Towards targeted therapy for Angelman syndrome

Abstract

Introduction: Angelman syndrome (AS) is a monogenic disorder with a prevalence of 1 in 10-15,000 and is characterized by severe developmental delay, ataxia, and epilepsy. AS is associated with a neuron-specific loss of function of the maternal UBE3A allele, a gene that encodes for a ubiquitin ligase. The null mutation AS mouse model lends well to therapeutic evaluation related to potential treatments for this disorder.

Areas covered: This outlook focuses on advances in both pharmacological and molecular therapies that have been explored specifically in the AS mouse model. The utility of the animal model has broadened our current understanding of the disorder and potential therapeutic targets, and provides a better idea of how therapeutics may look in the future as we advance toward clinical trials in this population.

Expert opinion: Great advances in all areas of Angelman syndrome research is tempered by requirements to be met at the level of target identification, models of AS, addressing the needs of the AS population, and the clinical trials that will seek their involvement.

Keywords:

• Angelman syndrome
• adeno-associated virus
• gene therapy
• imprinting
• animal models
• cerebellum and hippocampus

Article highlights

• Molecular targets for potential therapeutics and phenotypic rescues for Angelman syndrome (AS), a rare monogenic disorder, are illustrated.

• Therapeutic strategies focusing on four major areas of dysfunction reported in AS are discussed, focusing on genetic intervention, modulators of plasticity, gene replacement therapy, and targeted therapeutics.

• Possible therapeutic targets are examined, as AS has no current treatment.

• A particular focus has been placed on decreasing inhibition and affecting GABAergic signaling, as seizure activity is considerably under-researched in AS, but approximately 80% of the AS population are plagued by seizures.

• While utilization of a single animal model has allowed for comparison of various treatment options, additional models using more complex mammalian systems may be necessary for a refinement of translational therapeutics.

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Declaration of interest

Financial support was received from the Foundation for Angelman Therapeutics. S. Ciarlone and E. Weeber have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.