Fighting Back: New Drugs Against Flu
The traditional advice for treating flu—bed rest and fluids—works quite well in most cases. For the elderly, the very young and people with chronic illness, however, flu and its complications can be life-threatening. While several drugs exist to treat flu, they must be taken within 48 hours of the start of the illness. NIAID grantees, including Jianzhu Chen, Ph.D., and Mang Yu, Ph.D., are exploring ways some futuristic technologies might lead to better flu drugs.
A Welcome Interference
RNA interference (RNAi) is a cellular phenomenon that scientists are just now starting to understand and exploit. Jianzhu Chen, Ph.D., and his colleagues at the Massachusetts Institute of Technology are exploring the possibility of using RNAi to hinder the ability of the flu virus to multiply inside its target cells. RNAi can selectively inhibit gene activity in cells; essentially, the technique allows researchers to “turn off” individual genes. Dr. Chen and his team have experimented with a particular form of RNAi, called short interfering RNA (siRNA), specific for genes that the flu virus requires to reproduce inside human cells
In laboratory-grown cells and chicken embryos, the siRNAs exhibited a powerful effect on the virus' ability to make new copies of itself. Moreover, the tested siRNAs worked even at extremely small amounts, opening the possibility that they might prevent the flu virus from gaining a foothold and turning into full-blown disease. Also, the researchers note, siRNAs are attractive as potential flu preventives or drugs because they could be given through the nose and upper respiratory tract where flu viruses first enter the body.
A 2003 paper, "RNA interference of influenza virus production by directly targeting mRNA for degradation and indirectly inhibiting all viral RNA transcription," in the Proceedings of the National Academy of Sciences by Dr. Chen and his colleagues describes the technique.
Dr. Chen notes several key benefits of using siRNAs to halt the influenza virus:
- A cocktail of siRNAs targeting different influenza virus genes can prevent the emergence of resistant virus strains
- In mice, siRNAs can be used to both prevent and treat influenza virus
- Because siRNAs are designed to target regions of the influenza virus genome that are less likely to mutate, they can be used to prevent or treat influenza strains of both human and avian origin
The latter two points were demonstrated in two studies, one published by Dr. Chen and colleagues in 2004 in Proceedings of the National Academy of Sciences, "Inhibition of influenza virus production in virus-infected mice by RNA interference," in which siRNA prevented and treated influenza virus infection in mice, including the highly pathogenic avian influenza viruses H5N1 and H7N7.
Additional publications about the use of siRNAs to prevent and treat flu by Dr. Chen and his colleagues include
- Expert Opinion on Biological Therapy (2005): "Polycation-mediated delivery of siRNAs for prophylaxis and treatment of influenza virus infection"
- Virus Research (2004): "Use of siRNAs to prevent and treat influenza virus infection"
Blocking the Entryways
At the biotech company NexBio in San Diego, CA, NIAID grantee Mang Yu, Ph.D., is developing a kind of drug called a fusion protein, which is designed to guard against multiple flu strains. If successful, not only would such a drug be a strong weapon to fight the seasonal flu, but it could be on standby in case of an outbreak of pandemic flu.
Before it can cause disease, the flu virus must first enter a human cell. To enter, the virus passes through a gateway (receptor) on the cell's surface. NexBio is developing fusion proteins that disable receptors located on cells in the airway passages to render them inaccessible by flu virus particles.
Dr. Yu and his colleagues at NexBio are currently developing this fusion-protein drug, called Fludase, so that—as an inhalant—it can be applied to the upper airway surface for both prevention and treatment of flu viral infections. Whereas most inhalants are systemic drugs that enter the bloodstream and travel throughout the body, Fludase sticks onto the surfaces of the respiratory tract, allowing the drug to function only in the desired areas.
NexBio has successfully completed studies to assess Fludase efficacy and safety issues in two animal models. In 2005, the company began the application process for an Investigational New Drug with the U.S. Food and Drug Administration and is manufacturing Fludase for further laboratory studies and clinical trials.
Although NexBio is taking a novel approach to fight influenza virus, Dr. Yu and his colleagues are veteran drug developers in the field of respiratory viral infections. They have previously used special antibodies to block the entry of human rhinovirus, the cause of the common cold, into cells. Their cold virus research has led to a promising drug candidate, CFY 196, which was described in a 2003 paper, "Viral receptor blockage by multivalent recombinant antibody fusion proteins: inhibiting human rhinovirus (HRV) infection with CFY196," in The Journal of Antimicrobial Chemotherapy.
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