Learning objectives
Learning Objectives
By the end of this section, you will be able to:
- Summarize the mechanisms, risks, and potential benefits of gene therapy
- Identify ethical issues involving gene therapy and the regulatory agencies that provide oversight for clinical trials
- Compare somatic-cell and germ-line gene therapy
Many types of genetic engineering have yielded clear benefits with few apparent risks. Few would question, for example, the value of our now abundant supply of human insulin produced by genetically engineered bacteria. However, many emerging applications of genetic engineering are much more controversial, often because their potential benefits are pitted against significant risks, real or perceived. This is certainly the case for gene therapy, a clinical application of genetic engineering that may one day provide a cure for many diseases but is still largely an experimental approach to treatment.
Mechanisms and Risks of Gene Therapy
Human diseases that result from genetic mutations are often difficult to treat with drugs or other traditional forms of therapy because the signs and symptoms of disease result from abnormalities in a patient’s genome. For example, a patient may have a genetic mutation that prevents the expression of a specific protein required for the normal function of a particular cell type. This is the case in patients with Severe Combined Immunodeficiency (SCID), a genetic disease that impairs the function of certain white blood cells essential to the immune system.
Gene therapy attempts to correct genetic abnormalities by introducing a nonmutated, functional gene into the patient’s genome. The nonmutated gene encodes a functional protein that the patient would otherwise be unable to produce. Viral vectors such as adenovirus are sometimes used to introduce the functional gene; part of the viral genome is removed and replaced with the desired gene (OSC_Microbio_12_01_GeneTher). More advanced forms of gene therapy attempt to correct the mutation at the original site in the genome, such as is the case with treatment of SCID.
View original figure (external; image not reproduced in this text edition)
Original figure description: A diagram of gene therapy. A virus vector contains modified viral DNA that includes an inserted gene. First the vector binds to the cell membrane. The vector is then packaged in a vesicle. The vesicle then breaks down releasing the vector. The cell now makes protein using the new gene.
So far, gene therapies have proven relatively ineffective, with the possible exceptions of treatments for cystic fibrosis and adenosine deaminase deficiency, a type of SCID. Other trials have shown the clear hazards of attempting genetic manipulation in complex multicellular organisms like humans. In some patients, the use of an adenovirus vector can trigger an unanticipated inflammatory response from the immune system, which may lead to organ failure. Moreover, because viruses can often target multiple cell types, the virus vector may infect cells not targeted for the therapy, damaging these other cells and possibly leading to illnesses such as cancer. Another potential risk is that the modified virus could revert to being infectious and cause disease in the patient. Lastly, there is a risk that the inserted gene could unintentionally inactivate another important gene in the patient’s genome, disrupting normal cell cycling and possibly leading to tumor formation and cancer. Because gene therapy involves so many risks, candidates for gene therapy need to be fully informed of these risks before providing informed consent to undergo the therapy.
Oversight of Gene Therapy
Presently, there is significant oversight of gene therapy clinical trials. At the federal level, three agencies regulate gene therapy in parallel: the Food and Drug Administration (FDA), the Office of Human Research Protection (OHRP), and the Recombinant DNA Advisory Committee (RAC) at the National Institutes of Health (NIH). Along with several local agencies, these federal agencies interact with the institutional review board to ensure that protocols are in place to protect patient safety during clinical trials. Compliance with these protocols is enforced mostly on the local level in cooperation with the federal agencies. Gene therapies are currently under the most extensive federal and local review compared to other types of therapies, which are more typically only under the review of the FDA. Some researchers believe that these extensive regulations actually inhibit progress in gene therapy research. In 2013, the Institute of Medicine (now the National Academy of Medicine) called upon the NIH to relax its review of gene therapy trials in most cases.Kerry Grens. “Report: Ease Gene Therapy Reviews.” The Scientist, December 9, 2013. http://www.the-scientist.com/?articles.view/articleNo/38577/title/Report--Ease-Gene-Therapy-Reviews/. Accessed May 27, 2016. However, ensuring patient safety continues to be of utmost concern.
Ethical Concerns
Beyond the health risks of gene therapy, the ability to genetically modify humans poses a number of ethical issues related to the limits of such “therapy.” While current research is focused on gene therapy for genetic diseases, scientists might one day apply these methods to manipulate other genetic traits not perceived as desirable. This raises questions such as:
- Which genetic traits are worthy of being “corrected”?
- Should gene therapy be used for cosmetic reasons or to enhance human abilities?
- Should genetic manipulation be used to impart desirable traits to the unborn?
- Is everyone entitled to gene therapy, or could the cost of gene therapy create new forms of social inequality?
- Who should be responsible for regulating and policing inappropriate use of gene therapies?
The ability to alter reproductive cells using gene therapy could also generate new ethical dilemmas. To date, the various types of gene therapies have been targeted to somatic cells, the non-reproductive cells within the body. Because somatic cell traits are not inherited, any genetic changes accomplished by somatic-cell gene therapy would not be passed on to offspring. However, should scientists successfully introduce new genes to germ cells (eggs or sperm), the resulting traits could be passed on to offspring. This approach, called germ-line gene therapy, could potentially be used to combat heritable diseases, but it could also lead to unintended consequences for future generations. Moreover, there is the question of informed consent, because those impacted by germ-line gene therapy are unborn and therefore unable to choose whether they receive the therapy. For these reasons, the U.S. government does not currently fund research projects investigating germ-line gene therapies in humans.
Key Concepts and Summary
- While gene therapy shows great promise for the treatment of genetic diseases, there are also significant risks involved.
- There is considerable federal and local regulation of the development of gene therapies by pharmaceutical companies for use in humans.
- Before gene therapy use can increase dramatically, there are many ethical issues that need to be addressed by the medical and research communities, politicians, and society at large.
Multiple Choice
At what point can the FDA halt the development or use of gene therapy?
- on submission of an IND application
- during clinical trials
- after manufacturing and marketing of the approved therapy
- all of the answers are correct
D
Fill in the Blank
_____________ is a common viral vector used in gene therapy for introducing a new gene into a specifically targeted cell type.
Adenovirus
Short Answer
Briefly describe the risks associated with somatic cell gene therapy.
Critical Thinking
Compare the ethical issues involved in the use of somatic cell gene therapy and germ-line gene therapy.