RNAi mechanisms in Huntington’s disease therapy: siRNA versus shRNA

Aguiar, Sebastian; Gaag, Bram van der; Cortese, Filomeno

doi:10.1186/s40035-017-0101-9

Cited by 56 publications

(42 citation statements)

References 58 publications

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“…Side effects include peripheral neuropathy observed in clinical trials of siRNA. RNAi has been tested in rodents and its delivery system has been tested in nonhuman primates [119].…”

Section: Rnai Approachesmentioning

confidence: 99%

Therapeutic Advances for Huntington’s Disease

et al. 2020

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Huntington’s disease (HD) is a progressive neurological disease that is inherited in an autosomal fashion. The cause of disease pathology is an expansion of cytosine-adenine-guanine (CAG) repeats within the huntingtin gene (HTT) on chromosome 4 (4p16.3), which codes the huntingtin protein (mHTT). The common symptoms of HD include motor and cognitive impairment of psychiatric functions. Patients exhibit a representative phenotype of involuntary movement (chorea) of limbs, impaired cognition, and severe psychiatric disturbances (mood swings, depression, and personality changes). A variety of symptomatic treatments (which target glutamate and dopamine pathways, caspases, inhibition of aggregation, mitochondrial dysfunction, transcriptional dysregulation, and fetal neural transplants, etc.) are available and some are in the pipeline. Advancement in novel therapeutic approaches include targeting the mutant huntingtin (mHTT) protein and the HTT gene. New gene editing techniques will reduce the CAG repeats. More appropriate and readily tractable treatment goals, coupled with advances in analytical tools will help to assess the clinical outcomes of HD treatments. This will not only improve the quality of life and life span of HD patients, but it will also provide a beneficial role in other inherited and neurological disorders. In this review, we aim to discuss current therapeutic research approaches and their possible uses for HD.

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“…Side effects include peripheral neuropathy observed in clinical trials of siRNA. RNAi has been tested in rodents and its delivery system has been tested in nonhuman primates [119].…”

Section: Rnai Approachesmentioning

confidence: 99%

Therapeutic Advances for Huntington’s Disease

et al. 2020

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“…There are two main recent experimental approaches to try to develop a therapy (reviewed in Huang et al, 2016; Wright et al, 2017; Caron et al, 2018; Saavedra et al, 2018). One involves gene therapy, which includes knockdown of mHtt (Aguiar et al, 2017; Datson et al, 2017; Southwell et al, 2018) and expression of miRNAs (Miniarikova et al, 2017; Evers et al, 2018) (Table 1). Htt is necessary in embryonic development but it might be possible to eliminate it in the adult brain, (reviewed in Liu and Zeitlin, 2017).…”

Section: Therapeutic Approaches For Hdmentioning

confidence: 99%

Protein Misfolding and ER Stress in Huntington's Disease

Shacham

Sharma

Lederkremer

2019

Front. Mol. Biosci.

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Increasing evidence in recent years indicates that protein misfolding and aggregation, leading to ER stress, are central factors of pathogenicity in neurodegenerative diseases. This is particularly true in Huntington's disease (HD), where in contrast with other disorders, the cause is monogenic. Mutant huntingtin interferes with many cellular processes, but the fact that modulation of ER stress and of the unfolded response pathways reduces the toxicity, places these mechanisms at the core and gives hope for potential therapeutic approaches. There is currently no effective treatment for HD and it has a fatal outcome a few years after the start of symptoms of cognitive and motor impairment. Here we will discuss recent findings that shed light on the mechanisms of protein misfolding and aggregation that give origin to ER stress in neurodegenerative diseases, focusing on Huntington's disease, on the cellular response and on how to use this knowledge for possible therapeutic strategies.

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“…This can also be done in a mutant allele fashion [ 251 ], given that some SNPs are present during heterozygosis in the HTT sequence. Much research has been done using them on animal models of HD [ 252 ]. These techniques are much more mature than CRISPR, and this is why ssODNs are under investigation as therapy for HD in clinical trials (ClinicalTrials.gov, number NCT02519036) [ 253 ].…”

Section: Conclusion and Remarksmentioning

confidence: 99%

Reactive Species in Huntington Disease: Are They Really the Radicals You Want to Catch?

et al. 2020

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Huntington disease (HD) is a neurodegenerative condition and one of the so-called rare or minority diseases, due to its low prevalence (affecting 1–10 of every 100,000 people in western countries). The causative gene, HTT, encodes huntingtin, a protein with a yet unknown function. Mutant huntingtin causes a range of phenotypes, including oxidative stress and the activation of microglia and astrocytes, which leads to chronic inflammation of the brain. Although substantial efforts have been made to find a cure for HD, there is currently no medical intervention able to stop or even delay progression of the disease. Among the many targets of therapeutic intervention, oxidative stress and inflammation have been extensively studied and some clinical trials have been promoted to target them. In the present work, we review the basic research on oxidative stress in HD and the strategies used to fight it. Many of the strategies to reduce the phenotypes associated with oxidative stress have produced positive results, yet no substantial functional recovery has been observed in animal models or patients with the disease. We discuss possible explanations for this and suggest potential ways to overcome it.

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RNAi mechanisms in Huntington’s disease therapy: siRNA versus shRNA

Cited by 56 publications

References 58 publications

Therapeutic Advances for Huntington’s Disease

Therapeutic Advances for Huntington’s Disease

Protein Misfolding and ER Stress in Huntington's Disease

Reactive Species in Huntington Disease: Are They Really the Radicals You Want to Catch?

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