Rescue of a familial dysautonomia mouse model by AAV9-Exon-specific U1 snRNA

Romano, Giulia; Riccardi, Federico; Bussani, Erica; Vodret, Simone; Licastro, Danilo; Ragone, Isabella; Ronzitti, Giuseppe; Morini, Elisabetta; Slaugenhaupt, Susan; Pagani, Franco

doi:10.1016/j.ajhg.2022.07.004

Cited by 11 publications

(11 citation statements)

References 90 publications

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“…Many efforts have been undertaken to develop disease-modifying therapies including SMCs, ASOs, and modified exon-specific U1 snRNAs. 54 , 55 , 56 These modalities have shown promising effects in mice, 54 , 56 , 83 confirming that ELP1 splicing is a relevant therapeutic target. However, both ASO and U1 snRNA-based therapeutics have limitations, including poor brain penetration and cellular uptake, toxicity due to immune stimulation, and an invasive route of administration.…”

Section: Discussionmentioning

confidence: 85%

Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia

Morini¹,

Chekuri²,

Logan³

et al. 2023

The American Journal of Human Genetics

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Section: Discussionmentioning

confidence: 85%

Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia

Morini¹,

Chekuri²,

Logan³

et al. 2023

The American Journal of Human Genetics

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“…Many efforts have been undertaken to develop disease-modifying therapies including SMCs, ASO, and modified exon-specific U1 snRNAs 54–56 . These modalities have shown promising effects in mice 54,56,74 , confirming that ELP1 splicing is a relevant therapeutic target. However, both ASO and U1 snRNA-based therapeutics have limitations, including poor brain penetration and cellular uptake, toxicity due to immune stimulation, and an invasive route of administration 75–78 .…”

Section: Discussionmentioning

confidence: 83%

“…Many efforts have been undertaken to develop disease-modifying therapies including SMCs, ASO, and modified exon-specific U1 snRNAs [54][55][56] . These modalities have shown promising effects in mice 54,56,74 , confirming that ELP1 splicing is a relevant therapeutic target.…”

Section: Discussionmentioning

confidence: 83%

Development of a novel oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia

Morini

Chekuri

Logan

et al. 2022

Preprint

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Familial Dysautonomia (FD) is a rare neurodegenerative disease caused by a splicing mutation in the Elongator complex protein 1 gene (ELP1). This mutation leads to the skipping of exon 20 and a tissue-specific reduction of ELP1 protein, mainly in the central and peripheral nervous systems. FD is a complex neurological disorder accompanied by severe gait ataxia and retinal degeneration. There is currently no effective treatment to restore ELP1 protein expression in individuals with FD, and the disease is ultimately fatal. After identifying kinetin as a small molecule able to correct the ELP1 splicing defect, we worked on its optimization to generate novel splicing modulator compounds (SMCs) that can be used in patients. Here, we optimize the potency, efficacy, and bio-distribution of second-generation kinetin derivatives to develop an oral treatment for FD that can efficiently pass the blood-brain barrier and correct the ELP1 splicing defect in the nervous system. We demonstrate that the novel compound, PTC258, efficiently restores correct ELP1 splicing in mouse tissues, including brain, and most importantly, prevents the progressive neuronal degeneration that is characteristic of FD. Postnatal oral administration of PTC258 to the phenotypic mouse model TgFD9;Elp1 delta20/flox increases full-length ELP1 transcript in a dose-dependent manner and leads to a two-fold increase in functional ELP1 protein in the brain. Remarkably, PTC258 treatment improves survival, gait ataxia, and retinal degeneration in the phenotypic FD mice. Our findings highlight the great therapeutic potential of this novel class of small molecules as an oral treatment for FD.

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“…This breakthrough offered a promising avenue for the development of novel therapeutic interventions for SMA (Donadon et al, 2019). Recently, Romano et al also demonstrated that the delivery of exon‐specific U1 (ExSpeU1) small nuclear RNA by AAV9 can increase the inclusion of ELP1 exon 20 in a phenotypic mouse model of familial dysautonomia (FD) (Romano et al, 2022). Hence, we also attempted to demonstrate the therapeutic potential of modified U1 snRNA through rescue experiments.…”

Section: Discussionmentioning

confidence: 99%

Pathogenicity analysis and splicing rescue of a classical splice site variant (c.1343+1G>T) of CNOT1 gene associated with neurodevelopmental disorders

Yan

Wang

et al. 2023

American J of Med Genetics Pt A

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Mutations in the CNOT1 gene lead to an incurable rare neurological disorder mainly manifested as a clinical spectrum of intellectual disability, developmental delay, seizures, and behavioral problems. In this study, we investigated a classical splice site variant of CNOT1 (c.1343+1G>T) associated with neurodevelopmental disorders, which was a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. To link CNOT1 dysfunction with the neurodevelopmental phenotype observed in a patient, in vitro minigene assay was used to verify the effect of CNOT1 gene splice site variant c.1343+1G>T on mRNA splicing. We also explored the impact of transient transfection introducing modified U1 snRNA on correcting the splicing variant. Through minigene expression in mammalian cells, we demonstrated that the variant induced complete exon 12 skipping, which explained the patient's clinical condition and provided additional genetic diagnosis evidence for the clinical significance of the variant. Moreover, we confirmed that the aberrant splice pattern could be partially corrected by the modified U1 snRNA at the mRNA level, which provided strong evidence for the therapeutic potential of modified U1 snRNA in neutralizing the hazardous effect of incorrect splicing patterns.

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Rescue of a familial dysautonomia mouse model by AAV9-Exon-specific U1 snRNA

Cited by 11 publications

References 90 publications

Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia

Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia

Development of a novel oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia

Pathogenicity analysis and splicing rescue of a classical splice site variant (c.1343+1G>T) of CNOT1 gene associated with neurodevelopmental disorders

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