Title:Gene Therapy for Angelman Syndrome: Contemporary Approaches and Future Endeavors
Volume: 19
Issue: 6
关键词:
Angelman综合征，基因治疗，神经发育障碍，先天性，UBE3A，CNS，ATF。
摘要:
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.
