Progressive supranuclear palsy (PSP) is a primary tauopathy, which is caused by the insoluble intracellular accumulation of hyperphosphorylated forms of the microtubule associated protein tau (tau; MAPT gene). Recent studies suggest that the single nucleotide polymorphism (SNP) at rs242557 confers risk of the H1c sub-haplotype that is characteristic of PSP. The rs242557 SNP resides in a highly conserved repressor domain of the MAPT promoter suggesting that it may confer risk to PSP through instable regulation of expression. While previous studies have noted rs242557 allele-specific differences in the transcriptional repression, no causative relationship has been established between rs242557 alleles and tauopathy in human neurons. To address this question, and to control for variance associated with genetic heterogeneity that we have observed when comparing patient-derived human induced pluripotent stem cell (iPSC) lines, we sought to engineer an isogenic allelic series at the rs242557 locus of human iPSCs from a common donor. Using clustered-regularly interspaced short palindromic repeats (CRISPR)-based genome editing, we targeted the rs242557 locus to generate a series of iPSC lines a single point mutation in hopes of exploring possible expression changes driven by the rs242557/A risk allele. During iPSC line development, the project encountered unforeseen problems in the cell lines. Various lines undergone recombination events on Chromosome 17q, which includes the MAPT gene. The project then focused on the development of these amplification lines and what will happen with tau expression with an additional copy of the gene. These lines were measured for tau protein, isoform-specific and total tau expression as well as allele-specific expression from a SNP in linkage disequilibrium with rs242557. This SNP, rs7521, serves as a surrogate for rs242557 expression in order to explore the claims that the rs242557/A allele is driving higher expression to confer risk of PSP. Ultimately, the goal of this project was to support future in vitro model efforts for PSP and related tauopathies for which rs242557 is a risk factor. Additionally, these studies provide insight into the challenges of genetic engineering at a non-coding SNP locus, which is an important hurdle to overcome in the study of functional genomics of sporadic diseases.