Computational drug repurposing identifies N -acetylglucosamine as a potential therapeutic compound for CLN3 Batten disease

Batten disease, also known as neuronal ceroid lipofuscinoses, is one of the most common causes of childhood dementia. It is characterized by the accumulation of lipofuscin in lysosomes, leading to loss of brain cell function, onset of dementia-like symptoms, vision loss and seizures and has extremely limited treatment options. Here, we performed computational drug repurposing analysis to identify existing compounds that may target Batten disease risk genes. A total of 81 candidate compounds were identified, 6 of which were selected based on clinical tractability for downstream testing in Batten disease (CLN3) iPSC-derived models. After confirming disease phenotype and drug candidate safety, CLN3 brain cell cultures treated with and without drug candidates underwent bulk RNA-seq to identify drug responses. One of the candidate drugs N -acetylglucosamine (GlcNAc) significantly upregulated Batten disease risk gene CLN5 expression and several other lysosomal markers within CLN3 brain cells, and modulated several pathways implicated in lysosomal storage disorders. Importantly, GlcNAc significantly reduced lipofuscin burden in both CLN3 iPSC-derived neurons and astrocytes, supporting its investigation as an additional therapy for Batten disease.