RNA-based therapeutics for neurological diseases

Anthony, Karen

doi:10.1080/15476286.2021.2021650

Cited by 49 publications

(20 citation statements)

References 153 publications

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“…More generally, this study provides a unique catalog of circRNAs in two major types of human brain neurons that will be generally useful for decoding genome function in neuropsychiatric disease and for advancing the burgeoning field of RNA medicines and diagnostics [63][64][65] The alluvial plot visualizes 3,532 genetic loci that custom-tailored cell type-specific circRNAs to the cell identity of dopamine neurons (DA), pyramidal neurons (PY), and non-neuronal cells (NN), respectively (i.e., cell specificity score S < 0.5 and mean expression > mean + s.d.). b,c.…”

Section: Discussionmentioning

confidence: 99%

“…Control samples lacking template and those lacking reverse transcriptase showed virtually no expression of these target circRNAs indicating that DNA contamination did not materially influence results. Expression values were analyzed using the comparative threshold cycle method 63 . All the quantitative PCR reactions were conducted in triplicate.…”

Section: Confirming Circrna Expression By Qpcrmentioning

confidence: 99%

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Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease

Dong

Bai

Liao

et al. 2023

Preprint

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Little is known about circular RNAs (circRNAs) in specific brain cells and human neuropsychiatric disease. Here, we systematically identified over 11,039 circRNAs expressed in vulnerable dopamine and pyramidal neurons laser-captured from 190 human brains and non-neuronal cells using ultra-deep, total RNA sequencing. 1,526 and 3,308 circRNAs were custom-tailored to the cell identity of dopamine and pyramidal neurons and enriched in synapse pathways. 88% of Parkinson's and 80% of Alzheimer's disease-associated genes produced circRNAs. circDNAJC6, produced from a juvenile-onset Parkinson's gene, was already dysregulated during prodromal, onset stages of common Parkinson's disease neuropathology. Globally, addiction-associated genes preferentially produced circRNAs in dopamine neurons, autism-associated genes in pyramidal neurons, and cancers in non-neuronal cells. This study shows that circular RNAs in the human brain are tailored to neuron identity and implicate circRNA-regulated synaptic specialization in neuropsychiatric diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Confirming Circrna Expression By Qpcrmentioning

confidence: 99%

Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease

Dong

Bai

Liao

et al. 2023

Preprint

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“…Es handelt sich dabei um einen hoch individualisierten Therapieansatz, da solche ASOs nicht grundsätzlich bei AT wirksam, sondern nur für Patienten mit bestimmten Mutationen geeignet sind. Tatsächlich ist ein solches als Atipeksin bezeichnetes ASO einem AT-Patienten verabreicht worden [12]. Daten dazu wurden bisher nicht veröffentlicht.…”

Section: Ataxie-teleangiektasie (At)unclassified

Gentherapie für Ataxien

Klockgether

2023

Fortschr Neurol Psychiatr

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ZusammenfassungAtaxien sind progredient verlaufende Krankheiten, die meist Folge einer Degeneration des Kleinhirns sind. Ataxien werden in genetische, sporadisch degenerative und erworbene (sekundäre) Formen unterteilt. Während es bei den erworbene (sekundäre) Ataxien etablierte Therapien gibt, sind genetische und sporadische degenerative Ataxien derzeit nicht medizinisch behandelbar. Für diese Ataxien ist die Entwicklung somatischer Gentherapien ein vielversprechender Weg. Ziele der Gentherapien bei genetischen Ataxien sind die Inaktivierung schädlicher Gene durch Gen-Silencing oder der Ersatz oder die Korrektur eines nicht funktionsfähigen Gens. Eine weitere Option, die auch für sporadisch degenerative Ataxien in Betracht kommt, sind Therapien, bei denen neue oder modifizierte Gene transferiert werden. Bei den häufigeren Ataxien, wie Friedreich-Ataxie, bestimmten spinozerebellären Ataxien und Multisystematrophie werden aktiv Gentherapien entwickelt, und erste Phase I-Studien werden bereits durchgeführt.

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“…Remarkably, IT ASO administration has already been implemented for the treatment of SMA and has produced safe and tolerable results [ 58 , 59 ]. An ASO that targets ALS and is delivered via IT was also recently administered to one patient [ 60 ].…”

Section: Splicing: How It Work and How It Can Be Modulatedmentioning

confidence: 99%

Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example

Santos

Gonçalves

Matos

et al. 2022

Life

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Over recent decades, the many functions of RNA have become more evident. This molecule has been recognized not only as a carrier of genetic information, but also as a specific and essential regulator of gene expression. Different RNA species have been identified and novel and exciting roles have been unveiled. Quite remarkably, this explosion of novel RNA classes has increased the possibility for new therapeutic strategies that tap into RNA biology. Most of these drugs use nucleic acid analogues and take advantage of complementary base pairing to either mimic or antagonize the function of RNAs. Among the most successful RNA-based drugs are those that act at the pre-mRNA level to modulate or correct aberrant splicing patterns, which are caused by specific pathogenic variants. This approach is particularly tempting for monogenic disorders with associated splicing defects, especially when they are highly frequent among affected patients worldwide or within a specific population. With more than 600 mutations that cause disease affecting the pre-mRNA splicing process, we consider lysosomal storage diseases (LSDs) to be perfect candidates for this type of approach. Here, we introduce the overall rationale and general mechanisms of splicing modulation approaches and highlight the currently marketed formulations, which have been developed for non-lysosomal genetic disorders. We also extensively reviewed the existing preclinical studies on the potential of this sort of therapeutic strategy to recover aberrant splicing and increase enzyme activity in our diseases of interest: the LSDs. Special attention was paid to a particular subgroup of LSDs: the mucopolysaccharidoses (MPSs). By doing this, we hoped to unveil the unique therapeutic potential of the use of this sort of approach for LSDs as a whole.

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RNA-based therapeutics for neurological diseases

Cited by 49 publications

References 153 publications

Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease

Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease

Gentherapie für Ataxien

Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example

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