LYSOSOMAL STORAGE DISORDER THERAPEUTICS

Niemann-Pick Type C (NPC) and Stargardt Disease (SD) are a rare, panethnic diseases that are among the 46 different lysosomal storage disorders known. NPC patients suffer from accumulation of unesterified cholesterol in the lysosomes of their cells, ultimately leading to cell death and the development of neurological and multiple organ dysfunction. Several lines of evidence suggest that 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) derivatives are able to initiate the efflux of aberrantly stored unesterified cholesterol from the late endosomal/lysosomal (LE/LY) compartments of NPC-deficient cells and extend lifetime in animal models of NPC disease. Unfortunately, these effects are temporary after a single dose of HP-β-CD, therefore, repeated injections or continuous infusions are required to produce durable responses. In an effort to make HP-β-CD treatment a more efficacious, safe, and long-lasting therapeutic option, we have developed a family of HP-β-CD polyrotaxanes derived from biocompatible triblock copolymers that are enzymatically activated to release multiple copies of HP-β-CD within the LE/LY to remove cholesterol deposits that have accumulated in this cellular compartment. SD, a childhood blinding. dis-order, arises from aberrant accumulation of bisretinoids in the retinal pigmented epithelium leading to necroptosis within the retina. Polyrotaxane derivatives and small molecules that enhance bisretinoid clearance and suppress the necroptosis pathway are under development.