Therapies in preclinical and clinical development for Angelman syndrome

Abstract

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CRISPR activation rescues abnormalities in SCN2A haploinsufficiency-associated autism spectrum disorder

“…Nevertheless, brain development is a dynamic process that spans multiple decades of life, and interventions administered even later in life could have some therapeutic benefi t (Levy and Barak, 2021). A recent example is an antisense oligonucleotide therapy for Angelman Syndrome that improved communication and motor skills and reduced epileptiform discharges when administered to 4-17-year-old children (Markati et al, 2021), despite work in rodent models suggesting that therapies should ideally be administered prenatally (Silva-Santos et al, 2015;Wolter et al, 2020). Scn2a haploinsuffi ciency in mice results in life-long, cell-autonomous impairments in neocortical pyramidal cell dendritic excitability and synapse function (Spratt et al, 2019).…”

AntimiR targeting of microRNA-134 reduces seizures in a mouse model of Angelman syndrome

“…Indeed, clinical trials of UBE3A-rescuing strategies are under way for AS that use intrathecal delivery of ASOs. 43 An antimiR-based miRNA inhibitor would have similar pharmacokinetic and safety challenges, albeit with possibility of small, widespread effects on gene expression due to the multi-targeting action of miRNAs. There are alternative methods for silencing miRNAs, such as using gene therapy-based delivery of targeting sequences, which could offer longer lasting or cell type-specific delivery.…”

Gene Therapies for Monogenic Autism Spectrum Disorders

“…In contrast to ncRNA, antisense oligonucleotides (ASO) are in a more advanced stage of development. ASO are noncoding single-stranded DNA, RNA or DNA-RNA hybrid molecules, less than 50 bp in size and can be designed for various mechanisms of action [29]. In the simplest approach, comparable to ncRNA, an ASO can reduce the expression of a target gene by binding to the mRNA.…”

“…Therefore, an ASO targeted to this natural antisense transcript was able to un-silence the paternal allele, restoring normal expression of UBE3A in vitro and in vivo [6]. The ASO that targets UBE3A-ATS is under development by two pharmaceutical companies and currently in phase 1 or 2 clinical trials [29].…”