CLN5-supplemented hematopoietic stem cell transplantation for treatment of lysosomal storage diseases

Lysosomes maintain cellular homeostasis by catabolizing and recycling macromolecules, and regulating metabolism, signaling, and compensatory mechanisms via inter-organelle crosstalk. Batten disease is a rare, undertreated form of childhood neurodegeneration caused by mutations of essential endolysosomal protein-coding genes, several of which deplete a unique lysosomal phospholipid, bismonoacylglycerophosphate (BMP). We discovered that genetically deleting BMP synthase (CLN5-/-) in mice triggers global BMP depletion and downstream multi-organellar defects and compensatory responses. We will further characterize defects using transmission electron microscopy and artificial intelligence, and employ hematopoietic stem cell transplantation to rescue molecular and cell morphological phenotypes of three BMP-depleted Batten disease mouse models.