4e-2 Preclinical Models of Genetic Neurodevelopmental Disorders: Advancing Therapeutics
Project Description:
Preclinical Models of Genetic Neurodevelopmental Disorders
Dr. Silverman's team performs therapeutic assessment endeavors, using a wide range of therapeutics from small molecules, repurposed and novel compounds, and antisense oligonucleotides (ASOs), in addition to assessing precision- and targeted treatment including viral vector delivered gene replacement, CRISPR activation and interference, and novel tools rapidly evolving from genetic and epigenetic editing technologies. Her laboratory has a large sub-focus on genetic disorders of the chromosomal region 15q11.2-q13, a maternally derived duplication of the 15q11.2-q13 region.  In keeping up with this sub focus, over this year, her team pursued a collaboration with Dr. John Marshall from Brown University using his novel Syn class of compounds. We assessed several Syn compounds in preclinical models of Angelman Syndrome (AS), which is a disorder of a deletion in 15q11.2-q13. This year we evaluated Syn3 and its analog D-Syn3 (engineered using dextrorotary (D)-amino acids) in vivo using the common AS mouse model. Following systemic administration of Syn3 and D-Syn3, we demonstrated improvement in the seizure domain of AS. Learning and memory using the novel object recognition assay also illustrated improved cognition following Syn3 and D-Syn3, along with restored long-term potentiation. Finally, D-Syn3 treated mice showed a partial rescue in motor learning. Neither Syn3 nor DSyn3 improved gross exploratory locomotion deficits, nor gait impairments that have been documented in individuals with AS and the AS rodent models. This work is currently under review at Neuropsychopharmacology with the preprint on BioRx (Huie et al., 2024, Peptidomimetic inhibitors targeting TrkB/PSD-95 signaling improves cognition and seizure outcomes in an Angelman Syndrome mouse model).
Core Function(s):
Performing Research or Evaluation
Area of Emphasis
Health-Related Activities, Quality of Life, Other - Leadership
Target Audience:
Students/Trainees (long or intermediate trainees), Community Trainees / Short term trainees, Professionals and Para-Professionals, Family Members/Caregivers, Adults with Disabilities, Children/Adolescents with Disabilities/SHCN, Legislators/Policy Makers, General Public
Unserved or Under-served Populations:
Other
Primary Target Audience Geographic Descriptor:
State, National, International
COVID-19 Related Data:
N/A
