Angelman syndrome (AS) is a severe cognitive disorder caused by loss of expression of the maternally inherited allele of the Ube3A gene that encodes the Ube3A ubiquitin ligase. A mouse model of AS shows impairment in long-term potentiation (LTP) and behavior. Recent studies suggest that the deficits in synaptic plasticity stem from inappropriate expression of Arc/Arg3.1 (Arc), which associates with the synaptic scaffolding protein postsynaptic density-95 (PSD-95), to impair brain-derived neurotrophic factor (BDNF)-mediated PLC?/CaMKII and Akt/mTORC1 signaling. We have designed a novel water-soluble cyclic-peptide drug (MW 2376), CN2097, that crosses the BBB to selectively target PSD-95 to reinstate BDNF-signaling in AS mice. Critically, CN2097 produces a prolonged activation of enzymes involved in memory processes, to lower the threshold for synapse strengthening (long term potentiation, LTP). This property makes this compound suited to treat the memory and executive functioning deficits in AS. A unique feature of CN2097 is that it has no effect in the absence of BDNF, making CN2097 highly specific for ?active? synapses involved in learning, while avoiding adverse effects associated with widespread BDNF enhancement. The objective of this project is to evaluate the efficacy of CN2097 to mitigate the cognitive deficits in the AS mouse model. Assessment of restored function will be made by examining performance of CN2097 treated AS mice on tasks measuring simple associative learning and executive functions.
In Aim 1, we will investigate the pharmacokinetics of CN2097, examining the duration of action and optimal dose required to rescue signaling and LTP.
In Aim 2 we will examine effects on learning and memory using standard control procedures absent in prior studies and an expanded repertoire of learning tasks to characterize more fully the range of cognitive deficits expressed by AS mice. This project has the potential to lead to the first effective therapy for AS and autism spectrum disorders.

Public Health Relevance

This project is designed to undertake pre-clinical trials that will provide evidence that a patented drug, CN2097, has the potential to ameliorate the cognitive deficits in Angelman Syndrome (AS). This project has the potential to lead to the first effective therapy for AS and other autism spectrum disorders. Our work is also within the mission of the NIH as it will further neurological drug development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH104252-01A1
Application #
9243335
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Winsky, Lois M
Project Start
2016-09-14
Project End
2018-08-31
Budget Start
2016-09-14
Budget End
2017-08-31
Support Year
1
Fiscal Year
2016
Total Cost
$243,750
Indirect Cost
$93,750
Name
Brown University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Marshall, John; Zhou, Xiao-Zhong; Chen, Gang et al. (2018) Antidepression action of BDNF requires and is mimicked by G?i1/3 expression in the hippocampus. Proc Natl Acad Sci U S A 115:E3549-E3558
Darwish, Shaban; Parang, Keykavous; Marshall, John et al. (2017) Efficient synthesis of CN2097 using in situ activation of sulfhydryl group. Tetrahedron Lett 58:3053-3056
Marshall, John; Szmydynger-Chodobska, Joanna; Rioult-Pedotti, Mengia S et al. (2017) TrkB-enhancer facilitates functional recovery after traumatic brain injury. Sci Rep 7:10995