Results recently published in PLoS Biology (11, e1001478; 2013) elucidate the neurological disruptions that occur in Angelman syndrome and introduce a compound that can rescue the disruptions, restoring neural function in mice. John Marshall (Brown University, Providence, RI), senior author of the article, warned that it is too soon to tell when a clinical therapy might be available. But the results hold promise for those who have the disease.

Angelman syndrome is characterized by development delays, seizures, movement disorders, speech impediments and, often, features of autism. It is a genetic disorder caused by a lack of function of the enzyme Ube3A. The normal role of Ube3A is to regulate degradation of the synaptic protein Arc in the brain, limiting its availability. In the absence of functional Ube3A, however, levels of Arc are elevated. Arc hinders synaptic development in the hippocampus by interfering with PSD-95, which is required for the signaling activity of brain-derived neurotrophic factor (BDNF), a growth factor involved in long-term potentiation (LTP). BDNF activity strengthens neural connections or synapses that are essential to learning and memory formation. Hence, by inhibiting BDNF activity, Arc weakens these processes. “I think we are really beginning to understand what's going wrong. That's what's very exciting,” said Marshall in a press release.

With this understanding of the interaction between Arc, PSD-95, BDNF activity and LTP, Marshall and his team turned their attention to the compound CN2097, a synthetic, bridged cyclic peptide that enhances BDNF activity and protects neurons from damage from stroke and multiple sclerosis. CN2097 binds to PSD-95, protecting it from interference by Arc and, in turn, restoring BDNF activity and strengthening synapses. When tested in a mouse model of Angelman syndrome, CN2097 improved the induction of LTP, leading the study authors to suggest that the compound might offer an approach to reversing cognitive dysfunction.

The team has not yet tested whether CN2097 administration improves cognitive or behavioral function in mice carrying the genetic defect that causes Angelman syndrome. “Can we actually rescue learning deficits?” Marshall asked. “That would be the next stage to test. We haven't gotten that far yet.” Another limitation to further development of CN2097 as a treatment for Angelman syndrome is its rapid breakdown in the body; the drug might require frequent administration to maintain its efficacy. But the research is encouraging, said Marshall. “We think we are on the right track.”