'Living fossil' stops HIV in its tracks
be the 'living fossils' of a time when life was based on RNA - to
prevent the spread of HIV in the body.
The Medical Marketing International Group (MMI) is a pharmaceutical company that identifies, buys and develops drug candidates and technologies from academic organisations. Its scientists have used these ancient RNA catalysts to suppress key receptors that allow HIV to enter cells. As the HIV/AIDS epidemic worsens, the virus is also becoming increasingly resistant to existing therapies. Those drugs combined are currently worth an estimated $6.8bn (€5bn). However, the emergence of several new classes of drugs is set to boost that figure. Perhaps the most eagerly anticipated new class of drugs are 'entry inhibitors'. The MMI's new treatment is one such drug, although it is currently only in Phase I clinical trials. Rather than fighting HIV inside white blood cells, these drugs prevent the virus from entering uninfected CD4 cells by blocking its predominant entry route, the chemokine (C-C motif) receptor 5 (CCR5) and also fusin (CXCR4). The research is being conducted through one of MMI's subsidiaries, Viratis. The technology is based on using ribozymes to inhibit RNA- the intermediate between the genetic information stored in DNA and the cellular proteins it encodes. "We believe this is the first time that scientists have been able to show in vivo that the receptors that allow HIV entry can be eliminated using this approach," said David Best, the chairman of MMI. "Resistance is a major concern with current therapies, however, by targeting and silencing a cellular gene, we believe that this novel and attractive approach potentially avoids the problem of resistance." The ribozymes are delivered in vivo using a modified lentiviral vector (LV) that has been shown to be effective in tranducing genetic material into cells. Administration of LV intravenously resulted in a 70 per cent transduction of Peripheral Blood Mononuclear Cells (PBMC - HIV's target cells) in the body. This is turn reduced the number of PBMCs displaying CCR5 and CXCR4 by three times and six times respectively. This receptor suppression was achieved with a single dose of the ribozymes and the effect has, so far, lasted for over 35 days The preclinical proof of concept study can now be used for clinical trials, which MMi hopes will start in 2009. However, before the MMI drug gets anywhere near patients, the 'next big thing' looks likely to be Pfizer's offering, Selzentry (maraviroc). This entry inhibitor drug is expected on the market later this year and will be the first new type of oral HIV/AIDS therapy in over a decade. Another class of anti-retrovirals, called fusion inhibitors, block HIV from entering the cell. The first fusion inhibitor was Roche's Fuzeon (enfuvirtide), approved in 2003. It is, however, costly to prescribe and because of this, it is generally reserved for patients with multi-drug resistant HIV. As well as preventing the virus entering cells, two other steps in the lifecycle of a virus could be exploited as potential avenues to new classes of HIV drugs: virus maturation and viral integration. Merck & Co's integrase inhibitor, Isentress (raltegravir) is currently in Phase III trials. It is another potential first-in-class drug that prevents HIV viral DNA being integrated into human DNA. Merck & Co has said its plans to file the drug with the FDA in the second quarter of 2007. US pharmaceutical company Panacos is developing bevirimat (PA-457), which aims to prevent the virus maturing into infective particles that can subsequently spread around the body. This 'maturation inhibitor' is currently in Phase II trials. Perhaps the closest rival to MMI is an Australian company celled Benitec, which is currently testing an RNA therapy in Phase I clinical trials. It combines ribozymes, RNAi and RNA decoys into one therapy and the company claims it has the potential to make the patient's blood cells resistant to HIV after bone marrow derived stem cell transplantation. The very first HIV/AIDS drugs were nucleoside-based reverse transcriptase inhibitors. Since then, drugs have moved away from this area to small molecules and proteins. However, MMI and Benitec may well prove that drugs based on genetic material still have a role to play in fighting this virus. Either way, with all these new classes of drugs in development, the future looks brighter for those infected with HIV/AIDS. And with entry inhibitors predicted to gain a 24 per cent share of the HIV//AIDS market by 2014, it doesn't look bad for pharmaceutical firms either.
