Drug discovery for autism spectrum disorder: challenges and opportunities

Abstract

The rising rates of autism spectrum disorder (ASD) and the lack of effective medications to treat its core symptoms have led to an increased sense of urgency to identify therapies for this group of neurodevelopmental conditions. Developing drugs for ASD, however, has been challenging because of a limited understanding of its pathophysiology, difficulties in modelling the disease in vitro and in vivo, the heterogeneity of symptoms, and the dearth of prior experience in clinical development. In the past few years these challenges have been mitigated by considerable advances in our understanding of forms of ASD caused by single-gene alterations, such as fragile X syndrome and tuberous sclerosis. In these cases we have gained insights into the pathophysiological mechanisms underlying these conditions. In addition, they have aided in the development of animal models and compounds with the potential for disease modification in clinical development. Moreover, genetic studies are illuminating the molecular pathophysiology of ASD, and new tools such as induced pluripotent stem cells offer novel possibilities for drug screening and disease diagnostics. Finally, large-scale collaborations between academia and industry are starting to address some of the key barriers to developing drugs for ASD. Here, we propose a conceptual framework for drug discovery in ASD encompassing target identification, drug profiling and considerations for clinical trials in this novel area.

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

“…Presently, there is no clinically effective drug to treat the pathophysiology of ASD (94). Targeting NTR3/sortilin and/or using methoxyluteolin may provide important novel therapeutic approaches for ASD.…”

Mesenchymal stem cells in treating autism: Novel insights

“…The lack of safe and effective psychopharmaceuticals and other definitive medical therapies, together with the limited understanding of the pathophysiology, has created an urgency to identify novel and more effective therapies [47] . MSCs appear to offer a greater potential in regenerative medicine for complex disorder like autism than existing pharmaceutical protocols.…”

The complex genetics in autism spectrum disorders

“…2-methyl-6-(phenylethynyl)-pyridine (MPEP), a potent negative modulator of mGluR5 [60], consistently rescues many FXSrelated deficits in KO mice [50,55,56,[61][62][63], fly [64][65][66] and zebrafish [67], implying the therapeutic potential of FXS using mGluR5 inhibitors. Indeed, multiple human clinical trials with chemicals targeting mGluR5, or mGluRs-related signaling pathways, or presynaptic release of glutamate, such as gamma-aminobutyric acid (GABA) B receptor agonists, are being conducted, and are showing promising, but as yet inconclusive, results with regard to treating FXS [68][69][70][71].…”