Drug Treatment Corrects Hereditary Cholesterol Storage Disease

The hereditary cholesterol storage disorder Niemann-Pick type C disease has been corrected in a mouse model by a single injection of the compound 2-hydroxypropyl-beta-cyclodextrin (CYCLO).

Niemann-Pick type C (NP-C) disease is caused by an inactivating mutation of NPC1 protein, which normally aids movement of unesterified cholesterol from the endosomal/lysosomal compartment to the cytosolic compartment of cells throughout the body. This defect results in activation of macrophages in many tissues, progressive liver disease, and neurodegeneration. The vast majority of children diagnosed with NP-C die before they reach 20 years of age and many before age 10. Late onset of neurological symptoms such as clumsiness, mild retardation, and delayed development of fine motor skills can lead to longer life spans, but few people diagnosed with NP-C reach age 40.

Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) worked with a mouse model of NP-C. The affected mice have whole-animal cholesterol levels of around 2000 mg/kg of body weight that expands to about 5000 mg/kg during the first 49 days of age. The animals' liver cholesterol pools increase from 132 to 1,485 mg/kg of body weight over the same period.

In the current study, the investigators injected the NP-C mice with one dose of CYCLO when they were seven days old. They reported in the January 26, 2009, online edition of the journal Proceedings of the [U.S.] National Academy of Sciences (PNAS) that the drug immediately caused sequestered cholesterol to flow from the lysosomes to the cytosolic pool in many organs, resulting in a marked increase in cholesteryl esters, suppression of cholesterol but not fatty acid synthesis, down-regulation of genes controlled by sterol regulatory element 2, and up-regulation of many liver X receptor target genes. There was also decreased expression of pro-inflammatory proteins in the liver and brain. By 49 days of age, the single injection of CYCLO resulted in a reduction in whole-body cholesterol burden by more than 900 mg/kg, marked improvement in liver function tests, much less neurodegeneration, and, ultimately, significant prolongation of life.

"What we have shown is that very quickly after administration of this compound, the huge pool of cholesterol that has just been accumulating in the cells is suddenly released and metabolized normally," said senior author Dr. John Dietschy, professor of internal medicine at the University of Texas Southwestern Medical Center. "With just one dose, you excrete a large portion of this pool of cholesterol. The key idea is that we appear to have overcome the transport defect in the lysosome that is brought about by the genetic defect or mutation. We do not yet understand what is happening at the molecular level, but it is clear that this compound somehow overcomes the genetic defect that causes individuals to accumulate cholesterol."

"By treating at seven days, we eliminated approximately one-third of the accumulated cholesterol almost immediately," Dr. Dietschy said. "Now we want to see what happens if we give it every week. Can we maintain low cholesterol levels? That's what we are looking at now."

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University of Texas Southwestern Medical Center