Objectives: In designing an effective gene therapy for Angelman Syndrome, our goal is to reactivate the endogenous, paternal allele of Ube3a in an Angelman Syndrome mouse model.
Methods: To accomplish this goal Zinc Finger Artificial Transcription Factors (ATFs) are being utilized. Zinc Fingers are a class of DNA binding proteins that can be programmed to bind to a specific site in DNA. By attaching a repression domains to the Zinc Finger construct an Artificial Transcription Factor is formed, which can suppress transcriptional activity. The therapeutic approach being used involves delivering repressor ATFs to silence Ube3a-ATS, a transcript that silences the paternal copy of Ube3a. The therapy involves IP injecting purified ATF protein extracts into Angelman Syndrome Mice.
Results: Mice treated with the ATF have shown about a 1.5-1.8 fold increase in whole brain Ube3a protein levels, measured by IHC and Westerns. The ATFs are injected by IP, cross the blood brain barrier; repress the Ube3a-ATS transcript, increasing the expression of the paternal Ube3a.
Conclusions: Inducing paternal Ube3a expression through the use of ATFs can ameliorate the molecular symptoms of Angelman Syndrome. These results should have a broad impact on the Autism Spectrum Field as the same delivery and treatment methodologies can be applied toward many other syndromes including UBE3A Duplication and Prader-Willi Syndromes. The results could lead to future therapy options in humans.