Promising Drug For Lethal Mutagenesis Of HIV: Vidaza (5-AZC)

[Inchlingblue]

There was an interesting article in The New York Times about lethal mutagenesis or increasing mutation rates in order to wipe out viruses. This is the same approach as that of KP-1461 from Koronis. There is a drug (5-AZC/Azacitidine; Trade name: Vidaza) already approved for precancerous blood disorders so it should speed up the process of getting it into clinical trials for HIV.

From the article:

Despite these challenges, a number of researchers see reason for optimism about lethal mutagenesis. Dr. Mansky, for example, has been inspired by studies in the last few years that revealed how our own bodies use a natural kind of lethal mutagenesis. People produce proteins, known by the acronym Apobec, that fight off H.I.V. infections. They do so by adding mutations to the viruses as they replicate.

“To me that was important,” Dr. Mansky said. “It said that cells have evolved a mechanism for fending off viruses with lethal mutagenesis.”

In recent years Dr. Mansky has been seeking to overcome one of the big hurdles with lethal mutagenesis: toxic side effects. In November, he and his colleagues reported wiping out H.I.V. in infected cells with a drug called 5-AZC. He chose the drug to test because doctors regularly prescribe it for precancerous blood disorders. Now that Dr. Mansky has demonstrated that an approved drug can cause lethal mutagenesis in H.I.V., he is moving forward with preclinical trials on people.

LINKS:

Using a Virus’s Knack for Mutating to Wipe It Out

http://www.nytimes.com/2010/01/05/science/05lethal.html

http://en.wikipedia.org/wiki/Azacitidine

[J220]

Interesting. I bet the people over at Koronis are reading this closely too!

I hope the trials for HIV happen soon. Since this is an already approved drug it should be quicker to test, one would hope.

[Cosmicdancer]

I saw an interesting article about the Phase 2 trial of KP-1461 that gives a little more detail than what you find on Kronis Pharmaceuticals site.  Apparently, some of the 13 people who received KP-1461 had a dramatic drop in viral load, while others did not.  Researchers believe the drug is slow acting and takes time to generate a sufficient number of mutations, which is why some didn't experience a change in viral load during the short duration of the study.  I'm not sure how many weeks the trial was.

http://www.bukisa.com/articles/210962_new-experimental-hiv-drug

A short paper on the newest experimental drug for treating HIV & AIDS
Viral Decay Acceleration: KP-1461
Dec. 9, 2009

KP-1461 also known as SN1461 is an experimental drug in phase two trials. The drug is one of many in part of the antiviral drug therapy called Viral Decay Acceleration . Viral Decay Acceleration or VDA is the theory and works of a German scientist by the name of Manfred Eigan who came up with the concept of “quasispecies”.  “A viral quasispecies is a highly structured and interrelated population of constantly evolving virus whose stability is defined by its genomic replication error rate.” (Kronis Pharmaceuticals). The HIV virus along with a few other viral pathogens are being tested and treated with this new approach.
          KP-1461 is a mutagen, that is part of a drug class known as Nucleoside Reverse Transcript Inhibitors.(AIDSinfo) If you’ve ever taken a biology class, you’d know that the HIV virus is a retrovirus which means it’s a virus that affects the RNA and replicates itself by way of reverse transcript to produce its own DNA from the infected RNA. In theory and so far in clinical testing, KP-1461 works to change the chemical makeup of the infected DNA. The drug is currently only in testing for HIV-1 and does not cure or prevent the spread of the HIV infection or AIDS.
          In a February 2009 article of Discovery News, the Chief Operating Officer for Kronis Pharmaceuticals, the company producing and testing the KP-1461 drug, spoke out saying, “The HIV virus is so dependent on mutation that it really lives on the edge of existence. But we figured if we could increase this mutation rate, [HIV] might finally fall off that edge.” The drug is not to ease the symptoms in any way, but merely to speed up the production of the HIV virus itself, to overload it in a way and cause it to self destruct. (Bland par 2)
          In a normal DNA the two strands of DNA make up a double helix; one strand is composed of Adenine which lies together with Thymine and the other is of Guanine and Cytosine. Since KP-1461 is a mutagen it mutates to take on the form of whatever need be, in this case, it looks like both Thymine and Cytosine and will replace one of them in order to mess up the DNA even more. The unfortunate thing, as with all drugs is that it doesn’t work immediately, it does take time to build up in the system and start to work.  (Bland, par 3-4)
         Scientists are still working on publishing their findings from the 2008 KP-1461 drug trial but according to Bland’s article, of the 13 patients, the results were mixed as some people saw a dramatic drop in the viral load of their systems and some saw no change whatsoever. “What’s clear is that KP-1461 does eventually destroy HIV in some patients, unlike the current batch of antiretroviral drugs, which limit the production of the virus but fail to destroy it.” What this drug could mean to people living with the HIV virus is phenomenal but only time and much more testing will prove it worthy or not.

[Inchlingblue]

That's a good article Cosmicdancer.

It seems there is a mathematical formula that will help in fine-tuning the level of mutation necessary without going overboard:

Koronis’s clinical trials of KP-1461 last summer weren’t as effective as lab tests. Jeff Parkins, the vice president of clinical development, says researchers are honing the dosing strategy for trials planned for later this year.

Harnessing lethal mutagenesis may soon become easier, following a new mathematical formula by bioengineer Michael Deem of Rice University that could help researchers fine-tune compounds earlier in the process. Given a few key variables, such as how often viral genes shuffle inside cells, his equations can provide the minimum mutation rate to safely kill a virus. At this pace the virus won’t have time to correct errors or absorb drug-evading changes, and it will crash. “It’s not going to come back and cause problems,” Deem assures.

LINK:

http://www.popsci.com/node/31087