Gene suppression approaches to neurodegeneration

Abstract

Gene suppression approaches have emerged over the last 20 years as a novel therapeutic approach for the treatment of neurodegenerative diseases. These include RNA interference and anti-sense oligonucleotides, both of which act at the post-transcriptional level, and genome-editing techniques, which aim to repair the responsible mutant gene. All serve to inhibit the expression of disease-causing proteins, leading to the potential prevention or even reversal of the disease phenotype. In this review we summarise the main developments in gene suppression strategies, using examples from Huntington’s disease and other inherited causes of neurodegeneration, and explore how these might illuminate a path to tackle other proteinopathy-associated dementias in the future.

Systemic peptide mediated delivery of an siRNA targeting α-syn in the CNS ameliorates the neurodegenerative process in a transgenic model of Lewy body disease

“…Therefore, therapeutic strategies might involve decreasing synthesis, increasing clearance or promoting proper folding of these proteins (Valera et al, 2016a;Valera et al, 2016b). There has been progress in developing strategies to decrease the synthesis of proteins involved in neurological disorders by utilizing anti-sense oligonucleotides (Ghosh and Tabrizi, 2017;Schoch and Miller, 2017). Clinical trials are now underway with anti-sense oligonucleotides in HD (Dickey and La Spada, 2018;Ghosh and Tabrizi, 2017;Keiser et al, 2016) and similar strategies are being explored for PD and AD targeting α-syn (Alarcon-Aris et al, 2018) and Tau (Crunkhorn, 2017;DeVos and Hyman, 2017;Vossel et al, 2010).…”

“…There has been progress in developing strategies to decrease the synthesis of proteins involved in neurological disorders by utilizing anti-sense oligonucleotides (Ghosh and Tabrizi, 2017;Schoch and Miller, 2017). Clinical trials are now underway with anti-sense oligonucleotides in HD (Dickey and La Spada, 2018;Ghosh and Tabrizi, 2017;Keiser et al, 2016) and similar strategies are being explored for PD and AD targeting α-syn (Alarcon-Aris et al, 2018) and Tau (Crunkhorn, 2017;DeVos and Hyman, 2017;Vossel et al, 2010). In addition to anti-sense, another approach for reducing gene expression includes the use of short interfering RNA (siRNA) oligonucleotides that can bind specifically to target RNAs and target them for degradation via the RISC complex have been proposed for the treatment of neurodegenerative disorders (Alves et al, 2016;Koutsilieri et al, 2007;Magen and Hornstein, 2014;White and Mallucci, 2009).…”

Enhanced striatopallidal gamma‐aminobutyric acid (GABA)A receptor transmission in mouse models of huntington's disease

“…One way to address these questions is to regionally knockdown the expression of mHTT. In animal models this can be achieved with antisense oligonucleotides or zinc finger proteins . Viral delivery of Cre‐dependent expression plasmids for zinc finger proteins that specifically target mHTT could be used to knockdown expression in genetically defined subpopulations, such as iSPNs or prototypical GPe neurons.…”

“…In animal models this can be achieved with antisense oligonucleotides or zinc finger proteins. 66 Viral delivery of Credependent expression plasmids for zinc finger proteins that specifically target mHTT could be used to knockdown expression in genetically defined subpopulations, such as iSPNs or prototypical GPe neurons. This type of experiment could help define more precisely how mHTT drives both cellular and network pathophysiology.…”

Kynurenine 3-Monooxygenase Gene Associated With Nicotine Initiation and Addiction: Analysis of Novel Regulatory Features at 5′ and 3′-Regions

“…We noticed that the p1@ KMO 1 alternative promoter is more active in the brain compared with other KMO promoters. It is possible to suggest that p1@ KMO 1 is a candidate to lower KMO expression by suitable silencing methods, for example, RNAi, antisense oligonucleotides (ASOs), and CRISPR/Cas9 knockdown ( Mathupala, 2009 ; Kruspe and Giangrande, 2017 ; Ghosh and Tabrizi, 2017 ). However, this conclusion does not exclude the functions of additional regulatory factors associated with KMO expression besides alternative promoters, for example, miR and ncRNAs.…”