Objectives: We evaluated whether pharmacological interventions targeting RhoGTPases may be an effective therapeutic strategy for RTT.
Methods: To this aim, we performed a single CNF1 intracerebroventricular (icv) inoculation in a RTT mouse model, which expresses a truncated form of the MeCP2 gene (MeCP2-308 mice). Fully symptomatic MeCP2-308 male mice (8 months of age) were subsequently evaluated in a battery of tests specifically tailored to detect RTT-related impairments. At the end of behavioral testing, brain sections were immunohistochemically characterized. Magnetic resonance imaging (MRI) and spectroscopy (MRS) were also applied to assess morphological and metabolic brain changes.
Results: The CNF1 administration markedly improved the behavioral phenotype of MeCP2-308 mice. CNF1 also dramatically reversed the evident signs of atrophy in astrocytes of mutant mice and restored wt-like levels of this cell population. CNF1-induced brain metabolic changes detected by MRS analysis involved markers of glial integrity and bioenergetics, and point to improved mitochondria functionality in CNF1-treated mice.
Conclusions: These results clearly indicate that modulation of brain RhoGTPases by CNF1 may constitute a totally innovative therapeutic approach for RTT and, possibly, for other neurodevelopmental disorders.
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