Toward an NGF-based therapy for Rett syndrome

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by mutations in the MECP2 gene. Although recent therapeutic advances, such as the approval of Trofinetide, offer partial relief, no comprehensive curative treatment is currently available. Among the emerging strategies, nerve growth factor (NGF) has gained attention due to its neurotrophic and immunomodulatory properties. This review, in addition to discussing the key features of RTT and the role of growth factors, also highlights recent evidence supporting NGF-based strategies for RTT, focusing on two independent studies that tested intranasal administration of NGF-like molecules in Mecp2-mutant mice. Both recombinant human NGF (rhNGF) and a modified, "painless" variant (hNGFp) improved behavioral (cognitive and motor) symptoms. While rhNGF primarily restored mitochondrial function, hNGFp restored neuroinflammatory responses through microglial regulation. Despite differences in molecular mechanisms and dosages, both molecules demonstrated efficacy without adverse effects, especially when administered intranasally, preventively, and over longer periods. These findings suggest that NGF may act through dual mechanisms, by supporting energy homeostasis and regulating immune responses. The use of intranasal delivery further enhances translational potential by overcoming blood-brain barrier limitations. Together, these studies provide a strong rationale for pursuing NGF-based therapies in RTT and encourage further investigations to optimize dosing, timing, and safety in preclinical and clinical settings.