- to suppress the growth of the tumor/diseased cells but not kill the cells; these are called GROWTH SUPPRESSIVE GENES
- to replace a deficient, defective, or lacking-gene product; these are called THERAPEUTIC GENES
Scientists have to develop vectors that won’t cause inflammation and immune recognition so that these genes will not actually make the tumor worse (Chiocca 4). Vectors also have to be targeted as specifically as possible (reach the focal point of the problematic area) and not cause uncontrolled growth.
There are many types of vectors that are currently being tested, including the retrovirus vectors, adenovirus vectors, HSV recombinant vectors, AAV vectors, and others.
A retrovirus is a group of RNA-containing viruses in which the DNA is synthesized from an RNA template (Nester 815). In normal gene replication, the DNA is the “blueprint” of our genes. Because DNA cannot travel outside of the nucleus, a copy of the DNA is made, called RNA. The new gene (RNA) can then travel outside the cell be copied unto other cells. So a retrovirus does exactly the opposite of what normally happens. Instead, a copy is made from the RNA, which in turn becomes DNA (thus a retrovirus changes the “blueprint” of our genes). A retrovirus is very dangerous as displayed in the case of HIV, but in the case of gene therapy the new genes are ones that will benefit the host, not harm the host.
Retrovirus
An adenovirus contains DNA that’s shaped like a 20-sided polyhedron that may cause a respiratory disease, but again, scientists have found a way to change this virus to benefit the host (Webster).
Adenovirus—
Courtesy of Dr. Stephen Fuller
A HSV recombinant refers to a term that involves the herpes virus and cut up DNA molecules that are spliced to form specific DNA fragments (Webster).
Herpes Virus—Courtesy of Dr.
Linda M. Stannard
The other type of vector, AAV stands for adeno-associated virus—a defective small single-stranded DNA virus that includes a causative agent for an extreme type of rash (Webster). AAV is only capable of replication with the help of the adenovirus or herpes virus.
You many wonder then, how exactly is the vector delivered? The vector is delivered through an injection either into the cerebrum or directly into the tumor itself (Chiocca 297). Injecting a gene through a needle may sound easy, but keep in mind of the complexities of the brain. The blood brain barrier, for example, makes it difficult to transfer a gene. “The blood brain barrier is a barrier that’s created by brain capillaries that prevents substances from leaving the blood and crossing the capillary walls into the brain tissues” (Chiocca 295). Therefore, even though a gene may be inserted into the brain, it may not be delivered to the location as desired. Another problem scientists face is the inability to inject a large number of cells at a time and so the preferred amount of cells may not be delivered.
With all the technical terms and definitions, it may be difficult to see how all this works, so here’s an example of how the attenuated adenovirus would be used on a patient: a virus carries the gene for thymidine kinase, an enzyme for the herpes simplex virus (University of Pennsylvania Health System). After an injection of this gene, the patient is then given an antiviral drug GANCICLOVIR, intravenously (University of Pennsylvania Health System).
Then: GANCICLOVIR + thymidine kinase → becomes a chemical that cripples DNA synthesis of the diseased cells
This in turn will stop the tumor from growing. Of course, this idea will not work if the tumor cells do not take up the gene for thymidine kinase. However, results for this method have shown that the gene was successfully delivered to the cancer cells; unfortunately, toxicity was also seen. Overall though, “the treatment appeared to lengthen the survival of the patients enrolled in the trial” (University of Pennsylvania Health System). This treatment would be an example of using CYTOTOXIC GENES.
Results from the use of vectors have varied. Scientists continue to modify the vectors for a more efficient and safe delivery of the genes. The use of vectors seem promising as time progresses; however, that does not mean that scientists do not face many obstacles in this field.
Here is a case of a sad story:
“The whole thing [gene therapy] turns out to be far more complicated than first thought. And the whole effort suffered a severe setback when a teenage patient died during a gene therapy trial—apparently from the virus, not the introduced gene” (Wheelright).
Using a virus may seem ideal for delivering desired genes to the diseased cells. However, one cannot forget that it is still a virus, capable of causing fatal harm to a human if used incorrectly, and this was the unfortunate case with the teenage patient.
For now, a major problem that scientists currently face is finding a prototypical animal model to test improved vectors (Chiocca 313). The current models used under study are lab rats and even though this serves as a good start, a better model that resembles the human brain is needed.
Gene therapy for brain tumors is still at its beginning stages and no single vector has been perfected yet—further studies are still needed so that the method of gene transfer is efficient and safe. Through new and improved technology though, there is hope that one day gene therapy will be perfected if not become a crucial part in treating brain tumors. Chiocca says that “molecular biology is probably the right tool to address the basic questions and solve the classic problems of brain cancer, a disease of the genes” (223). This is a very new and exciting field indeed, and we shall wait to see where gene therapy will lead us.
Article written by: Shirley Tran
For more information about Gene Therapy, please visit the websites listed.
Works Cited
Chiocca, E. Antonio, and Xandra O.
Breakefield, eds. Gene Therapy for
Neurological Disorders and Brain
Tumors. Boston: Humana Press,
1998.
Fuller, Stephen, and Linda M. Stannard.
“Virology-Lecture Six: Oncogenic
Viruses.” Microbiology and Immunology: University of South Carolina, School of Medicine. 5 Mar. 2001 <http://www.med.sc.edu:85/lecture/RETRO.HTM>.
Johnson, Keith A., and J. Alex Becker.
“The Whole Brain Atlas.” Harvard Medical. 5 Mar. 2001 <http://www.med.harvard.edu/AANLIB/home.html>.
National Health Museum, “Diagram of a
Retrovirus.” Access Excellence: About Biotech. 5 Mar. 2001 <http://www.accessexcellence.org/AB/GG/diagram.html>.
Nester, Eugene W., et al. Microbiology:
A Human Perspective. 2nd Ed. Boston: McGraw-Hill, 1998.
University of Iowa. “University of Iowa
Researchers Find Potential Way To Improve Gene Therapy Delivery To Brain.” Science Daily. March 2000. 26 Feb. 2001 <http://www.sciencedaily.com/releases/2000/03/000322091215.htm>.
University of Pennsylvania Health
System. “An Arsenal of Promising Therapies: New Treatment for Brain Tumors.” Penn Today. 26 Feb. 2001 <http://www.med.upenn.edu/health/pf_files/penntoday/v10n1ca_1.html>.
Webster, Merriam. “Medical
Dictionary: The latest word on
medical terms.” Inteli-Health: The
Trusted Source. 27 Feb. 2001
<
IH/WSIHW000/331/9276.html>.
Wheelwright, Jeff. “Betting on Designer
Genes.” Smithsonian Magazine. Jan. 2001 <http://www.smithsonianmag.si.edu/smithsonian/issues01/jan01/gene.html>.