Adeno-Associated Virus-Mediated Rescue of the Cognitive Defects in a Mouse Model for Angelman Syndrome

Abstract

Angelman syndrome (AS), a genetic disorder occurring in approximately one in every 15,000 births, is characterized by severe mental retardation, seizures, difficulty speaking and ataxia. The gene responsible for AS was discovered to be UBE3A and encodes for E6-AP, an ubiquitin ligase. A unique feature of this gene is that it undergoes maternal imprinting in a neuron-specific manner. In the majority of AS cases, there is a mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental disomy or mismethylation of the maternal gene. While most human disorders characterized by severe mental retardation involve abnormalities in brain structure, no gross anatomical changes are associated with AS. However, we have determined that abnormal calcium/calmodulin-dependent protein kinase II (CaMKII) regulation is seen in the maternal UBE3A deletion AS mouse model and is responsible for the major phenotypes. Specifically, there is an increased αCaMKII phosphorylation at the autophosphorylation sites Thr286 and Thr305/306, resulting in an overall decrease in CaMKII activity. CaMKII is not produced until after birth, indicating that the deficits associated with AS are not the result of developmental abnormalities. The present studies are focused on exploring the potential to rescue the learning and memory deficits in the adult AS mouse model through the use of an adeno-associated virus (AAV) vector to increase neuronal UBE3A expression. These studies show that increasing the levels of E6-AP in the brain using an exogenous vector can improve the cognitive deficits associated with AS. Specifically, the associative learning deficit was ameliorated in the treated AS mice compared to the control AS mice, indicating that therapeutic intervention may be possible in older AS patients.

Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model

“…The finding that LTP could be fully recovered at all ages is consistent with previous findings showing that the hippocampal LTP deficit in adult AS mice is reversible upon acute pharmacological treatment with an ErbB inhibitor or with ampakine cognitive enhancers (18,19). However, expression of UBE3A in adult Ube3a m-/p+ mice through a viral-mediated approach only partially recovered synaptic plasticity (20). This apparent discrepancy likely reflects the limited efficiency of in vivo virally mediated neuronal transduction, compared with the more homogeneous biodistribution of systemically administered pharmacological compounds.…”

Angelman syndrome: review of clinical and molecular aspects

“…Transcriptional upregulation has been approached by both gene therapy141 and pharmacologic intervention 142. Daily et al showed that direct injection of a recombinant adeno- associated viral vector carrying Ube3a into the hippocampi of adult AS mice could significantly improve associative learning (contextual fear conditioning) 141.…”

Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression

“…The AS mouse model has been used extensively for testing potential drugs and gene therapies for treating AS (13,14). One therapeutic approach has been to identify proteins that are upregulated in the brains of AS mice and to then search for pharmacological agents that target the expression or activity of the up-regulated protein.…”

“…In addition, AS mice display defects in learning and memory, motor coordination, locomotor activity (14,17,20,21), and an increased number of seizures when exposed to an audiogenic challenge (6,11). However, there have been conflicting reports regarding the robustness of the AS phenotypes observed (22).…”