RNA Interference Therapy for Machado–Joseph Disease: Long-Term Safety Profile of Lentiviral Vectors Encoding Short Hairpin RNAs Targeting Mutant Ataxin-3

Nóbrega, Clévio; Codêsso, José Miguel; Mendonça, Liliana; Almeida, Luís Pereira de

doi:10.1089/hum.2018.157

Cited by 18 publications

(20 citation statements)

References 50 publications

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“…These RNAi constructs could be delivered to patients using vectors such as adeno-associated virus (AAV) [57] and lentivirus [58] or by non-viral systems such as lipid nanoparticles [59]. In either case, efficient long-term expression of the RNAi is required to suppress protein aggregation.…”

Section: Rnai Silencing Of Ataxin-3 Expressionmentioning

confidence: 99%

Identifying Therapeutic Targets for Spinocerebellar Ataxia Type 3/Machado–Joseph Disease through Integration of Pathological Biomarkers and Therapeutic Strategies

Chen

Hong

Lin

et al. 2020

IJMS

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Spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) is a progressive motor disease with no broadly effective treatment. However, most current therapies are based on symptoms rather than the underlying disease mechanisms. In this review, we describe potential therapeutic strategies based on known pathological biomarkers and related pathogenic processes. The three major conclusions from the current studies are summarized as follows: (i) for the drugs currently being tested in clinical trials; a weak connection was observed between drugs and SCA3/MJD biomarkers. The only two exceptions are the drugs suppressing glutamate-induced calcium influx and chemical chaperon. (ii) For most of the drugs that have been tested in animal studies, there is a direct association with pathological biomarkers. We further found that many drugs are associated with inducing autophagy, which is supported by the evidence of deficient autophagy biomarkers in SCA3/MJD, and that there may be more promising therapeutics. (iii) Some reported biomarkers lack relatively targeted drugs. Low glucose utilization, altered amino acid metabolism, and deficient insulin signaling are all implicated in SCA3/MJD, but there have been few studies on treatment strategies targeting these abnormalities. Therapeutic strategies targeting multiple pathological SCA3/MJD biomarkers may effectively block disease progression and preserve neurological function.

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Section: Rnai Silencing Of Ataxin-3 Expressionmentioning

confidence: 99%

Identifying Therapeutic Targets for Spinocerebellar Ataxia Type 3/Machado–Joseph Disease through Integration of Pathological Biomarkers and Therapeutic Strategies

Chen

Hong

Lin

et al. 2020

IJMS

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“…Another gene-directed strategy that has been tested with positive results is the use of short hairpin RNAs (shRNAs) targeting mutant ATXN3 [283]. Moreover, the safety profile of lentiviral-mediated delivery of shRNAs has also been established, making a step towards translation [284]. However, the challenges for viral-mediated approaches are some of the largest in the clinical trial setting: the inflammatory response to viral particles, the tissue-unspecific uptake of the content, the lack of entry in target cells, oncogenic side effects, and the overall absence of effect in most clinical trials carried out are some of the aspects that make these types of approaches hard to implement [285][286][287][288].…”

Section: Mobility Aidsmentioning

confidence: 99%

From Pathogenesis to Novel Therapeutics for Spinocerebellar Ataxia Type 3: Evading Potholes on the Way to Translation

2019

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Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a neurodegenerative disorder caused by a polyglutamine expansion in the ATXN3 gene. In spite of the identification of a clear monogenic cause 25 years ago, the pathological process still puzzles researchers, impairing prospects for an effective therapy. Here, we propose the disruption of protein homeostasis as the hub of SCA3 pathogenesis, being the molecular mechanisms and cellular pathways that are deregulated in SCA3 downstream consequences of the misfolding and aggregation of ATXN3. Moreover, we attempt to provide a realistic perspective on how the translational/clinical research in SCA3 should evolve. This was based on molecular findings, clinical and epidemiological characteristics, studies of proposed treatments in other conditions, and how that information is essential for their (re-)application in SCA3. This review thus aims i) to critically evaluate the current state of research on SCA3, from fundamental to translational and clinical perspectives; ii) to bring up the current key questions that remain unanswered in this disorder; and iii) to provide a frame on how those answers should be pursued.

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“…Additionally, Nóbrega and colleagues also showed the recovery of neuropathological and motor features associated with SCA3/MJD after disease onset, following mutant ATXN3 silencing in a transgenic mouse model [75]. Furthermore, the long-term expression of the shRNA used in these studies did not lead to toxic effects, in a recent safety assessment [64]. In an alternative approach, siRNAs targeting mutant ATXN3 were encapsulated in SNALPs and delivered intravenously to different SCA3/MJD mouse models.…”

Section: Short Hairpin and Small Interfering Rnas Mediated Silencingmentioning

confidence: 97%

“…Experimentally, the mechanism of RNAi can thus be triggered by different RNA molecules: miRNAs, siRNAs and shRNAs [62], which may be delivered in different ways. They can be introduced into the cell as small interfering RNAs (siRNAs), similarly to a protein-based therapy, or via plasmids and viral vectors, which incorporate into the genome and are endogenously expressed in the form of short hairpin RNAs (shRNAs), which, contrary to siRNAs, result in enduring gene silencing [63,64].…”

Section: Rnai-based Gene Silencing Strategiesmentioning

confidence: 99%

Current Status of Gene Therapy Research in Polyglutamine Spinocerebellar Ataxias

Afonso-Reis

Afonso

Nóbrega

2021

IJMS

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Polyglutamine spinocerebellar ataxias (PolyQ SCAs) are a group of 6 rare autosomal dominant diseases, which arise from an abnormal CAG repeat expansion in the coding region of their causative gene. These neurodegenerative ataxic disorders are characterized by progressive cerebellar degeneration, which translates into progressive ataxia, the main clinical feature, often accompanied by oculomotor deficits and dysarthria. Currently, PolyQ SCAs treatment is limited only to symptomatic mitigation, and no therapy is available to stop or delay the disease progression, which culminates with death. Over the last years, many promising gene therapy approaches were investigated in preclinical studies and could lead to a future treatment to stop or delay the disease development. Here, we summed up the most promising of these therapies, categorizing them in gene augmentation therapy, gene silencing strategies, and gene edition approaches. While several of the reviewed strategies are promising, there is still a gap from the preclinical results obtained and their translation to clinical studies. However, there is an increase in the number of approved gene therapies, as well as a constant development in their safety and efficacy profiles. Thus, it is expected that in a near future some of the promising strategies reviewed here could be tested in a clinical setting and if successful provide hope for SCAs patients.

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RNA Interference Therapy for Machado–Joseph Disease: Long-Term Safety Profile of Lentiviral Vectors Encoding Short Hairpin RNAs Targeting Mutant Ataxin-3

Cited by 18 publications

References 50 publications

Identifying Therapeutic Targets for Spinocerebellar Ataxia Type 3/Machado–Joseph Disease through Integration of Pathological Biomarkers and Therapeutic Strategies

Identifying Therapeutic Targets for Spinocerebellar Ataxia Type 3/Machado–Joseph Disease through Integration of Pathological Biomarkers and Therapeutic Strategies

From Pathogenesis to Novel Therapeutics for Spinocerebellar Ataxia Type 3: Evading Potholes on the Way to Translation

Current Status of Gene Therapy Research in Polyglutamine Spinocerebellar Ataxias

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