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Pharmacological therapies for Angelman syndrome

Pharmakologische Therapien bei Angelman-Syndrom

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Summary

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). We reviewed the published information on clinical trials that have been completed as well as the publicly available information on ongoing trials of therapies for AS. Attempts at hypermethylating the maternal locus through dietary compounds were ineffective. The results of a clinical trial using minocycline as a matrix metalloproteinase-9 inhibitor were inconclusive; another clinical trial is underway. Findings from a clinical trial using L-dopa to alter phosphorylation of calcium/calmodulin-dependent kinase II are awaited. Topoisomerase inhibitors and antisense oligonucleotides are being developed to directly 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 debilitating manifestations of AS.

Zusammenfassung

Das Angelman-Syndrom (AS) ist eine schwerwiegende neurologische Entwicklungsstörung, die durch die fehlende Expression des maternal vererbten UBE3A-Gens verursacht wird; das paternale UBE3A wird in Neuronen durch einen Mechanismus stillgelegt, der ein Antisense-Transkript (UBE3A-AS) involviert. Publizierte Daten zu abgeschlossenen klinischen Studien sowie vorliegende Informationen aus laufenden Studien zur AS-Therapie wurden überprüft. Versuche, den maternalen Genort mittels diätetischer Präparate zu hypermethylieren, sind wirkungslos geblieben. Als inkonklusiv erwiesen sich die Ergebnisse einer klinischen Studie, die Minocyclin zur Hemmung der Matrix-Metalloprotease-9 einsetzte; eine weitere klinische Studie ist in Ausarbeitung. Die Ergebnisse einer klinischen Untersuchung zur Änderung der Phosphorylierung der Calcium/Calmodulin-abhängigen Kinase II durch Levodopa werden erwartet. Topoisomerasehemmer und Antisense-Oligonukleotide werden zur direkten UBE3A-AS-Hemmung entwickelt. Andere Strategien zur Targetierung spezifischer Leitungsbahnen werden kurz besprochen. Die heute eingesetzten medikamentösen Therapien bei einigen der schwerwiegendsten AS-Manifestationen – Insulten und Dyssomnien – wurden gesichtet.

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Acknowledgements

The authors would like to thank Stormy J. Chamberlain, Ph.D. (University of Connecticut Health Center) for reviewing and revising the sections in this manuscript that describe imprinting in Angelman syndrome.

Conflict of interest

Wen-Hann Tan and Lynne Bird declare that they have no conflict of interest.

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  1. Division of Genetics and Genomics, Boston Children’s Hospital; Harvard Medical School, Boston, MA, USA

    Wen-Hann Tan

  2. Department of Pediatrics, University of California, San Diego, CA, USA

    Lynne M. Bird MD

  3. Division of Genetics/Dysmorphology, Rady Children’s Hospital San Diego, 3020 Children’s Way, # 5031, 92123, San Diego, CA, USA

    Lynne M. Bird MD

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  1. Wen-Hann Tan
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  2. Lynne M. Bird MD
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Correspondence to Lynne M. Bird MD.

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Tan, WH., Bird, L.M. Pharmacological therapies for Angelman syndrome. Wien Med Wochenschr 167, 205–218 (2017). https://doi.org/10.1007/s10354-015-0408-z

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  • DOI: https://doi.org/10.1007/s10354-015-0408-z

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