June 15, 2008 (Vol. 28, No. 12)
Rapidly Emerging Technology Has Potential to Treat Hemophilia, AIDS, and Cancer
Whether it’s vaccines, protein production, or biotherapeutics, lentiviral vectors are increasingly being recognized for their central role as an enabling technology. The ability of lentiviral vectors to stably and efficiently deliver heterologous genes into mammalian cells opens a new gateway to the creation of medicines. At Lentigen (www.lentigen.com), we view them as comparable to the microchip—the unifying technology of the electronics industry.
Use as Cellular Engineers
Lentiviruses are part of the retrovirus family, which is unique in its ability to permanently engineer mammalian cells and modify their genetic character. Vectors, as all good Latin scholars know, are bearers or carriers. In this case, they are carriers of genes into the DNA of target cells.
Scientists have learned that lentiviral vectors are especially effective at introducing new genes into cells and importantly can do so permanently and with high efficiency in both dividing and nondividing cells. This sets lentiviruses apart as virus vectors. Other vectors such as plasmids cannot deliver genetic payloads permanently with high efficiency. Onco-retroviral vectors can only transfect when they are actively dividing and are unable to match the high efficiencies of transfection seen with lentiviral vectors.
The ability to include a safety gene in the transfection payload, one which when activated can remove the transfected cells, provides an important capability to reverse engineer should it be necessary to manage a safety event, for example.
Role in Production
Today’s protein-production processes typically measure their success in single-digit grams per liter. With these productivity limits, manufacturers are committed to large and expensive bioreactors. Current technology is also leaving potentially important proteins on the lab bench, as they are difficult to express in practical quantities.
Lentiviral vector transfected cell systems are now achieving titers in excess of several grams per liter, offering the promise of higher yields, smaller bioreactors, and improved economics. This is attracting the attention of biogenerics manufacturers who are seeking improved economics and from the research community, which is seeking to express biotherapeutics, especially those that are difficult to express in current systems.
Hen’s Eggs vs. Bioreactors
Early each year, government agencies and vaccine manufacturers make critical choices regarding the influenza strains to be included in the next season’s flu vaccine. These decisions have significant public health consequences.
If choices could be made later in the year, the ability to accurately predict the prevailing influenza strains would be improved. Unfortunately an early decision is required because of the lead time to produce the vaccine in the traditional hen’s egg-batch production systems. For pandemic influenza, the ability to respond rapidly and scale up production efficiently is similarly clear.
Imagine instead a world where influenza vaccines could be produced in several weeks rather than several months, in continuous rather than batch culture, and at a lower cost. Lentiviral vector-based influenza vaccines modeled upon virus-like particles offer this potential and are in development. In addition to providing these potential benefits, they avoid the problem of genetic drift so users consistently get the strains they want.
All the body’s components are genetically represented in the human genome. Each disease, whether it is genetic, infectious, or environmentally caused involves a genetic component. The ability to alleviate or cure diseases through the genetic axis has tremendous potential. Potential cures for hemophilia, AIDS, and various forms of cancer are in progress.
In hemophilia A, lentiviral vectors could be used to express the Factor VIII protein by engineering the body’s hematopoetic stem cells. The gene would be delivered into stem cells using a lentiviral vector that efficiently delivers payloads to these cells. Other diseases, particularly blood related, could be effectively targeted by lentiviral vectors that express specific payload genes to alleviate various diseases. This could be achieved by either regenerating various cells and tissues or restoring endogenous production of a particular biochemical.
Although current drug therapies can effectively manage AIDS, they do not represent a cure. The problem with long-term management of AIDS with antiretroviral drug therapy is the cumulative toxicities endured with prolonged drug use. In addition, viral resistance is making these therapies increasingly ineffective. A lentiviral vector armed with an anti-HIV payload gene could be delivered into the cells that HIV intends to infect, making them resistant to infection.
The efficient delivery properties of lentiviral vectors could also be used to deliver genes in a variety of anticancer strategies, including stem cell therapy. One method is to improve existing therapies by limiting their toxicity. Lentiviral vectors are now being used to deliver detoxifying genes to make these cells resistant to the toxic effects of chemotherapy.
Making It Happen
The lentiviral vector field has seen significant progress in the last decade. Much has been learned along the way, improving the technology and maximizing safety for clinical use. Although it is still an emerging technology, its central, enabling role in many aspects of tomorrow’s medicine is clear and is witnessing increased momentum.
Tim Ravenscroft is CEO at Lentigen. Web: www.lentigen.com.