Science fiction? Aerosol delivery of an engineered virus halts lung cancer progression in mice
July 4, 11:29 AM
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Nasal sprays containing special viruses may revolutionize the field of pharmacology to correct a multitude of devastating genetic and sporadic human diseases including lung cancer. Lung cancer in conjunction with liver and pancreatic cancer are aggressive and common manifestations of this disease worldwide. Lung cancer tops the list with over 1.3 million deaths worldwide. Currently, the prognosis for lung cancer is extremely poor and multiple options for treatments include surgical removal of lung tumors, chemotherapy and radiation. Nowadays, scientists are relentlessly working to make gene therapy delivery to the lungs a viable alternative in order to correct a variety of pulmonary dysfunctions and illnesses which include cystic fibrosis, pulmonary fibrosis and lung cancer.
Different approaches for pulmonary gene delivery include intravenous injection, nasal or intratracheal instillation. On the other hand, aerosolized or intranasal gene delivery is a very attractive approach for treating lung cancer as it is a non-invasive, fast and an efficient delivery method with high a patient compliance rate.
So what are the current technologies that have been developed to make gene delivery possible to lungs in lung cancer patients?
Nowadays, biomedically engineered viruses are being used in certain academic and
Cryoelectron microscopy image of a
a lentivirus particle. Courtesy of the University
of Iowa Lentiviral Core Facility.
clinical institutions in small scale or large scale quantities to combat a variety of genetic diseases which include cystic fibrosis and hemophilia. Many classes of viruses have been used in the past by scientists to infect a variety of organs and tissues including adenoviruses, adeno-associated viruses, and retroviruses such as lentiviruses.
Lentiviruses are the most promising for gene delivery therapies since
this type of virus not only infects dividing cells but also infect non-dividing cells such as neurons. On the plus side, lentiviruses allow the long-term stable integration of their genes into the genome of target cells making it possible for researchers to correct congenital deficiencies in patients by using this technology. For instance, lentiviruses carrying a copy of the cystic fibrosis transmembrane receptor have successfully being used in mouse model of
cystic fibrosis to correct this disease.
Lentiviruses is a genus of the
Retroviridae family of whose members include the human immunodeficiency virus (AIDS virus), feline immunodeficiency virus (FIV), the causative agent of AIDS in cats, and the simian immunodeficiency virus (SIV), the causative virus of AIDS in chimps and monkeys. These viruses are used in small quantities to infect different mouse models of disease to test different hypothesis or used in large scale quantifies for clinical applications. Of course, there is the concern that these viruses may expose the researcher or patients to the risk of developing AIDS. However, academic and federal regulations obligate scientists to take necessary safety precautions and commercially lentiviruses are modified to make them non-pathogenic. The genomes of these viruses are modified to make them replication deficient and to only induce a single round of infection. For instance, modifications of lentiviruses include deletions of accessory genes (
gag, env and
pol) or the genome is cut into pieces and re-packaged in more than one vector. Thus in the inconvenient event of an accidental breach in the laboratory, these lentiviruses will not survive outside the laboratory and are replication deficient. To increase their infectivity to allow researchers to infect a whole variety of cell lines, the the vesicular stomatitis virus glycoprotein (VSVG) has been added to lentiviruses to allow them to infect but a whole range of tissues including brain.
One ground-breaking study have shown the validity and practical application of lentiviruses to correct lung cancer in mice.
In the June 15 edition of the
American Journal of Respiratory and Critical Care Medicine, South Korean scientists have engineered a novel intranasal delivery of special viral particles that express a tumor suppressor gene to blunt cancer progression in mice. Tumors form due to an accumulation of mutations in several genes in the cell over time which aberrantly tip the balance of many signaling pathways in cells which lead to the slow progression of neoplasms (adenomas) into a malignant tumor, and ultimately form metastases. Dr. Cho and colleagues targeted the Akt (a protein kinase) signaling pathway.
Akt is a master regulator of cell survival and cell proliferation and a persistent increase in the Akt signaling can lead to a transformation of normal cells into cancer cells in vitro and in vivo. In further support of this observation, a plethora of gene expression and proteomics profiling studies in lung and many other types of cancer have demonstrated that the Akt signaling pathway is up-regulated. Moreover,
the Akt gene is amplified in many cancer cells just like the epidermal growth factor receptor is overexpressed in breast cancer. Relevant to lung cancer, it has been found that 90 percent of non-small cell lung carcinomas were associated with an aberrant activation of the Akt signaling pathway. Dr. Cho chose a commercial lentiviral vector for the same reasons that these type of viruses infect non-dividing cells and promote persistent and table genetic changes in cells. Dr. Cho and colleagues further modified the lentiviral vector to include a negative regulator of Akt signaling, carboxyl-terminal modulator protein (CTMP). This bioengineered CTMP lentiviral vector was repackaged with specific viral components and amplified by infecting a human renal cell line (ie., NIH 293 cells). The supernatant containing the virus was collected from the infected cells, concentrated, lyophilized, vaporized and contained in aerosol sprays.
The scientists then
wanted to determine whether intranasal delivery of the CTMP lentivirus is able to suppress lung cancer progression in mice containing lung tumors. Thus by generating this lentivirus, Dr. Cho postulated that the progression of lung cancer may be halted by inhibiting the Akt signaling pathway in cancer cells by overexpressing CTMP in the lung.
Indeed, their results showed just that. Long-term repeated intranasal delivery of CTMP containing lentiviruses particles (twice a week for one month) effectively reduced tumor progression in the lungs at different stages of development in a mouse model of lung cancer (K-rasLA1 mice). Histopathological analyses showed a significant reduction in the number and size of lung tumors and led to a near complete absence of bronchoalveolar tumors. This is a very important piece of data because it shows that the progression of cancer is halted at the benign state (adenoma) and does not develop in the bronchioles.
So how does CTMP halt cancer progression? Using biochemical analysis to analyze the expression levels of certain proteins, scientist found that overexpression of CTMP shut down not only Akt signaling but also protein synthesis, proliferation, angiogenesis and cell cycle progression of lung cancer cells while normal cells were not affected. Not only was lung cancer progression halted in 9-week old mice but the authors of the study found that cancer cells died from apoptosis.
Unlike chemotherapy which preferentially affects cancer cells but still has deleterious consequences to normal tissue after prolonged treatment,
lentiviral mediated gene therapy “surgically” targets tumor cells while sparing normal tissue.
Dr. Cho’s concluding remarks stated that "Repeated aerosol gene delivery may provide an effective noninvasive model of gene delivery and understanding the role of CTMP in the multistage lung tumorigenesis may be essential in developing effective therapeutics for lung cancer.” These results will open the door towards patenting and openly marketing this technology in the US. More importantly, the use of many different biomedically engineered lentiviruses to treat a variety of genetic and sporadic human illnesses and can attract venture capitalism for creating start-up companies in the US. Obviously, patenting this technology will have to undergo major scrutiny in the US through the conventional, protracted and painstaking process of FDA clinical trials before aerosolized or injectable lentiviral particles may be available for gene therapy.
For more information:
To read the original press release:
www.eurekalert.org/pub_releases/2009-06/ats-vvv060809.php#
http://www.examiner.com/x-11432-Pittsburgh-Medical-Technology-Examiner~y2009m7d4-Science-fiction-Aerosol-delivery-of-an-engineered-virus-halts-lung-cancer-progression-in-mice
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