New non-drug fix for HIV?

The Scientist Magazine
By Alison McCook
30th June 2009

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.

“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.

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.”

Wacker Chemie Expands US Based Cyclodextrin Facility To Meet Increase In Worldwide Demand For Sugar Molecule

Wacker Chemie, the Munich-based chemical company, announced that is has expanded its US based cyclodextrin facility in Eddyville, Iowa.  According the the press release issued by Wacker, the new cyclodextrin facility increases the company’s capacity for alpha (α) and beta (β) cyclodextrins by 50 percent and doubles its capacity for gamma (γ) cyclodextrins.

Investment in the entire facility totaled over $21 million and will enable Wacker to produce up to 7,500 metric tons of cyclodextrins a year.  The extra capacity is needed to meet the worldwide rise in cyclodextrin demand.

According to the press release, “the ability to reversibly enclose other substances makes cyclodextrins invaluable in many products such as pharmaceuticals, cosmetics, textiles and food, not to mention in the household-care, personal-care and construction sectors.”

What about entrapping cholesterol in the human body and helping get rid of it?  Interestingly, Wacker’s press release does not mention hydroxy propel beta cyclodextrin (HPBCD) and its potential health benefits.

This is the type of cyclodextrin we are giving via intravenous infusions to Addi and Cassi for their fatal cholesterol metabolism disease, Niemann Pick Type C (otherwise known as the “childhood Alzhiemer’s.”)   Hydroxy propel beta cyclodextrin is somehow grabbing the stuck cholesterol and taking it out of the twins’ bodies through urine/stool.  I wonder if Wacker even knows of this cyclodextrin project or the fact that HPBCD also kills the HIV AIDS virus.

Here are some great facts on cyclodextrins from Wacker:

• Cyclodextrins are cyclic sugar molecules. The number of glucose units defines the size of the sugar ring – alpha-cyclodextrin has six, beta-cyclodextrin seven, and gamma-cyclodextrin eight glucose units

• Cyclodextrins are able to enclose other substances in their interiors, much like a cone encloses a scoop of ice-cream. This enables cyclodextrins to bind ingredients, release active agents and stabilize sensitive substances such as vitamins and coenzyme

• Cyclodextrins have the ability to reversibly enclose other substances making cyclodextrins invaluable in many products such as pharmaceuticals, cosmetics, textiles and food, household and personal-care

The best part of the whole announcement was this statement — cyclodextrins of all types are non-toxic, non-allergenic and pose no known health risks based on today’s scientific findings!

Anthrax Bacteria Killed By Simple Sugar Compound Called Cyclodextrin. Is CDC Looking Into This?

We all remember the Anthrax-laced letters that killed five people and severely rattled the country post-9/11. Just when you thought there might not be a way to stop this lethal infectious disease along comes beta cyclodextrin, a non toxic sugar compound.

A researcher by the name of Vladimir Karginov at a company called Innovative Biologics is working with beta cyclodextrin and Anthrax.  Karginov has designed and synthesized a number of beta-cyclodextrin derivatives and evaluated their ability to inhibit the lethal toxin action of Anthrax.  Several compounds displayed anti-toxin activity at low micromolar concentrations in cell-based assays and preliminary toxicity and efficacy studies in rodents produced very promising results.  You can read about the research project here.

Anthrax is a highly lethal and infectious disease caused by the bacterium Bacillus anthracis, a bacteria that forms spores, or dormant cells, which can come to life under the right temperature, nutrients and other conditions to allow growth. Anthrax occurs in humans after exposure to an infected animal or infected animal tissue or when anthrax spores are used as a bioterrorist weapon.   There are some effective vaccines against anthrax, and some forms of the disease respond well to antibiotic treatment shortly after exposure. But there is need for new, safe and effective treatments approved by the FDA to supplement traditional intravenous and oral antibiotic therapy such ciprofloxacin (cipro), doxycycline or vancomycin.

I have now reported on beta cyclodextrins ability to kill the HIV AIDS virus and now the deadly Anthrax bacterium.  This same non toxic sugar compound is also being used to treat my 5 year old identical twins who have a fatal cholesterol metabolism disorder called Niemann Pick Type C, or the “childhood Alzheimer’s.”

What other lethal bacterias and viruses does this non toxic cyclodextrin compound kill?   What does the Centers of Disease Control and Prevention and the United States Department of Health and Human Services know about cyclodextrin and are they studying it?

Journal Of Virology Reports On Link Between HIV and Niemann Pick Cholesterol Gene: Intact Intracellular Cholesterol Trafficking Pathways Mediated by NPC1 are Needed for Efficient HIV-1 Production

Journal of Virology
May 27, 2009

Deficiency of Niemann-Pick type C-1 Protein Impairs HIV-1 Release and Results in Gag Accumulation in Late Endosomal/Lysosomal Compartments

Tang Y, Leao IC, Coleman EM, Broughton RS, Hildreth JE.

Human immunodeficiency virus type 1 (HIV-1) relies on cholesterol-laden lipid raft membrane microdomains for entry into and egress out of susceptible cells. In the present study, we examine the need for intracellular cholesterol trafficking pathways with respect to HIV-1 biogenesis using Niemann-Pick type C1 deficient cells (NPCD) wherein these pathways are severely compromised, causing massive accumulation of cholesterol in late endosomal/lysosomal (LE/L) compartments.

We have found that induction of an NPC disease-like phenotype through treatment of various cell types with the commonly-used hydrophobic amine drug U18666A resulted in profound suppression of HIV-1 release.

Further, NPCD EBV-transformed B lymphocytes and fibroblasts from patients with NPC disease infected with a CD4-independent strain of HIV-1 or transfected with an HIV-1 proviral clone, respectively, replicated HIV-1 poorly when compared to normal cells.

Infection of the NPCD fibroblasts with a VSV-G pseudotyped strain of HIV-1 produced similar results, suggesting a post-entry block to HIV-1 replication in these cells. Examination of these cells using confocal microscopy showed an accumulation and stabilization of Gag in LE/L compartments. Additionally, normal HIV-1 production could be restored in NPCD cells upon expression of a functional NPC1 protein, and overexpression of NPC1 increased HIV-1 release.

Taken together, our findings demonstrate that intact intracellular cholesterol trafficking pathways mediated by NPC1 are needed for efficient HIV-1 production.

A Promising Compound That Could Stop HIV AIDS. Why Is It Not Being Supported?

In chapter 18 of a book by Stefano Bertozzi referenced by famous health economist Robert H. Topel in his article in the Journal of Political Economy, several insightful comments about HIV research funding and needs for prevention in the face of a rapidly increasing HIV infection rate are highlighted.

The points made by Bertozzi et all about the lack of funding for research into preventive treatments for HIV are directly applicable to the difficulties I am facing obtaining funding and support from for a cheap sugar compound called cyclodextrin that has great potential to help stop the spread of HIV/AIDS.

Even though the U.S. President’s Emergency Plan for AIDS Relief and the Gates Foundation are funneling a  great deal of money into AIDS research, introduction of ameliorative therapy projects based on simple and available non toxic compounds such as hydroxypropyl beta cyclodextrin have not gotten past the initial screener. Why is further research into this simple sugar compound being held back?

Bertozzi et al attribute such resistance to compounds like cyclodextrin to the perception that preventive research is viewed as “less innovative scientifically” and “typically less experimental” by funding organizations.  They suggest earmarking such ameliorative therapy approaches to redress this imbalance.

The ameliorative therapy approach with hydroxypropel beta cyclodextrin also addresses the cited need for well-defined control or comparison groups necessary to measure the effectiveness of this preventive therapy.

It’s also interesting that a ready-to-use cheap formulation of cyclodextrin that would cost 10 cents per dose to deploy into Africa (!) and simply needs quick re-packaging doesn’t interest the funding organizations or the NIH.  It would seem that immediate relief for people and saving lives is far less exciting than the thought of basic research and making money.

It is hard to believe that a compound promising a stop to the method of transmission responsible for 80% of the HIV infections around the world does not create a compelling reason for funding and testing.   It would only cost $500,000 dollars to test cyclodextrin, the cost of caring for approximately one AIDS patient over their lifetime.  Surely Mr. Gates could direct $500,000 dollars at this sugar compound to see if it works before spending millions on something less effective?

Finally, there is money in cyclodextrin and very smart people are researching it.  The ability for HIV AIDS to assemble in the human body is directly tied to the Niemann Pick Type C cholesterol gene on Chromosome 18, one of the most important genes in the body (this gene is now tied to obesity!).   And look what hydroxy propel beta cyclodextrin is doing for my 5 year old twins, Addi and Cassi, who suffer from one of the worst cholesterol diseases on the planet.

The Wall Street Journal Reports On FDA Approval of Addi and Cassi’s Cyclodextrin Treatment

By AMY DOCKSER MARCUS
April 3, 2009

A Mom Brokers Treatment for Her Twins’ Fatal Illness
Bucking Scientific Convention, Ms. Hempel Gets Researchers From Different Fields to Share Data on Potential Therapy

From the moment her twin daughters, Addison and Cassidy, were diagnosed with a fatal genetic disease in October 2007, Chris Hempel has been searching for a drug that might save their lives.

The 5-year-old girls were diagnosed with a devastating cholesterol metabolism disorder known as Niemann-Pick Type C, which is ultimately fatal. Soon after, Ms. Hempel learned that researchers found that a form of a compound called cyclodextrin extended the lives of affected mice.

Ms. Hempel set out to gather as much data as possible. She got a list of all major cyclodextrin distributors and connected with one in Florida, who shared scientific studies and other information with her. She found a short report in the medical literature about a doctor who had treated a child with a different disease using cyclodextrin and tracked him down. She became increasingly hopeful that, although cyclodextrin isn’t approved as a drug in the U.S., she might get the Food and Drug Administration to allow her to give cyclodextrin infusions to her girls as an experimental treatment.

Her search for information also led her to James Hildreth, 52, a pre-eminent AIDS researcher who heads the Center for AIDS Health Disparities Research at Meharry Medical College in Nashville, Tenn. It turned out that he too was seeking FDA approval to run a trial using cyclodextrin, in a vaginal cream to help prevent HIV transmission during heterosexual sex. Ms. Hempel wanted him to combine forces with the NP-C investigators to push forward cyclodextrin research.

That was only the beginning of Ms. Hempel’s long journey through the health-care research community — a distributed and labyrinthine collection of researchers who, for all their expertise, often remain unaware of advances made elsewhere. The problem is even more acute among researchers working on different diseases. But for some serendipity, curiosity — or, in this case, a willful Ms. Hempel — some knowledge in one lab may never make its way to another that could be on the verge of a new therapy.

Drugs approved for one disease often turn out to be effective in others — frequently when someone has a hunch. Thalidomide, originally used for morning sickness but taken off the market because it caused birth defects, is being used in cancer treatment.

Researchers at Pfizer were developing Viagra to treat high blood pressure when they noticed during early tests that it treated impotence. But that happened within the same company. It is even more difficult when researchers are at different labs.

When Ms. Hempel, who lives in Reno, Nev., became passionate about Dr. Hildreth’s work, she was determined to bridge the disparate knowledge. “Right now we have limited data on cyclodextrin. But what if a lot of people started looking at it from different angles and across different diseases?” Ms. Hempel said. “It could lead to something that helps save Addi and Cassi’s lives.”

Ms. Hempel had been researching cyclodextrin for months when she attended the June 2008 meeting in Tucson, Ariz., of the Ara Parseghian Medical Research Foundation, set up by the family of the legendary football coach who lost three grandchildren to NP-C disease. The foundation was providing some funding for cyclodextrin studies in the rare disease, and the latest data were presented there. In an email sent after the meeting, Ms. Hempel wrote to the NP-C researchers that, based on the data she heard, she and her husband, Hugh, planned to seek FDA approval to give the girls cyclodextrin infusions. “I feel very strongly that we must try this to help save Addi and Cassi from this horrible disease,” she wrote.

She had already put together a three-inch binder of research studies about cyclodextrin. Working with three other families whose children have NP-C disease, they hired a scientist who began writing a request to the FDA for the Hempel children to receive cyclodextrin infusions. But Ms. Hempel knew that she needed more human data if she was going to persuade the FDA that the drug was safe enough to use in her children.

While searching for safety data on cyclodextrin, she spoke with Charles E. Strattan, a cyclodextrin expert and CEO of CTD Holdings Inc., who was helping Ms. Hempel do research. He told her Dr. Hildreth was interested in the same compound for his work in HIV and suggested that the two of them talk.

During a long phone conversation in October 2008, Dr. Hildreth told Ms. Hempel that he believed the protein responsible for NP-C disease also plays an important role in HIV. And in previously published work, he showed that cyclodextrin appeared to inactivate the HIV virus and prevent it from replicating.

The talk galvanized Ms. Hempel. Dr. Hildreth offered to share what he knew about cyclodextrin’s safety with the FDA in support of the Hempels’ request. Ms. Hempel proposed that the two of them go to Johnson & Johnson, which had studied cyclodextrin, to see if the company would be interested in sponsoring a clinical trial. “I knew our stories would be even more powerful if we told them together,” she said.

As is typical in the field, Dr. Hildreth was reluctant to share unpublished data, and he rarely went to scientific meetings that weren’t related to HIV. He was moved by Ms. Hempel’s efforts to help her children, but also surprised by her embrace of his work. “Some of the things we as scientists take for granted about how work will be done and the fact there are silos, with her there is none of that at all,” he said.

When Ms. Hempel called a top National Institutes of Health AIDS researcher to tell him about Dr. Hildreth’s findings and propose joint work in HIV and NP-C disease, Dr. Hildreth told her that a scientist never would have made such a call. In recent months, Ms. Hempel has introduced Dr. Hildreth to NP-C researchers who were also studying cyclodextrin. She also arranged for him to discuss his HIV findings with two Nobel Prize-winning scientists interested in Niemann-Pick proteins. “Our paths would not have crossed otherwise,” he said.

He and Ms. Hempel recently had a conversation with senior officials at Johnson & Johnson. The FDA at first turned down the Hempels’ request to do cyclodextrin infusions in the girls, concerned there wasn’t enough human safety data. But after Ms. Hempel contacted them about her plight, the company wrote a letter to the FDA giving the agency permission to look at all of the safety data it had submitted related to cyclodextrin. The FDA subsequently gave permission for the Hempels to proceed. The girls will start cyclodextrin infusions this month.

That might have been the end of the story except for Ms. Hempel’s insistence that more was at stake, says Steven A. Silber, a vice president at Johnson & Johnson. After listening to Ms. Hempel and Dr. Hildreth’s presentation, Dr. Silber set up a meeting so Dr. Hildreth can present his data to the head of one of its companies that makes anti-viral medications. Dr. Hildreth says that Ms. Hempel’s involvement got his research “the attention of individuals higher up in the organization than I might have been able to get on my own.”

This May, the Parseghian Foundation will host its annual scientific meeting. The group plans to hold a special session dedicated to the work on cyclodextrin. Cindy Parseghian, president of the foundation, says she hopes researchers working with cyclodextrin in other diseases will also attend. “We think there should be more cross-fertilization,” she said. Dr. Hildreth says he plans to share his findings at the meeting.

Dr. Hildreth recognizes that his unusual partnership with Ms. Hempel also has some risks for the HIV trial he is planning. “It is a remote possibility, but is a possibility, that if her beautiful girls are done some harm by the infusions, that would clearly do harm to our efforts,” he said. Still, he adds, “I spent a lot of time thinking about what I would do if I were in her position. My answer is I would do exactly the same thing.”

Late last month, the Hempel girls underwent surgery at a California hospital to get a small medical device implanted under their skin to make it easier to receive regular cyclodextrin infusions. Dr. Hildreth visited them in the hospital.