Recent Advances in RNA Interference Therapeutics for CNS Diseases

Ramachandran, Pavitra S.; Keiser, Megan S.; Davidson, Beverly L.

doi:10.1007/s13311-013-0183-8

Cited by 24 publications

(10 citation statements)

References 172 publications

(213 reference statements)

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“…It is well established that the lacZ transgenic reporter mice is a reliable model for natural floxed genes. Our approach can also be extended to overexpress wild-type and mutant genes ( Eschbach and Danzer, 2014 ) and interference RNA ( Murphy et al, 2013 ; Ramachandran et al, 2013 ). With stereotactic virus injection, we can achieve long-term gene expression in either a single or multiple brain regions, enabling systematic investigation of how different brain regions participate in various biological processes, for example, learning and memory.…”

Section: Discussionmentioning

confidence: 99%

Inducible and combinatorial gene manipulation in mouse brain

Dogbevia

Marticorena-Alvarez

Bausen

et al. 2015

Front. Cell. Neurosci.

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We have deployed recombinant adeno-associated viruses equipped with tetracycline-controlled genetic switches to manipulate gene expression in mouse brain. Here, we show a combinatorial genetic approach for inducible, cell type-specific gene expression and Cre/loxP mediated gene recombination in different brain regions. Our chemical-genetic approach will help to investigate ‘when’, ‘where’, and ‘how’ gene(s) control neuronal circuit dynamics, and organize, for example, sensory signal processing, learning and memory, and behavior.

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Section: Discussionmentioning

confidence: 99%

Inducible and combinatorial gene manipulation in mouse brain

Dogbevia

Marticorena-Alvarez

Bausen

et al. 2015

Front. Cell. Neurosci.

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“…This might be accomplished with RNA interference, which allows the specific targeting of the mutant HTT transcript. 80, 106, 107, 108, 109, 110 …”

Section: Therapeutic Approachesmentioning

confidence: 99%

Mechanisms of RNA-induced toxicity in CAG repeat disorders

et al. 2013

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Several inherited neurodegenerative disorders are caused by CAG trinucleotide repeat expansions, which can be located either in the coding region or in the untranslated region (UTR) of the respective genes. Polyglutamine diseases (polyQ diseases) are caused by an expansion of a stretch of CAG repeats within the coding region, translating into a polyQ tract. The polyQ tract expansions result in conformational changes, eventually leading to aggregate formation. It is widely believed that the aggregation of polyQ proteins is linked with disease development. In addition, in the last couple of years, it has been shown that RNA-mediated mechanisms also have a profound role in neurotoxicity in both polyQ diseases and diseases caused by elongated CAG repeat motifs in their UTRs. Here, we review the different molecular mechanisms assigned to mRNAs with expanded CAG repeats. One aspect is the mRNA folding of CAG repeats. Furthermore, pathogenic mechanisms assigned to CAG repeat mRNAs are discussed. First, we discuss mechanisms that involve the sequestration of the diverse proteins to the expanded CAG repeat mRNA molecules. As a result of this, several cellular mechanisms are aberrantly regulated. These include the sequestration of MBNL1, leading to misregulated splicing; sequestration of nucleolin, leading to reduced cellular rRNA; and sequestration of proteins of the siRNA machinery, resulting in the production of short silencing RNAs that affect gene expression. Second, we discuss the effect of expanded CAG repeats on the subcellular localization, transcription and translation of the CAG repeat mRNA itself. Here we focus on the MID1 protein complex that triggers an increased translation of expanded CAG repeat mRNAs and a mechanism called repeat-associated non-ATG translation, which leads to proteins aberrantly translated from CAG repeat mRNAs. In addition, therapeutic approaches for CAG repeat disorders are discussed. Together, all the findings summarized here show that mutant mRNA has a fundamental role in the pathogenesis of CAG repeat diseases.

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“…When considering such paradigms, one critical demand will be that the overall efficacy supersedes that of current standard or alternative experimental therapeutic options (even if the threshold to clinical translation appears somewhat lower due to the perceived “safer” character of such sources [ 12 , 13 ]). In addition to continuously improving pharmacological therapies (for review, see [ 14 ]), as well as neurostimulatory approaches using electrode implantation (deep brain stimulation) (for review, see [ 15 ]), RNA interference-based approaches that aim for amelioration of disease by preventing formation of the pathognomonic neural protein aggregates, for instance, have to be considered as potentially feasible, promising therapeutic alternatives (for review, see [ 16 ]). Still, the lasting structural and functional repair of neural circuits by means of cell replacement is a worthy goal with potential biomedical benefit beyond what experimental alternatives may offer [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

A brief perspective on neural cell therapy

Pruszak¹

2014

Molecular and Cellular Therapies

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For a range of nervous system disorders current treatment options remain limited. Focusing on Parkinson’s disease as a neurodegenerative entity that affects an increasing quantity of people in our aging societies, we briefly discuss remaining challenges and opportunities that neural stem cell therapy might be able to offer. Providing a snapshot of neural transplantation paradigms, we contemplate possible imminent translational scenarios and discuss critical requirements to be considered before clinical implementation.

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Recent Advances in RNA Interference Therapeutics for CNS Diseases

Cited by 24 publications

References 172 publications

Inducible and combinatorial gene manipulation in mouse brain

Inducible and combinatorial gene manipulation in mouse brain

Mechanisms of RNA-induced toxicity in CAG repeat disorders

A brief perspective on neural cell therapy

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