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Review
. 2024 Dec 6;25(1):7.
doi: 10.1007/s11910-024-01394-3.

Drug Treatments for Neurodevelopmental Disorders: Targeting Signaling Pathways and Homeostasis

Walter E Kaufmann  1   2 , Skylar Luu  3 , Dejan B Budimirovic  4
Affiliations
Review

Drug Treatments for Neurodevelopmental Disorders: Targeting Signaling Pathways and Homeostasis

Walter E Kaufmann et al. Curr Neurol Neurosci Rep. .

Abstract

Purpose of the review: Preclinical and clinical evidence support the notion that neurodevelopmental disorders (NDDs) are synaptic disorders, characterized by excitatory-inhibitory imbalance. Despite this, NDD drug development programs targeting glutamate or gamma-aminobutyric acid (GABA) receptors have been largely unsuccessful. Nonetheless, recent drug trials in Rett syndrome (RTT), fragile X syndrome (FXS), and other NDDs targeting other mechanisms have met their endpoints. The purpose of this review is to identify the basis of these successful studies.

Recent findings: Despite increasing evidence of disruption in synaptic homeostasis, most genetic variants associated with NDDs implicate proteins involved in cell regulation and not in neurotransmission. Metabolic processes, in particular mitochondrial function, appear to play a role in NDD pathophysiology. NDDs are also characterized by distinctive cell signaling abnormalities, which link cellular and synaptic homeostasis. Recent successful trials in NDDs, including those of trofinetide, the first drug specifically approved for one of these disorders (i.e., RTT), implicate the targeting of downstream processes (i.e., signaling pathways) rather than neurotransmitter receptors. Recent positive drug studies in NDDs and their underlying mechanisms, in conjunction with new knowledge on the pathophysiology of these disorders, support the concept that targeting signaling and cellular and synaptic homeostasis may be a preferred approach for ameliorating synaptic abnormalities in many NDDs.

Keywords: Cell signaling; Drug trial research; Excitatory/inhibitory balance; Homeostasis; Mitochondrial dysfunction; Neurodevelopmental disorders.

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Conflict of interest statement

Declarations. Conflict of Interest: W.E.K. was the Chief Scientific Officer and currently a consultant to Anavex Life Sciences Corp., which is developing drug treatments for neurodevelopmental disorders. He has received current or past funding from Acadia, AveXis, Biohaven, EryDel/Quince, GW Pharmaceuticals, Hoffmann-La Roche, Marinus, Neuren, Newron, Novartis, Ovid, Seaside, Stalicla, Tetra, and Zynerba/Harmony for consulting and/or conducting clinical trials in neurodevelopmental disorders. D.B.B. has received current or past funding through his institution from Ovid, Seaside, and Zynerba/Harmony for consulting and/or conducting clinical trials in fragile X syndrome. S.L. reports no conflicts of interest. Human and Animal Rights: All reported studies with human subjects and animal models, performed by the authors, have been previously published and complied with all ethical standards.

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