CRISPR/Cas9 directed to the Ube3a antisense transcript improves Angelman syndrome phenotype in mice

Schmid, Ralf S.; Deng, Xuefeng; Panikker, Priyalakshmi; Msackyi, Msema; Breton, Camilo; Wilson, James M.

doi:10.1172/jci142574

Cited by 32 publications

(28 citation statements)

References 26 publications

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“…Given the widespread use of mouse models in Angelman syndrome research and the recent reports involving ASOs and CRISPR/Cas9 to reactivate paternal Ube3a expression [16,17,39], we thought it was essential to assess the conservation of the mouse Ube3a-AS transcript with the human UBE3A-AS transcript. Our findings that the mouse Ube3a-AS transcript has diverged substantially from humans indicate that the sequence-based therapies targeting this region in mice will likely not translate to human patients.…”

Section: Discussionmentioning

confidence: 99%

Development of an ASO therapy for Angelman syndrome by targeting an evolutionarily conserved region at the start of theUBE3A-AStranscript

Dindot

Christian

Murphy

et al. 2021

Preprint

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Angelman syndrome is a devastating neurogenetic disorder for which there is currently no effective treatment. It is caused by mutations or epimutations affecting the expression or function of the maternally inherited allele of the ubiquitin-protein ligase E3A (UBE3A) gene. The paternal UBE3A allele is imprinted in neurons of the central nervous system (CNS) by the UBE3A antisense (UBE3A-AS) transcript, which represents the distal end of the SNHG14 transcription unit. Reactivating the expression of the paternal UBE3A allele in the CNS has long been pursued as a therapeutic option for Angelman syndrome. Here, we designed and optimized antisense oligonucleotides (ASO) targeting an evolutionarily conserved region demarcating the start of the human UBE3A-AS transcript and show that ASOs targeting this region can reverse imprinting of UBE3A in cultured Angelman syndrome neurons and throughout the CNS of a non-human primate model. Findings from this study advanced the first investigational molecular therapy for Angelman syndrome into clinical development (ClinicalTrials.gov, NCT04259281).

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Section: Discussionmentioning

confidence: 99%

Development of an ASO therapy for Angelman syndrome by targeting an evolutionarily conserved region at the start of theUBE3A-AStranscript

Dindot

Christian

Murphy

et al. 2021

Preprint

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“…Molecular therapies such as these are promising, but not yet feasible as therapeutic options due to the need for continued re-administration and lack of an optimized delivery method. Recently, two publications regarding the use of CRISPR/Cas9 nuclease to disrupt the Ube3a-ATS were described [142,143]. In both studies, guide RNAs were used to target nuclease activity to a site-specific region of the region between Snord115.…”

Section: Therapies Targeted To Reactivate the Paternal Ube3a Allele By Suppressing Ube3a-atsmentioning

confidence: 99%

“…al. designed [142,143]. Both strategies utilized AAV gene therapy for delivery of the Cas9 nuclease and guide RNA constructs.…”

Section: Therapies Targeted To Reactivate the Paternal Ube3a Allele By Suppressing Ube3a-atsmentioning

confidence: 99%

Emerging Gene and Small Molecule Therapies for the Neurodevelopmental Disorder Angelman Syndrome

et al. 2021

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Angelman syndrome (AS) is a rare (~1:15,000) neurodevelopmental disorder characterized by severe developmental delay and intellectual disability, impaired communication skills, and a high prevalence of seizures, sleep disturbances, ataxia, motor deficits, and microcephaly. AS is caused by loss-of-function of the maternally inherited UBE3A gene. UBE3A is located on chromosome 15q11–13 and is biallelically expressed throughout the body but only maternally expressed in the brain due to an RNA antisense transcript that silences the paternal copy. There is currently no cure for AS, but advancements in small molecule drugs and gene therapies offer a promising approach for the treatment of the disorder. Here, we review AS and how loss-of-function of the maternal UBE3A contributes to the disorder. We also discuss the strengths and limitations of current animal models of AS. Furthermore, we examine potential small molecule drug and gene therapies for the treatment of AS and associated challenges faced by the therapeutic design. Finally, gene therapy offers the opportunity for precision medicine in AS and advancements in the treatment of this disorder can serve as a foundation for other single-gene neurodevelopmental disorders.

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“…A leading approach to UBE3A reinstatement centers on unsilencing paternal UBE3A expression in neurons. This can be achieved through small molecules (15), antisense oligonucleotides (ASOs) (16), or other agents (17)(18)(19) that block the expression of, or otherwise interfere with, the UBE3A antisense transcript (UBE3A-ATS). Processed from a long noncoding RNA that initiates from SNRPN promoters on the paternally inherited chromosome, UBE3A-ATS silences paternal UBE3A in cis in neurons (20).…”

Section: Introductionmentioning

confidence: 99%

“…Paternal UBE3A unsilencing offers an attractive opportunity for UBE3A reinstatement under control of an endogenous promoter, presumably recapitulating optimal patterns and levels of UBE3A expression, including the proper representation of protein isoforms. Whether this advantage of unsilencing drugs outweighs their potential pitfalls -toxicity, off-target effects, and, excepting CRISPR-based gene therapies (18,19), the need for repeated dosing -will be determined through clinical trials, some of which are currently underway (NCT04259281, NCT04428281).…”

Section: Introductionmentioning

confidence: 99%

Dual-isoform hUBE3A gene transfer improves behavioral and seizure outcomes in Angelman syndrome model mice

Judson¹,

Shyng

Simon

et al. 2021

JCI Insight

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BDP are inventors of a gene therapy for Angelman syndrome evaluated in this paper. This intellectual property has been filed, and a patent is pending (WO 2020/237130). Some of this research was conducted under a term of a license agreement with Asklepios BioPharmaceutical, and the technology is now licensed to Taysha Gene Therapies. MCJ, CS, SJG, and BDP received royalties from Asklepios BioPharmaceutical. BDP also served on a program committee and consulted for Asklepios BioPharmaceutical. These relationships have been disclosed to, and are under management by, UNC at Chapel Hill and UT Southwestern.

show abstract

CRISPR/Cas9 directed to the Ube3a antisense transcript improves Angelman syndrome phenotype in mice

Cited by 32 publications

References 26 publications

Development of an ASO therapy for Angelman syndrome by targeting an evolutionarily conserved region at the start of theUBE3A-AStranscript

Development of an ASO therapy for Angelman syndrome by targeting an evolutionarily conserved region at the start of theUBE3A-AStranscript

Emerging Gene and Small Molecule Therapies for the Neurodevelopmental Disorder Angelman Syndrome

Dual-isoform hUBE3A gene transfer improves behavioral and seizure outcomes in Angelman syndrome model mice

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