Antisense Oligonucleotide Therapy: From Design to the Huntington Disease Clinic

Rook, Morgan E.

doi:10.1007/s40259-022-00519-9

Cited by 63 publications

(67 citation statements)

References 102 publications

(121 reference statements)

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“…Other ways to do so are the use of antisense oligonucleotides (ASO) to block the translation of this messenger. ASOs are currently being used in clinical trials [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ]. Some strategies that are under investigation involve gene targeting to edit HTT, using CRISPR, for example, to remove the CAG expansion from the gene [ 65 ].…”

Section: Resultsmentioning

confidence: 99%

Mn(II) Quinoline Complex (4QMn) Restores Proteostasis and Reduces Toxicity in Experimental Models of Huntington’s Disease

Merino¹,

Sequedo

Sanchez‐Sanchez³

et al. 2022

IJMS

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Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder, of the so-called minority diseases, due to its low prevalence. It is caused by an abnormally long track of glutamines (polyQs) in mutant huntingtin (mHtt), which makes the protein toxic and prone to aggregation. Many pathways of clearance of badly-folded proteins are disrupted in neurons of patients with HD. In this work, we show that one Mn(II) quinone complex (4QMn), designed to work as an artificial superoxide dismutase, is able to activate both the ubiquitin-proteasome system and the autophagy pathway in vitro and in vivo models of HD. Activation of these pathways degrades mHtt and other protein-containing polyQs, which restores proteostasis in these models. Hence, we propose 4QMn as a potential drug to develop a therapy to treat HD.

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Section: Resultsmentioning

confidence: 99%

Mn(II) Quinoline Complex (4QMn) Restores Proteostasis and Reduces Toxicity in Experimental Models of Huntington’s Disease

Merino¹,

Sequedo

Sanchez‐Sanchez³

et al. 2022

IJMS

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“…Overall, despite some recent setbacks of withdrawals of some clinical trials of ASOs targeting SOD1 in symptomatic ALS patients 98 and HTT in early manifest HD patients, 99 efforts continue with the use of enhanced medicinal chemistry and different cohort designs (i.e., presymptomatic patients) with the hope of clinical success in the future.…”

Section: Rna Therapeutics For Genetically Determined Neurological Dis...mentioning

confidence: 99%

Brain somatic mutations as RNA therapeutic targets in neurological disorders

Lee¹,

Lee

2022

Annals of the New York Academy of Sciences

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Research into the genetic etiology of a neurological disorder can provide directions for genetic diagnosis and targeted therapy. In the past, germline mutations, which are transmitted from parents or newly arise from parental germ cells, were considered as major genetic causes of neurological disorders. However, recent evidence has shown that somatic mutations in the brain, which can arise from neural stem cells during development or over aging, account for a significant number of brain disorders, ranging from neurodevelopmental, neurodegenerative, and neuropsychiatric to neoplastic disease. Moreover, the identification of disease-causing somatic mutations or mutated genes has provided new insights into molecular pathogenesis and unveiled potential therapeutic targets for treating neurological disorders that have few, or no, therapeutic options. RNA therapeutics, including antisense oligonucleotide (ASO) and small interfering RNA (siRNA), are emerging as promising therapeutic tools for treating genetic neurological disorders. As the number of approved and investigational ASO and siRNA drugs for neurological disorders associated with germline mutations increases, they may also prove to be attractive modalities for treating neurologic disorders resulting from somatic mutations. In this perspective, we highlight several neurological diseases caused by brain somatic mutations and discuss the potential role of RNA therapeutics in these conditions.

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“…A number of gene-specific treatments including RNA-targeting therapies are under evaluation in clinical trials, such as for Dravet syndrome ( Han et al, 2020 ; Laux et al, 2020 ) and are an approved treatment in spinal muscular atrophy ( Passini et al, 2011 ; Hill and Meisler, 2021 ; Osredkar et al, 2021 ). However clinical trials of other ASO therapies for conditions such as Huntington’s disease have not been successful, despite promising pre-clinical studies ( Tabrizi et al, 2019 ; Kwon, 2021 ; Rook and Southwell, 2022 ). Here we review the potential and challenges of using antisense oligonucleotides in brain organoid systems to better target neurological diseases.…”

Section: Introductionmentioning

confidence: 99%

Cerebral Organoids and Antisense Oligonucleotide Therapeutics: Challenges and Opportunities

Lange

Zhou

McTague

2022

Front. Mol. Neurosci.

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The advent of stem cell-derived cerebral organoids has already advanced our understanding of disease mechanisms in neurological diseases. Despite this, many remain without effective treatments, resulting in significant personal and societal health burden. Antisense oligonucleotides (ASOs) are one of the most widely used approaches for targeting RNA and modifying gene expression, with significant advancements in clinical trials for epilepsy, neuromuscular disorders and other neurological conditions. ASOs have further potential to address the unmet need in other neurological diseases for novel therapies which directly target the causative genes, allowing precision treatment. Induced pluripotent stem cell (iPSC) derived cerebral organoids represent an ideal platform in which to evaluate novel ASO therapies. In patient-derived organoids, disease-causing mutations can be studied in the native genetic milieu, opening the door to test personalized ASO therapies and n-of-1 approaches. In addition, CRISPR-Cas9 can be used to generate isogenic iPSCs to assess the effects of ASOs, by either creating disease-specific mutations or correcting available disease iPSC lines. Currently, ASO therapies face a number of challenges to wider translation, including insufficient uptake by distinct and preferential cell types in central nervous system and inability to cross the blood brain barrier necessitating intrathecal administration. Cerebral organoids provide a practical model to address and improve these limitations. In this review we will address the current use of organoids to test ASO therapies, opportunities for future applications and challenges including those inherent to cerebral organoids, issues with organoid transfection and choice of appropriate read-outs.

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Antisense Oligonucleotide Therapy: From Design to the Huntington Disease Clinic

Cited by 63 publications

References 102 publications

Mn(II) Quinoline Complex (4QMn) Restores Proteostasis and Reduces Toxicity in Experimental Models of Huntington’s Disease

Mn(II) Quinoline Complex (4QMn) Restores Proteostasis and Reduces Toxicity in Experimental Models of Huntington’s Disease

Brain somatic mutations as RNA therapeutic targets in neurological disorders

Cerebral Organoids and Antisense Oligonucleotide Therapeutics: Challenges and Opportunities

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