Individuals with ICD/UPD Mutations Participating in ASO Trials
Angelman syndrome (AS) is caused by loss of maternal UBE3A expression. In neurons, paternal UBE3A is silenced by the UBE3A-ATS transcript, resulting in a total loss of UBE3A in AS neurons. Promising preclinical data by the Beaudet and Elgersma labs showed that ASO therapy is effective in activating the paternal Ube3a gene which results in an improvement of several phenotypes of Ube3a mice.
Phase I clinical trials are currently evaluating ASO safety in individuals with AS. However, these trials do not enroll AS patients carrying imprinting center defects (ICD) or uniparental disomy (UPD) mutations because there is a potential risk for negative effects of UBE3A overexpression in these patients. Although recent studies indicate that 2-fold UBE3A overexpression in mice does not induce deleterious effects, we do not know the consequences of UBE3A overexpression in the ICD/UPD genomic context in which the MKRN3, MAGEL2, NDN, SNRPN proteins as well as overexpression of the SNORD115, 116 gene cluster are overexpressed. Notably, recent studies suggest that there is a synergy between UBE3A overexpression with overexpression of other genes in the 15q-11 locus as observed in individuals with Dup15q syndrome. Hence it is important to be careful.
The Resnick lab has recently generated an ICD/UPD mouse model for AS, and we found that these mice robustly recapitulate all the phenotypes that we previously identified in Uba3a mice (unpublished data). In addition, together with the Philpot lab, we have recently generated and characterized a transgenic mouse line which overexpresses UBE3A (Ube3a+2 OE mice). Hence, we can now combine these models to address the concern if 2-fold overexpression of UBE3A in the ICD/UPD background would result in a full behavioral rescue, or in an incomplete rescue or possible even in deleterious phenotype.
Although our working hypothesis is that the ICD/UPD x Ube3a+2 mice will show a full rescue, we believe that demonstrating this in mice, is critical to move forward with ASO therapy in AS individuals with ICD and UPD mutations.
Why this study is important
ASOs are exciting therapeutics because they replace the very gene product missing in individuals with AS. However, we don’t really understand how well they work when administered at different times during development, and we also don’t know how well they work in individuals with AS due to different causes (i.e. UPD or deletions). Even with two papers published in this area using UBE3A mutation mice, different ASOs may have different effects, and restoring UBE3A from both copies in mice with UPD and/or large deletion may have different results.
The first mouse cohorts have been treated with different ASO doses and are currently being tested.