Gene Therapy for Angelman Syndrome: Contemporary Approaches and Future Endeavors

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.

CIM6P/IGF‐2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice

“…Except for approaches that aim at unsilencing the paternal allele, therefore restoring the genetic defect, which could in principle repair all deficits, but are still underdeveloped and debated [Tsagkaris et al, 2020], to our knowledge, comprehensive alternative therapeutic agents that broadly ameliorate cognitive, motor and neurological impairments have been lacking [Jamal et al, 2017; Meng et al, 2013; Sun et al, 2016; Yang, 2019]. Our findings suggest that it may be possible to design drug targets against the CIM6P/IGF‐2R that can broadly treat AS symptoms and could be readily developed for clinical testing.…”

Relationships between UBE3A and SNORD116 expression and features of autism in chromosome 15 imprinting disorders

“…Together with the genotype-phenotype relationships reported in this study using PBMCs, this suggests that the immune response regulated by microglial cells (comprising almost half of all cells in the brain) may play a broader role in chromosome 15 imprinting disorder pathology. Abnormal expression of UBE3A in AS leucocytes, where UBE3A is not imprinted, may also have implications for clinical trials targeting UBE3A re-activation in the brain 41 . Specifically, UBE3A expression and regulation in other tissues may need to be monitored for non-specific impacts of the intervention on pathways regulated by UBE3A in non-neuronal cell types.…”

A Systematic Framework for Identifying Prognostic Genes in the Tumor Microenvironment of Colon Cancer

“…The function of multiple cell types in the TME of colon cancer has been well elucidated. In addition to acting as a physical scaffolding for tumor cells, ECM also contributes to colon cancer cells adhesion, immune evasion, and metastasis ( 21 ). Tumor-associated neutrophils enhance invasiveness by influencing angiogenesis and response to vascular endothelial growth factor (VEGF) inhibition in colon cancer ( 22 ).…”