases

Developing RNA Aptamers for Potential Treatment of Neurological Diseases

Aptamers Selected for Recognizing Amyloid β-Protein—A Case for Cautious Optimism

Testing of the therapeutic efficacy and safety of AMPA receptor RNA aptamers in an ALS mouse model

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