The lack of therapeutics for devastating CNS diseases and the high failure rate of promising new drugs in clinical trials argue for the need to improve drug discovery strategies. Improving clinical relevance along the drug discovery pipeline can increase the likelihood of clinical success. Using BrainXell’s patient iPSC-derived neurons in high-throughput screens for new therapeutics improves the clinical relevance at the initial stages of drug discovery. For example, spinal muscular atrophy (SMA) patient motor neurons were used in phenotypic screening for small molecules that can upregulate expression of endogenous SMN2 protein, a promising strategy for treating this fatal disease. More than a billion spinal motor neurons were produced to screen more than 500,000 analytes in 1536-well format. Such a large screen has never been performed using patient-derived neurons, and several technological innovations were developed to enable this high-throughput screen: 1) genetic engineering of patient derived iPSCs to generate a HTS compatible readout of SMN2 expression, 2) large and consistent production of neurons (10^9 motor neurons per batch), and 3) consistent plating of rapidly maturing neurons across hundreds of 1536-well plates. These innovations can be applied to other cortical or motor neuron disease drug discovery in an effort to improve clinical translatability (and success) at the earliest stage of drug discovery.