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Cyclodextrins (CD) are cyclic sugar molecules that form a complex with many different substrates due to their hydrophobic inner cavity and hydrophilic outside. This property makes CDs widely used in the pharmaceutical industry as an excipient, or delivery agent, for other drugs. There are three main types of CDs (alpha, beta, and gamma; see image) which can be modified by the addition of side chains, resulting in a vast number of CD derivatives. These derivatized CDs are generally less toxic and several are FDA approved for use as excipients, but not as therapeutic agents.

Treatment of Niemann-Pick type C disease with CD will be the first indicated use of CD as the active pharmaceutical ingredient. Click here to learn more about SOAR and the research that helped bring about this monumental step forward in the fight against NPC.

Exactly how CD mediates amelioration of NPC disease is still being investigated, but many researchers believe it involves an interaction between CD and cholesterol, a lipid which accumulates within nearly all cells of NPC patients. Administration of CD to mice or cats affected with NPC disease leads to delay in onset of clinical signs, a reduction in storage of cholesterol and other lipids within cells, and an increase in lifespan of treated animals. While the beneficial effects of CD are quite extensive, it does not limit progression of all aspects of NPC disease. Additionally, direct delivery of CD to the central nervous system in animal models has shown to be more effective than peripheral administration.

CD is currently in a Phase 1 clinical trial at the National Institutes of Health and several NPC patients have received lumbar injections of CD. One of the three SOAR-NPC labs is providing the biomarker analysis to determine if CD is impacting markers of disease in the participants. Planning for a Phase 2/3 clinical trial is already underway and anticipated to begin shortly after conclusion of the Phase 1 trial.

While animal studies have provided strong evidence suggesting CD will benefit NPC patients, there are still important aspects to address with this therapeutic agent. Lumbar administration of CD is not the ideal route of delivery, as providing CD directly to the brain is expected to yield the greatest impact on disease progression. One way to address this issue is to find a safe and effective indwelling catheter, providing direct access to the central nervous system. Another means is to create a modified CD that more efficiently crosses the blood brain barrier, thus eliminating the difficulty of repeatedly accessing the central nervous system through a catheter. However, a CNS-targeted CD is not without its own set of complications, and while it would likely reduce patient risk associated with delivery, this agent would be a new chemical entity and thus require a new clinical trial to gain FDA approval.