RNAi Therapy: Hope or Hype?

Touted as the latest cutting-edge therapy to turn the tide of battle against the AIDS pandemic, will RNA interference (RNAi) therapy succeed where protease inhibitor based drugs failed?

By: Ringo Bones


Growing up during the 1980’s, one can’t seem to ignore the doomsayer’s predictions on how humanity will be wiped out by the relentless spread of HIV infection or AIDS. Since at the time the existing therapeutic regimen are next to useless compared to the drugs set to replace them in the coming years. In the 1990’s came protease inhibitor based drugs that proved very promising – albeit very expensive – in saving the lives of AIDS sufferers in the early stages of the disease. Due to the high cost of the therapeutic regimen (Did it used to cost US$30,000 a year per patient?), only the extremely rich like NBA basketball star Magic Johnson can afford the expense. A decade or so later, the cost of the drugs came down dramatically that philanthropic institutions - like the Bill and Melinda Gates Foundation - could provide the same therapy to parts of Africa seriously affected by AIDS at a cost of less than a dollar a day for every patient.

Though somewhat still awaiting field trials, RNA interference or RNAi therapy is the latest cutting edge therapy that has the necessary fighting chance to cure AIDS. RNAi therapy has the capability of switching off the pathogen that causes disease. If successful, RNAi therapy could not only cure AIDS but also hepatitis-C infections and further research could make RNAi therapy as a cure for cancer.

RNAi therapy was pioneered by an Australian biotech company called BENITEC. On July 2007, BENITEC was about to start dosing patients in the first human trials of their RNAi therapy, which attacks HIV infections on three separate fronts. Dr John Rossi from the Beckman Research Institute, City of Hope, California, outlined BENITEC’s RNA interference (RNAi) therapy – which he has collaborated on – and said that the first patient in the Phase I clinical trial will be dosed sometime by the end of July 2007.

Although the virus that causes HIV / AIDS can built up resistance to existing protease inhibitor based drugs alarmingly quickly, Dr John Rossi explained that attacking the virus on three separate fronts could enable the RNAi based drug to fend resistance for longer. It’s easy for the AIDS virus to mutate around one thing but much more difficult if there are three factors to contend with. Also, the mutated viruses that he has observed so far are much weaker that their previous “generation / parents” as observed by Dr Rossi. But later, the virus reverted back to its original sequence.

Dr Rossi explained that the RNAi based drug uses a lentivirus vector to deliver the genes that encode for the three different forms of RNA to battle the virus. RNAi in the form of short hairpin RNA (shRNA), that targets an exon in the transactivator or transcription (Tat) and Regulator of Virion (Rev) gene (ShI). A decoy for the HIV TAT – reactive element (TAR) and a ribozyme that targets the host cell CCR5 chemokine receptor (CCR5RZ).

The scientists at BENITEC are using two different techniques to introduce the DNA into the body. The first one is where they remove the patient’s own bone marrow progenitor cells, genetically modifying them using the virus and then reinfuse them into the patient during a bone marrow transplant. BENITEC claims that – if successful – the new treatment could allow patients’ bodies to produce HIV-resistant white blood cells indefinitely.

BENITEC and City of Hope are also using a similar approach, only with T cells instead of stem cells explained Rossi. He went on to explain that the anti-CCR5 ribozyme may prevent the virus from entering the cell but if it does get in and starts to produce RNA’s, the drug will capture that RNA and also move the Tat away from the virus.

Not only does the drug attempt to knock back virus levels, Rossi said it also aims to destroy the lymphoma that develops in many HIV-positive patients. The trial itself will be treating five patients in this subgroup, with the results expected within a year.

From what I learned so far from virus physiology, using the “reproductive” phase of the pathogenic virus to “kill” it or render the virus impotent is a good way to tackle fast mutating RNA based viruses like HIV / AIDS. But a part of me that’s been reading (and watching) far too many science fiction stories find this technology rife for abuse. Especially further on when the science behind RNA interference therapy can be made to make one’s own immune system attack ones own body or make each and every cell in one’s body into a bunch of malignant tumors. As with any scientific “tool”, it’s up to the global community to police its applications.