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Mini-Review Article

Gene Therapy for Angelman Syndrome: Contemporary Approaches and Future Endeavors

Author(s): Christos Tsagkaris*, Vasiliki Papakosta, Adriana Viola Miranda, Lefkothea Zacharopoulou, Valeriia Danilchenko, Lolita Matiashova and Amrit Dhar

Volume 19, Issue 6, 2019

Page: [359 - 366] Pages: 8

DOI: 10.2174/1566523220666200107151025

Price: $65

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Abstract

Background: Angelman Syndrome (AS) is a congenital non inherited neurodevelopmental disorder. The contemporary AS management is symptomatic and it has been accepted that gene therapy may play a key role in the treatment of AS.

Objective: The purpose of this study is to summarize existing and suggested gene therapy approaches to Angelman syndrome.

Methods: This is a literature review. Pubmed and Scopus databases were researched with keywords (gene therapy, Angelman’s syndrome, neurological disorders, neonates). Peer-reviewed studies that were closely related to gene therapies in Angelman syndrome and available in English, Greek, Ukrainian or Indonesian were included. Studies that were published before 2000 were excluded and did not align with the aforementioned criteria.

Results: UBE3A serves multiple roles in signaling and degradation procedures. Although the restoration of UBE3A expression rather than targeting known activities of the molecule would be the optimal therapeutic goal, it is not possible so far. Reinstatement of paternal UBE3A appears as an adequate alternative. This can be achieved by administering topoisomerase-I inhibitors or reducing UBE3A antisense transcript (UBE3A-ATS), a molecule which silences paternal UBE3A.

Conclusion: Understanding UBE3A imprinting unravels the path to an etiologic treatment of AS. Gene therapy models tested on mice appeared less effective than anticipated pointing out that activation of paternal UBE3A cannot counteract the existing CNS defects. On the other hand, targeting abnormal downstream cell signaling pathways has provided promising rescue effects. Perhaps, combined reinstatement of paternal UBE3A expression with abnormal signaling pathways-oriented treatment is expected to provide better therapeutic effects. However, AS gene therapy remains debatable in pharmacoeconomics and ethics context.

Keywords: Angelman syndrome, gene therapy, neurodevelopmental disorder, congenital, UBE3Α, CNS, ATFs.

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