Enlightening molecular mechanisms of abnormal cerebellum development in mouse models of human Niemann-Pick C 1 disease: the efficacy of hydroxypropyl-betacyclodextrin in correcting the phenotype

Niemann-Pick C1 (NPC1) is a devastating neurodegenerative disorder with a subtle beginning: a normal appearing child develops the disease in the mid-to-late childhood and dies during the teenage years. It is a “recessive” disease so parents show no sign that they are carriers. On the average, one in four children to a couple who are carriers will develop the disease but multiple children may be affected. Because the children are normal at birth, there is a window of opportunity to treat them before they begin to develop symptoms. As the Western world moves to DNA-based methods of newborn screening, it is increasingly likely that such children will be identified at birth. We have been studying a drug (hydroxypropyl-beta-cyclodextrin) which doubles life expectancy in mouse models if started early enough. It is already being used in children in the USA under a “compassionate use” exemption by the US Food and Drug Administration. It has recently received approval for use in Europe by the Commission for Orphan Medicine Products of the European Medicines Agency. Although not published, children's symptoms are decreased even though it has not been started until symptoms are strongly developed (see addiandcassi.com for videos). It greatly affects the development of the part of the brain which controls muscle movement (the cerebellum). However, little is known about how this drug changes the development of the cerebellum in Niemann-Pick C1. Using mouse models, we are unraveling this exciting effect of the drug.We have found that the number of movement control (Purkinje) cells are maintained by a single injection of the drug when given at the equivalent of infancy. We wish to study the molecular pathways involved in the drug's ability to cause this effect. A better understanding of the disease’s effect on the developing cerebellum, and how this drug modifies it, could lead to additional treatments to delay or reverse the disease.