Spliceosome-mediated RNA trans-splicing as a tool for gene therapy

Puttaraju, M.; Jamison, Sharon F.; Mansfield, S. Gary; García-Blanco, Mariano A.; Mitchell, Lloyd G.

doi:10.1038/6986

Cited by 180 publications

(178 citation statements)

References 38 publications

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“…215 Spliceosome-mediated RNA trans-splicing (SMarT) is another method for mRNA reprogramming, and has been tested in tau transfected cells. 216,217 Trans-splicing occurs between the 5= splice site of a pre-mRNA and the 3= splice site of a second mRNA at the spliceosome. With SMarT, the endogenous target pre-mRNA becomes trans-spliced to an exogenously delivered pre-transsplicing molecule.…”

Section: Isoform Approachesmentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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Section: Isoform Approachesmentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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“…[1][2][3][4][5][6][7][8][9] We are developing a technology called spliceosome mediated RNA trans-splicing (SMaRT) to take advantage of the cell's endogenous splicing machinery as a strategy for modifying pre-mRNA. 10 The SMaRT process uses pretherapeutic RNA molecules (PTMs) that are designed to base pair with the intron of a targeted pre-mRNA to suppress target cis-splicing while enhancing trans-splicing between the PTM and target. A potential application for SMaRT involves repairing mutant pre-mRNA molecules associated with genetic diseases.…”

Section: Introductionmentioning

confidence: 99%

Repair of CFTR mRNA by spliceosome-mediated RNA trans-splicing

Mansfield¹,

Kole

Puttaraju³

et al. 2000

Gene Ther

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Most messenger RNA precursors (pre-mRNA) undergo cissplicing in which introns are excised and the adjoining exons from a single pre-mRNA are ligated together to form mature messenger RNA. This reaction is driven by a complex known as the spliceosome. Spliceosomes can also combine sequences from two independently transcribed pre-mRNAs in a process known as trans-splicing. Spliceosome-mediated RNA trans-splicing (SMaRT) is an emerging technology in which RNA pre-therapeutic molecules (PTMs) are designed to recode a specific pre-mRNA by suppressing cis-splicing while enhancing trans-splicing between the PTM and its premRNA target. This study examined the feasibility of SMaRT as a potential therapy for genetic diseases to correct mutations using cystic fibrosis (CF) as an example. We used several versions of a cystic fibrosis transmembrane conduc-

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“…This is consistent with observations in a previously reported study, which concluded that the presence of the safety molecule was associated with reduced trans-splicing efficiency. 28 In conclusion, we have shown that our ATMs can specifically target and trans-splice DMPK pre-mRNA. Although the amount of trans-splicing achieved was not high, the findings offered support for the potential of trans-splicing as a novel therapeutic strategy in myotonic dystrophy.…”

Section: Exon 15 Mcsmentioning

confidence: 63%

“…28 In our study, we included this safety molecule in four of the eight ATMs. We observed only a single specific trans-spliced RT-PCR product with ATMs with the safety molecule.…”

Section: Exon 15 Mcsmentioning

confidence: 99%

Correction of dystrophia myotonica type 1 pre-mRNA transcripts by artificial trans-splicing

et al. 2008

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Dystrophia myotonica type 1 (DM1), the most common muscular dystrophy in adults, results from expansion of a CTG repeat in the 3 0 -untranslated region of the dystrophia myotonica protein kinase gene (DMPK). Correction of the mutant DMPK transcript is a potential therapeutic strategy in DM1. We investigated the efficacy of artificial trans-splicing molecules (ATMs) to target and correct DMPK transcripts. ATMs designed to target intron 14 of DMPK pre-mRNA transcripts were tested for their ability to trans-splice the transcripts of a DMPK mini-gene construct and the endogenous DMPK transcripts of human myosarcoma cells (CCL-136). On agarose gel electrophoresis analysis, six of eight ATMs showed trans-splicing efficacy when applied to DMPK mini-gene construct transcripts, of which three were able to trans-splice endogenous DMPK pre-mRNA transcripts in myosarcoma cells, with trans-splicing efficiency ranging from 1.81 to 7.41%. These findings confirm that artificial trans-splicing can repair DMPK pre-mRNA and provide proof-of-principle evidence for this approach as potential therapeutic strategy for DM1.

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Spliceosome-mediated RNA trans-splicing as a tool for gene therapy

Cited by 180 publications

References 38 publications

Tau-Based Treatment Strategies in Neurodegenerative Diseases

Tau-Based Treatment Strategies in Neurodegenerative Diseases

Repair of CFTR mRNA by spliceosome-mediated RNA trans-splicing

Correction of dystrophia myotonica type 1 pre-mRNA transcripts by artificial trans-splicing

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