Huntington’s disease (HD) is a fatal, dominantly inherited neurodegenerative disorder that primarily affects neurons in the striatum and cortex. Studies have identified striatal developmental impairments in HD and transcriptional pathways that are amenable to disease-modifying interventions. Our central hypothesis is that HD MSNs manifest developmental alterations that cause their dysfunction, dedifferentiation and potentially dysregulation with inappropriate neuronal markers for MSNs. We further hypothesize that these HD phenotypes can be corrected by modulating MSN developmental transcription factors or via drugs that correct transcriptional dysregulation. Specifically, the failure of HD MSNs to differentiate properly makes them more susceptible to neurodegeneration. Therefore, we can use our newly discovered MSN transcription factors to rescue this HD phenotype. The early developmental alterations in MSNs set the stage for developing HD symptoms later in life. In support of this hypothesis: 1) the maturation or maintenance of medium spiny neurons (MSNs) is dysregulated in human isogenic HD-iPSCs with corrected alleles; 2) that the developmental trajectory is distinct and alters the DLX gene family, key MSN developmental transcription factors, as determined by bulk and scRNAseq; 3) using bioinformatics, drugs can be identified that can be repurposed to rescue this altered developmental trajectory; 4) the key developmental MSN transcription factor, Bcl11b (also known as Ctip2), is also a key maintenance factor in the mature MSNs, as conditional and specific deletion in postnatal mouse MSNs converts their transcriptome to one that mimics human and mouse HD gene expression and 5) identification of novel TFs required for striatal compartmentation and striosome maturation may be potential HD therapeutic targets. Therefore, the specific aims are: Specific Aim 1 will characterize the cellular, developmental and functional deficits in human isogenic HD-MSNs derived from induced pluripotent stem cells, and evaluate if predicted key TFs or drugs rescue HD phenotypes; Specific Aim 2 will characterize the cellular, developmental and functional deficits in isogenic human HD-organoids (structural organization and diversity of cells) and evaluate if predicted key TFs or drugs rescue HD phenotypes. Specific Aim 3 will determine if overexpression of MSN TFs corrects abnormalities in the Q175 mouse model with focus on the striosomal compartment. These studies will advance our understanding of how to model HD in striatal MSNs/organoids and identify novel mechanistic pathways and therapeutic targets for HD.