Gene Therapy for Cystic Fibrosis

Hopes and Heartaches

Robert Knorr

copyright 1996

Modern molecular genetics has given hopes and heartaches to thousands of people around the world. These people are looking towards gene therapy for an answer to their questions. To some people such as NIH director Harold Varmus the answer is a better understanding of basic genetic research and to others the answer is a cure, a hope, that their lethal disease will someday be cured. This essay touches on the background of gene therapy for Cystic Fibrosis (CF), current social and ethical issues facing gene therapy for CF, and some thoughts on the importance of this controversial subject.

Gene therapy is the application of the technique where the defect-causing "bad" genes are replaced by correct "good" genes. The idea of gene therapy is to treat the disease by correcting the "bad" DNA (Deoxyribonucleic acid) rather than the current me thod of providing drugs, or proteins not produced by the defective gene. Gene therapy addresses the problem first hand by directly working with the genetic information causing the disease. From the book Shaping Genes, Dr. Darryl Macer says "It is like f ixing a hole in the bucket, rather than trying to mop up the leaking water." There are two kinds of gene therapy, somatic cell gene therapy and germline gene therapy.

Somatic cell gene therapy is where genes can be put into specific cells and areas of the body which are affected by the disease. All cellular DNA in our body is essentially the same because it was replicated from the same zygote (fertilized egg). Cel ls differentiate into their respective tissues depending upon which part of the total genome is used.

Germline gene therapy is where the correct "good" gene is inserted into the germline in place of the defective "bad" gene, and when reproduction occurs the gene will be passed on to the progeny. Inserting the "good" gene into the very early embryo sta ges of development allows for both germline and somatic cells to be corrected. Government has limited the research to only somatic cell gene therapy such as performed in Cystic Fibrosis research.

Cystic fibrosis is one of the most common lethal mutations in humans. The autosomal recessive allele is carried by 1/20 Caucasians, 1/400 couples will have children with the disease, and ľ children will be afflicted. If untreated, 95% of affected ch ildren will die before age five (Bell, 1996). There are over 30,000 Americans who currently suffer from CF. With continuous and expensive treatment, survival can be extended into their 20ís. Their bodies have a defective gene, Cystic Fibrosis Transmemb rane conductance Regulator (CFTR), that prohibits cells lining the lungs from transferring water and salts across their membranes. Their lungs become covered with mucus secretions causing infections. These infections can become severe and lead to death at an early age.

In 1989, the defective gene was found as a 250 kb long fragment with 24 exons. The gene was cloned for a final cost of $170 million (Bell, 1996). In at least 90% of CF patients, the mutation in CFTR is a three-nucleotide deletion that results in th e loss of phenylalanine (Featherstone, 1996). "In these patients, the mutant CFTR protein is synthesized at normal levels but it does not fold properly so it is not transported to the cell surface", says Bill Colledge of the University of Cambridge, UK.

Due to the nature of CF, it makes it an excellent candidate for gene therapy. Researchers have shown promise by being able to transfer a good CFTR working gene into the surface airway cells of lab mice. They have had trouble transferring sufficient q uantities of the CFTR gene into patientsí cells. The virus used as a vector has caused an immune reaction in some patients. Therefore a crucial objective is to find safe vectors that can transport genes efficiently into the target lung cells. In the fo llowing few paragraphs I will explain the positive and negative features of the three vectors, the retrovirus, adenovirus, and adeno-associated virus (AAV), of gene therapy being used by researchers today.

There are several features that make retroviruses the most popular vector used today in gene therapy. The easily produced modified "crippled" retrovirus can be loaded down with therapeutic genes for transfer. This is the most efficient agent identif ied for transferring genes. This retrovirus is used in "ex-vivo" procedures in which the cells are removed from the patient, treated, and then replaced.

Besides being difficult to produce in large quantities, retroviruses have a very low efficiency in transferring good genes into the defective cells. The expression of these cells has also been notably low but variable. The retroviruses insert themse lves randomly into their host DNA. This poses a small risk of cancer because if a retrovirus gene would settle near an oncogene or tumor suppresser gene, it might trigger tumor formation by turning on or off the native gene. Probably the main drawback i s that retroviruses insert genes into cells that are actively dividing and growing (T cells). This would eliminate the use of the retrovirus in treating CF because the target cells in our lungs arenít dividing.

Most CF research trials have used the "crippled" adenovirus. This virus naturally infects about 75% young people without causing illness. The adenovirus seeks the lungs, targeting the nondividing cells that will allow it to express the viral DNA. At high dosages, the adenovirus genes encode proteins that trigger an immune response. This provokes an acute inflammation of the lung cavity. These activities neutralize cells containing the adenovirus genes in them. Therefore, the minimized effects of the adenovirus will last up to six weeks. A second dose with the adenovirus vector would not be beneficial because the immune system will "remember" the antigen and attack it again with more vigor. A low initial dose would be inefficient because the vir us would not get into the nasal cavity nor airway cells and express the corrected CFTR gene.

A new vector being investigated today that holds potential is the adeno-associated virus (AAV). There are no known toxicities (nonimmunogenic) to this virus. The virus is only activated by the presence of a "helper virus." This would allow for more control and safety of the experiment. Also, due to the simpler life cycle of the virus it may persist and deliver genes for a longer time.

The promising new virus does come with some negative consequences. The virus is difficult to produce in large quantities. Also, the technology is inefficient and costly making the research and treatments more expensive to those seeking an answer.

There have been over 100 clinical trials started involving more than 600 Americans, and yet the millions of dollars spent by private and public industry has provided no significant results. Many questions are being raised right now about advancing gen e therapy research. Is the government getting its moneys worth? The NIH is questioning the placement of their funds: basic research on vectors or clinical trials involving gene therapy (some $200 million per year (Gorman, 1995)). The public expects t hat with the incredible sum of money available for gene therapy research results will come right away. What these people are not realizing is that with each experiment that takes place we are gaining knowledge. Science uses the scientific method as a mo del to follow for experimentation. This is a systematic procedure for gaining knowledge. In science, as much or more knowledge can be learned from the failures as can be the successes. The United States is getting itís moneys worth by furthering the u nderstanding in this fascinating field.

Should the entity that discovers the genetic therapy have the right to patent it? If the entity receives a patent, it will have protected their financial interest in the therapy. On a negative side, this will allow the entity to charge higher prices for the treatment and deny more people the treatment.

The work that is being done with gene therapy and cystic fibrosis must not stop. The public and press have overenvisioned the immediate results of gene therapy. Money should still be allocated to both basic molecular research and gene therapies. I t takes scientists from both areas working together to try and put the pieces of the puzzle of life in place.

Someday, someone or some people will find a genetic therapy for CF. That entity should have the right to patent their genetic therapy. The entity will have spent a lot of money finding and refining the technique, therefore they will need some sort o f protection. But there must be equal rights for all to receive itís benefit. Through working with the ethical, social, and legal programs of the scientific community, answers can be found ensuring that everyone will be treated fairly and equally.

Starting back in the early 1970ís, scientists have proven that they are concerned and are constantly acting on behalf of societies best interest. The unknown future is always scary but as long as safety parallels the gain of knowledge society will be nefit and endure. All areas of science, basic molecular research, somatic and germ-line gene therapies, etc..., need to keep striving forward at a regulated but not hindered pace.

Gene therapy is an incredibly fascinating field which holds promise for opening up new doors of knowledge and learning. As scientists acquire more knowledge through molecular biology and gene therapy they are not sealing our fate but reaching new leve ls of understanding. History has shown us that science will proceed, and learning will never end. How we decide to apply these new findings will form the future of mankind. In the thoughts of L.D. Loftsgard, it is up to us to employ our knowledge towar ds humane and positive ends ensuring hope to the thousands of children suffering from Cystic Fibrosis.


Begley, S. (1995, October 9). Promises, Promises. Newsweek, 126 (15), 60-63.

Bell, J. Cystic Fibrosis. Obtained from the WWW 10/25/96:

Featherstone, C. (1996, June 1). Old Hopes and New Horizons for Treating Cystic Fibrosis. Lancet, 347 (9014), 1544.

Gorman, C. (1995, October 9). Has Gene Therapy Stalled? Time, 146 (15), 62-64.

Macer, D.R.J. Shaping Genes: Ethics, Law and Science of Using New Genetic Technology in Medicine and Agriculture. Obtained from the WWW 10/20/96:

Marshall, E. (1995, August 25). Gene Therapy's Growing Pains. Science, 269, 1050-1055.

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