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Systematic Screening of Pharmacological Compounds in Human Pluripotent Stem Cells-Derived Neurons to Identify Patient-Oriented Treatment for Autism: A Proof of Concept
Autism spectrum disorders (ASD) affect millions of individuals worldwide but the heterogeneity of the symptoms lead to therapeutic intervention choices often based on ‘trial and error’. A versatile yet relevant cellular model developed to rationally screen among hundreds of therapeutic options in a patient-oriented manner would help improving clinical practice.
Objectives:
Here we investigated whether neurons differentiated from pluripotent stem cells can provide such a tool using ASD associated to SHANK3 haploinsufficiency as a proof of principle.
Methods:
Pharmacological FDA approved compounds (N=205) were screened first for their potential to increase SHANK3 mRNA content in neurons differentiated from control human embryonic stem cells using Taqman probes in a fully automated process. Successful compounds were then challenged for efficacy at correcting pathological phenotypes in neurons differentiated from individuals with deleterious SHANK3 point mutations using the induced pluripotent stem cell derived from the patients.
Results:
Among the 205 compounds tested, 15 increased significantly SHANK3 expression, including 6 FDA-approved drugs. Further investigation demonstrated that 2 of the latter, lithium and valproic acid, efficiently increased SHANK3-containing synapses and neuronal connectivity. These 2 drugs were efficient at correcting functional phenotypes associated with SHANK3 haploinsufficiency in patient-derived neurons. Lithium pharmacotherapy was then tested in one patient. After one year, a clinically-significant decrease in symptom severity has been observed.
Conclusions:
Pluripotent stem cells-derived neurons can help define more specific treatment for autism by focusing on gene or pathway correction rather than on symptoms. They allow the pre-screening of hundreds of therapeutic options on patients-derived neurons, thus increasing the chance of success of a candidate treatment.