Towards Molecular Therapy for Angelman Syndrome

Background:  Angelman Syndrome is a severe form of Autism with the children exhibiting ataxic gait, language and intellectual deficiencies, seizures and sleep disorders.  The disease occurs in about 1:12,000 births and is mostly due to de-novo deletions.  Angelman Syndrome occurs when an affected individual fails to inherit the normally active maternal UBE3A, while the paternal UBE3A is silenced, resulting in reduced expression of UBE3A in the development of critical brain tissue. 

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.