Correction of Alternative Splicing of Tau in Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17

Kalbfuss, Bernd; Mabon, Stephen A.; Misteli, Tom

doi:10.1074/jbc.m105113200

Cited by 108 publications

(69 citation statements)

References 48 publications

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“…We have demonstrated here the potent impact of peptide delivery on PMO SSO therapy. In addition to SMA, other diseases for antisense oligonucleotide therapies include ALS (56, 57), Huntington's disease (58,59), and Parkinson's disease (60,61), which all ideally require both systemic and CNS SSO delivery. Future work will focus on extending further the clinical applications of Pip-PMOs.…”

Section: Discussionmentioning

confidence: 99%

Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy

Hammond

Hazell

Shabanpoor

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

169

129

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The development of antisense oligonucleotide therapy is an important advance in the identification of corrective therapy for neuromuscular diseases, such as spinal muscular atrophy (SMA). Because of difficulties of delivering single-stranded oligonucleotides to the CNS, current approaches have been restricted to using invasive intrathecal single-stranded oligonucleotide delivery. Here, we report an advanced peptide-oligonucleotide, Pip6a-morpholino phosphorodiamidate oligomer (PMO), which demonstrates potent efficacy in both the CNS and peripheral tissues in severe SMA mice following systemic administration. SMA results from reduced levels of the ubiquitously expressed survival motor neuron (SMN) protein because of loss-of-function mutations in the SMN1 gene. Therapeutic splice-switching oligonucleotides (SSOs) modulate exon 7 splicing of the nearly identical SMN2 gene to generate functional SMN protein. Pip6a-PMO yields SMN expression at high efficiency in peripheral and CNS tissues, resulting in profound phenotypic correction at doses an order-of-magnitude lower than required by standard naked SSOs. Survival is dramatically extended from 12 d to a mean of 456 d, with improvement in neuromuscular junction morphology, down-regulation of transcripts related to programmed cell death in the spinal cord, and normalization of circulating insulin-like growth factor 1. The potent systemic efficacy of Pip6a-PMO, targeting both peripheral as well as CNS tissues, demonstrates the high clinical potential of peptide-PMO therapy for SMA.spinal muscular atrophy | survival motor neuron | antisense oligonucleotide | splice switching oligonucleotide | cell-penetrating peptide S pinal muscular atrophy (SMA), a leading genetic cause of infant mortality primarily due to lower motor neuron degeneration and progressive muscle weakness, results from loss of the ubiquitous survival motor neuron 1 gene (SMN1) (1, 2). Humans have a second nearly identical copy, SMN2, that differs from SMN1 by a crucial nucleotide transition within exon 7 leading to the predominant generation of an alternative exon 7-excluded transcript and only marginally functional protein (3-7). SMN2 therefore fails to compensate for loss of SMN1 unless sufficient copies are present to generate functional levels of full-length SMN protein (2).A rational, gene therapy-based approach for SMA uses singlestranded antisense splice-switching oligonucleotides (SSOs) to enhance SMN2 pre-mRNA exon 7 inclusion via steric block of splice regulatory pre-mRNA elements (8). Targeting the intron splice silencer N1 (ISS-N1) site within intron 7, by deletion or SSOmediated splice switching, improves exon 7 inclusion (9, 10). ISS-N1-targeted SSOs used to treat presymptomatic severely affected neonatal SMA mice, via systemic or intracerebroventricular administration, extend survival from 10 to >100 d (11, 12). Although SSO targeting to the CNS is essential, there is also evidence for a peripheral role for the SMN in SMA (13-24).Although SSO therapy is currently at an advanced stage of de...

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Section: Discussionmentioning

confidence: 99%

Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy

Hammond

Hazell

Shabanpoor

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

169

129

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“…To date, the only attempt to modulate tau exon 10 splicing has been by using blocking oligonucleotides binding to exon 10 splice junctions in PC12 cells, which express predominantly tau4R (34). Other, very elegant strategies to interfere with splicing events are based on the design of bifunctional oligoribonucleotides with a first domain complementary to an exonic enhancer or silencer element in the target pre-mRNA, and a second domain recruiting specific splicing factors near the splice site (35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Reprogramming of tau alternative splicing by spliceosome-mediated RNA trans-splicing: Implications for tauopathies

Rodríguez-Martín

García-Blanco

Mansfield

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is caused by mutations in the gene encoding the microtubule-associated protein, tau. Some FTDP-17 mutations affect exon 10 splicing. To correct aberrant exon 10 splicing while retaining endogenous transcriptional control, we evaluated the feasibility of using spliceosome-mediated RNA trans-splicing (SMaRT) to reprogram tau mRNA. We designed a pre-trans-splicing molecule containing human tau exons 10 to 13 and a binding domain complementary to the 3 end of tau intron 9. A minigene comprising tau exons 9, 10, and 11 and minimal flanking intronic sequences was used as a target. RT-PCR analysis of SH-SY5Y cells or COS cells cotransfected with a minigene and a pre-trans-splicing molecule using primers to opposite sides of the predicted splice junction generated products containing exons 9 to 13. Sequencing of the chimeric products showed that an exact exon 9 -exon 10 junction had been created, thus demonstrating that tau RNA can be reprogrammed by trans-splicing. Furthermore, by using the same paradigm with a minigene containing full-length intronic sequences, we show that cis-splicing exclusion of exon 10 can be by-passed by trans-splicing and that conversion of exon 10 ؊ tau RNA into exon 10 ؉ tau RNA could be achieved with Ϸ34% efficiency. Our results demonstrate that an alternatively spliced exon can be replaced by trans-splicing and open the way to novel therapeutic applications of SMaRT for tauopathies and other disorders linked to aberrant alternative splicing.T au is a microtubule-associated protein predominantly expressed in neurons and specifically localized in axons that promotes microtubule polymerization and stabilization (1, 2). Mutations in the MAPT gene, encoding tau, on chromosome 17, cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) (3-5). FTDP-17 is characterized by intraneuronal aggregates of tau and, as such, belongs to the group of dementias that includes Alzheimer's disease and collectively referred to as tauopathies.The human MAPT gene is a large gene of Ϸ134 kb comprising 16 exons (6). Alternative splicing of exons 2, 3, and 10 in the tau pre-mRNA results in the expression of six isoforms in the brain. Exon 10 encodes the second of four imperfect microtubulebinding repeats in the C-terminal half of the tau protein.Exclusion or inclusion of exon 10 gives rise to tau isoforms with three (tau3R, exon 10 Ϫ ) or four (tau4R, exon 10 ϩ ) microtubulebinding repeats (7). Furthermore, inclusion or exclusion of exons 2 and 3 produces tau isoforms with zero, one, or two inserts near the N terminus. Only tau3R is expressed during embryogenesis whereas tau3R and tau4R are expressed in approximately equal amounts in adult human brain. Exon 10 splicing is regulated by multiple cis-acting elements comprising exonic and intronic silencers and enhancers (for reviews, see refs. 8 and 9). In particular, intron 10 contains a bipartite element comprising a silencer and a modulator downstream to the 5Ј splice...

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“…Promising results have already been achieved, with antisense oligonucleotides directed against the splice junction of exon 10 in PC12 cells leading to reduced exon 10 splicing. 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.…”

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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Correction of Alternative Splicing of Tau in Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17

Cited by 108 publications

References 48 publications

Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy

Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy

Reprogramming of tau alternative splicing by spliceosome-mediated RNA trans-splicing: Implications for tauopathies

Tau-Based Treatment Strategies in Neurodegenerative Diseases

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