Dual targeting of defective lipid and metal pathways in Niemann-Pick type C disease: an in vitro pilot study

NHMRC Australia Fellow

Institution: The Florey Institute of Neuroscience and Mental Health

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The long-term goal of this project is to develop a treatment strategy that will prolong the life of Niemann-Pick disease type C1 (NP-C1) patients and restore their brain and other functions. Currently there is no cure for NP-C1 disease.

NP-C1 disease is a rare disorder affecting about 500 people worldwide. The brain and other organs of NP-C1 patients become damaged due to abnormal processing and storage of cholesterol and other fats. Patients develop movement and memory problems. NP-C1 disease is usually fatal within 10 years of diagnosis.

Balanced level and distribution of biological metals such as iron, copper and zinc are critical to health. We recently found perturbed biological metal balance in blood and tissue samples from NP-C1 disease patients and mice. Corrupted biological metal regulation is a key contributor to oxidative stress, which is a feature of NP-C1 disease. Current available treatments that target faulty fats and cholesterol pathways, such as miglustat and 2-hydroxypropyl-β-cyclodextrin (HPβCD), do not address this problem.

This project proposed to test and identify a beneficial combination treatment that restores metal and cholesterol balance in skin cells from NP-C1 patients. We have available to us a number of new drugs developed by Collaborative Medicinal Development, LLC (CMD) that facilitate the movement of metals. Notably, NP-C1 patient skin cells treated with a number of CMD drugs alone showed marked reduction in cholesterol storage. A combined treatment of a CMD drug plus HPβCD showed a potential to further reduce cholesterol storage in NP-C1 patient skin cells. Therefore, our proof-of-concept study demonstrates promise for a novel combination treatment approach to combat both cholesterol and metal problems in NP-C1 disease.