Researchers are slowly establishing a connection between an extremely rare genetic disease and HIV -- and homing in on a safe, non-prescription compound that could treat both.

Recently, James Hildreth at the Meharry Medical College School of Medicine in Nashville, Tenn., and his colleagues found that cells affected by Niemann-Pick Type C (NPC), which disrupts cholesterol trafficking, were unable to release HIV, suggesting these cells would not spread the virus.

These findings, published May 27 in the Journal of Virology, are rooted in a hypothesis Hildreth has explored for a long time: that "cholesterol is somehow essential" to HIV, he said. For instance, HIV-1 relies on specialized structures known as lipid rafts, which are rich in cholesterol, to infect new cells.

That line of thinking has led him to investigate whether a compound widely employed by the food and chemical industries (and used as a drug solubilizer) which depletes cells of cholesterol could serve as a preventative agent -- or even a treatment -- for HIV. And his growing body of evidence is suggesting the compound, known as cyclodextrin, might do just that.

Cyclodextrin infusions Image: Chris Hempel

"There are very few [compounds] that rival the safety profile" of cyclodextrin, said Hildreth. If further research confirms it has an effect on a disease that affects millions of people worldwide, that would be a major advance, he noted. "It's been exciting for me from the beginning."

Cyclodextrin appears to also show some benefit in NPC, pointing further to a connection between HIV and the rare genetic disease. Indeed, a family with identical 5-year-old twins with NPC recently received permission from the US Food and Drug Administration to give the girls regular infusions of cyclodextrin. NPC leads to marked abnormalities in the liver and brain and is invariably fatal.

"You have no idea what a relief it is to have something to try," said Chris Hempel, mother to Addi and Cassi. The girls have so far received several infusions, starting with one continuous 4-day infusion, and are now getting a series of 8-hour weekly infusions of increasing doses. Hempel said the girls improved remarkably after the first 4-day infusion, showing better control of their head and neck and better balance, and were more affectionate and responsive to people. These improvements waned a bit once the girls switched to weekly doses, but seem to be returning as the doses increase.

Addi and Cassi getting their infusions Image: Chris Hempel

In a previous experiment, Hildreth and his colleagues found that adding cyclodextrin to uninfected cells to deplete cellular cholesterol warded off HIV infection. Restoring normal cholesterol levels removed that protection. In a mouse model of HIV, cyclodextrin prevented vaginal transmission of the virus by infected cells.

In a primate model, the data were somewhat less promising. When macaques received topical cyclodextrin before being exposed to the virus, the treatment appeared to prevent infection initially, but offered little protection upon re-exposure to SIV, again following cyclodextrin prophylaxis.

Hildreth said that may be because the animals received a massive dose of the virus -- "way more than you'd ever see in seminal fluid in a natural setting" -- and the batches of cyclodextrin used for the repeated doses were not of the same quality. He said he is now repeating the study using a "physiologically relevant" amount of the virus. "We're pretty confident."

Hildreth explained that NPC is likely disrupting HIV transmission by affecting the trafficking of the viral protein Gag. "The very dramatic thing in NPC cells is the Gag protein seems to never make it to the plasma membrane."

Currently, Hildreth is developing cyclodextrin as a microbicide against HIV. He has filed an investigational new drug application with the FDA, and is investigating whether the compound could serve as a therapeutic.

Steven Walkley, who studies lysosomal storage disorders such as NPC at Albert Einstein College of Medicine in New York, said his own data show cyclodextrin has a "remarkable" effect on mice with NPC. "They're living literally twice as long as they would otherwise, " he said. "We were very surprised, to say the least." (He and his colleagues have submitted their findings for publication.)

Walkley noted that his mice receive 4000 milligrams per kilogram of cyclodextrin -- 10 times a recent dose the Hempel girls received -- and he hasn't noticed any side effects. However, it's still unclear how exactly cyclodextrin is warding off NPC, which means there could be some side effects scientists have not yet discovered, he added. "Maybe there's something going on and we just haven't found it yet."

Peter Pentchev, a retired scientist who worked with NPC for decades at the National Institutes of Health, echoed Walkley's opinion about the promise of cyclodextrin in NPC, dubbing it the "perfect drug" for the disease. He cautioned, though, that "we know what [cyclodextrin] does, but we don't know why or how." But scientists are working on those questions, he added. "In the next year, I'd be really surprised if we don't get some answers."

Hempel, too, has failed to notice a single side effect since her girls began cyclodextrin infusions. "We're proving the safety of this compound," she said. "I definitely feel like Addi and Cassi are leading the way here, not only for NPC kids, but potentially for AIDS patients."




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