Multiple lysosomal storage disorders, including CLN3 (juvenile Batten) disease, are associated with the accumulation of complex lipids such as glycosphingolipids (GSLs). Substrate reduction therapy aims to reduce the production of these lipids, and thereby limit their accumulation. This has led to development of several small molecule inhibitors of UDP-glucose ceramide glucosyltransferase (UGCG, also known as glucosylceramide synthase [GCS]), including miglustat that is currently being trialled for treatment of CLN3 disease. However, for some people, miglustat produces side effects that lead to discontinued use, and alternative drugs are either not yet approved or exhibit little blood-brain barrier permeability. An alternative to inhibiting UGCG enzymatic activity is to inhibit production of the protein. We have designed UGCG-targeting antisense oligonucleotides (ASOs), and tested their ability to reduce expression of UGCG and accumulation of GM1-ganglioside, using human patient-specific cell models. Specifically, we have used induced pluripotent stem cell (iPSC)-derived neuronal models of CLN3 disease, Niemann-Pick type C1 disease, and Tay-Sachs disease (GM2-gangliosidosis). We have identified lead ASOs from a low-resolution screen that we are now benchmarking against small molecule inhibitors of UGCG, including miglustat, ibiglustat, and eliglustat; for CLN3 disease and Tay-Sachs disease, we are also comparing to gene-edited isogenic neuronal cultures. These data will evaluate the effectiveness of ASOs in comparison to existing and emerging strategies, and inform steps to refine our lead ASOs. We anticipate optimised UGCG-targeting ASOs, delivered intrathecally, will be a suitable treatment option for neurodegenerative diseases where side effects associated with orally administered small molecule inhibitors are not tolerated.