Angelman syndrome: Current and emerging therapies in 2016

Abstract

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by a loss of the maternally-inherited UBE3A; the paternal UBE3A is silenced in neurons by a mechanism involving an antisense transcript (UBE3A-AS) at the unmethylated paternal locus. We reviewed all published information on the clinical trials that have been completed as well as the publicly available information on ongoing trials of therapies in AS. To date, all clinical trials that strove to improve neurodevelopment in AS have been unsuccessful. Attempts at hypermethylating the maternal locus through dietary compounds were ineffective. The results of an 8-week open-label trial using minocycline as a matrix metalloproteinase-9 inhibitor were inconclusive, while a subsequent randomized placebo-controlled trial suggested that treatment with minocycline for 8 weeks did not result in any neurodevelopmental gains. A 1-year randomized placebo-controlled trial using levodopa to alter the phosphorylation of calcium/calmodulin-dependent kinase II did not lead to any improvement in neurodevelopment. Topoisomerase inhibitors and antisense oligonucleotides are being developed to directly inhibit UBE3A-AS. Artificial transcription factors are being developed to "super activate" UBE3A or inhibit UBE3A-AS. Other strategies targeting specific pathways are briefly discussed. We also reviewed the medications that are currently used to treat seizures and sleep disturbances, which are two of the more common complications of AS. © 2016 Wiley Periodicals, Inc.

An overview of health issues and development in a large clinical cohort of children with Angelman syndrome

“…Considering the potential upcoming treatments in AS, it is important to get a more detailed view of all the health issues in AS, with a focus on epilepsy and neurodevelopmental outcomes as these are likely to be the target of future interventions (Beaudet & Meng, ; Tan & Bird, ). Previous studies presented data of children with AS on specific aspects like epilepsy, development, or growth and mainly collected in a research setting (Gentile et al, ; Granild Bie Mertz, Christensen, Vogel, Hertz, & Ostergaard, ; Mertz, Thaulov, et al, ; Tan et al, ; Thibert et al, ; Thibert, Larson, Hsieh, Raby, & Thiele, ).…”

Lovastatin suppresses hyperexcitability and seizure in Angelman syndrome model

“…The electroencephalogram (EEG) in AS patients has a characteristic pattern of large-amplitude slow-spike waves at 1–2 or 4–6 Hz (Sidorov et al 2017; Vendrame et al 2012). A significant fraction of clinical seizures is medically intractable and the quality of life is significantly compromised in these individuals (Tan and Bird 2016). …”

“…The specific clinical seizures may vary from atypical absence, myoclonic, generalized tonic-clonic, tonic and atonic seizures (Dan 2009; Tan and Bird 2016). The genotype and phenotype correlation for seizure presentation has been described.…”

A randomized controlled trial of levodopa in patients with Angelman syndrome

“…Previous studies have shown that children with AS who are deletion-positive tend to be more developmentally delayed and are more likely to have seizures than those who are deletion-negative [Gentile et al, 2010; Tan et al, 2011]. Treatment for AS is currently limited to developmental interventions and symptomatic treatment for complications including seizures, sleep disturbances, and hyperactivity [Tan and Bird, 2016]. A previous study showed that a mouse model of AS had diminished calcium/calmodulin-dependent kinase II (CaMKII) activity associated with increased phosphorylation at the threonine residues at positions 286, 305, and 306 (i.e., Thr286, Thr305, Thr306 respectively) of this enzyme [Weeber et al, 2003].…”