Cyclodextrin Polymers Targeted to Late Endosomes and Their Use

Invention Summary

This invention provides novel cyclodextrin polymers with cell targeting agents and methods to use these polymers to treat diseases related to elevated cholesterol levels and lysosomal storage disorders (e.g, Niemann-Pick C).

Technology Overview

Nieman-Pick type C disease (NPC) is a lysosomal storage disorder causing accumulation of unesterified cholesterol in lysosomal storage organelles (LSO). Recent studies have shown that hydroxypropyl-β-cyclodextrin (HPβCD) is effective in treating NPC.

The inventors studied the mechanisms and demonstrated that reduction in cholesterol accumulation in NPC is due to CD action from inside late endosomes/lysosomes. They demonstrated that CDs were delivered to LSO and were effective at reducing the cholesterol accumulation inside LSO. They also demonstrated that methyl-β-cyclodextrin (MβCD) is more potent than HPβCD in reducing cholesterol.

Based on their discoveries, the inventors have designed and synthesized MβCD polymers containing cell targeting agents. These novel polymers increase cellular uptake and reduce elimination via the kidney. The cell targeting agent effectively delivers MβCD to a specific cellular location, such as LSOs, and reduces the concentration of CD needed for an effect. These novel polymers effectively correct NPC deficiency in cells.

The invention provides compositions and methods to treat patients suffering from an elevated cholesterol level or suffering from a lysosomal storage disorder.

Potential Commercial Applications

• Therapeutics for diseases related to elevated cholesterol levels and lysosomal storage disorders (e.g, Niemann-Pick C)
• Potential Advantages:
• Significantly enhanced drug potency and reduced the dosage needed for treatment
• Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells. Proc Natl Acad Sci USA, 2010, 107, 5477-82.
• US patent application. US20120077774