Sometimes it is All in the Genes

As Nancy used her cupped hands to pound on her son's back, she reflected on what her family had been through in the seven years since she had volunteered for the genetic screening research.  Joshua was a wonderful, loving son.  She wouldn't trade a minute with Joshua for anything in the world, but motherhood was not quite what she had envisioned in her dreams.  Raising a child with CF was tough, no way around it.  Joshua was lying on an incline with his head below his chest.  The angle and the vigorous chest percussion helped the mucus to move out of his lungs.  As a newborn, his first symptom of CF was overly salty sweat.  This is actually the most common diagnostic test for CF.  During his first months of life, Joshua didn't eat well and he had numerous loose bowel movements.  Since then, part of his daily regimen included supplements of digestive enzymes that substituted for those that his poorly functioning pancreas couldn't supply.  Fat-soluble vitamins helped him gain weight.  I'll never have to buy clothes in "husky." Nancy thought to herself.  But at least Joshua is now on the pediatrician's growth curves.

Just as the doctors had predicted, the biggest problem was with Joshua's lungs.  He was almost always on antibiotics.  These were usually taken by breathing in a medicated vapor from a nebulizer.  The medicated vapor also helped to open up the mucus-clogged airways.  However, hospital stays for intravenous antibiotics and "pulmonary clean-outs" were not uncommon.  So far, Joshua was doing well in school, but Nancy was concerned about the number of days he had to miss.  In fact, she would have to take him out of school early tomorrow to make their appointment at the pediatrician's office.

"Well, Joshua, it looks like you are doing great.  How is school?  Any more home runs in kickball?"  Although her extensive training meant that Dr. Julia Bryant had some of the sickest patients in town, her bedside manner meant that her little friends still liked to visit her.

"Yes!"  Joshua responded enthusiastically.  "I had one on Monday.  A grand slam!"

"Wow!  I wish I could have seen it.  Do you want to get down and play a little while I talk with your mother?"

"Sure, Dr. Julia."

For once, Julia's demeanor didn't lose any of its cheerfulness as she turned to Nancy.  "Joshua really is doing well.  You and Jake do such a good job with the home therapy."

Julia glanced over to see that Joshua was starting a jigsaw puzzle.  "You know how I had warned you off of gene therapy a couple of years ago when you asked me about it?"  Nancy nodded in agreement.  "There is a new cystic fibrosis gene therapy clinical trial over at People's Best.  They have asked us here at Children's Coolest Clinic for volunteers.  I'm not telling you to run out and get involved, but I do think that it's time to carefully consider it."

Experience had taught Nancy not to get too optimistic, but her pulse began to race nonetheless.  "Why should we consider it now?"

"I'm sure you remember that the first patient treated with gene therapy was a four-year-old girl back in the early 90s.  She had an inherited form of severe combined immunodeficiency, also known as the 'boy-in-the-bubble syndrome' or SCID.  Because the treatment was such a success, many people jumped on the gene therapy bandwagon.  Unfortunately, after those initial successes, gene therapy has not produced the hoped-for results."

Nancy did remember that and more.  "Didn't someone even die from gene therapy treatments?"

"Yes, in the fall of 1999 an 18-year-old man died from his gene therapy treatments.  Doctors were trying to correct his inherited enzyme deficiency.  That case is why I think we should be very cautious before we decide whether or not to get Joshua involved."

"First you don't think it's worthwhile.  Then someone dies, and now it's a good idea?  What aren't you telling me, Julia?"

"Well, in the spring of 2000, there were reports of two more successes with gene therapy.  The two patients also had the boy-in-the-bubble syndrome, not CF. However, their illness was caused by a mutation in a different gene than the first successful patients, meaning that gene therapy can work with other genes."

"That is encouraging, but what actually killed the young man who died?  Was the gene poisonous?"  Nancy was still focused on that death.

"No, the gene wasn't 'poisonous'.  The death had nothing to do with the gene itself but how the gene was delivered.  As you know, a gene is simply a stretch of DNA in the chromosomes of your cells.  In a recessive, inherited disease, the DNA in both copies of the gene, like the CFTR gene in Joshua's case, has errors in its code.  The goal of gene therapy is to get an error-free copy of the gene back into the patient's cells.  The new, good copy can then do the job for the patient's own bad ones.

"The trick is in inserting the good DNA into the patient's cells so that the gene is used by those cells.  The most heavily studied and commonly used means for this DNA delivery is using viruses.  One of those viruses is called adenovirus, which is one of the causes of the common cold.  Part of the virus's natural life cycle is to get its DNA inside human cells and have its genes used by the human cells.  To use adenovirus for gene therapy, researchers take the genes that cause illness out of the viral DNA and replace them with the human gene that the patient needs.  Unfortunately, the virus still causes the patient's immune system to respond and it tries to fight off the infection.  In the case of the man who died, doctors gave him a dose of adenovirus that was too high.  The virus escaped the target organ, the liver, and infected tissues throughout his body.  This caused an immune reaction that led to inflammation throughout his body.  His temperature shot up to 104.5º F, and he was in a coma on the second day.  Eventually, his lungs began to fill with fluid, so much so that he soon died."

"Why did the doctors give him too much virus?"

"They had no way of knowing it would be too much.  The previous work at lower doses suggested the higher level would be safe.  However, they apparently passed a critical threshold that no one could foresee."

"How do we know there won't be the same sort of hidden threshold in these CF gene therapy trials?"

"Until you and I find out more information about the specific clinical trials at People's Best, we don't.  Even then we probably won't be 100 percent sure.  Clinical trials are research, you know."

"Yes, but if Joshua could be helped...."  Nancy's voice trailed off momentarily.  "Besides the new boy-in-the-bubble success, what makes you think gene therapy might work now?"

"Well, different kinds of viruses that get the gene into cells by different means are being developed.  In addition, researchers are experimenting with using liposomes or fat droplets to deliver the gene to the target cells.  That would eliminate the risk posed by viruses.  I know that both of these approaches are being tested in clinical trials for CF, but I don't know yet which will be conducted here in town."  Julia felt guilty for not knowing more, but she had just heard about the program at People's Best and wanted to get Joshua in as early as possible.

"Liposomes?  That sounds like skin cream stuff."

"It is basically the same approach.  Just a little more sophisticated for gene therapy."  Julia brought the topic to a close for the day.  "If you are interested in finding out more, I'll set up an appointment for both of us with one of the leaders of the study.  We'll tag-team them with questions."

"Of course I want to find out more.  Boy, am I going to have a long discussion with Jake tonight!"

Questions:

1. The current therapies available to treat CF only treat the symptoms of the disorder.  However, if gene therapy were to work, it could be considered a cure rather than a mere treatment of the symptoms.  Explain why this could be the case.
2. "The successful use of gene therapy to cure SCID syndrome (2000) is hoped to be a permanent cure for those patients because a good copy of the problem gene was inserted into the patients' blood stem cells in the bone marrow (hematopoietic stem cells).  Once white blood cells enter the blood stream they have a limited life span, on the order of a few week to months.  The blood stem cells are the cells that create more white blood cells to replace those that are lost.  If the gene was only inserted into the circulating mature white blood cells, the patient would only be temporarily cured until those cells were used up or died."
   The current gene therapy approaches to cure CF involve inserting a functional CFTR gene into the mature epithelial cells of the lungs.  In light of the preceding paragraph, do you think that this approach would be a "permanent" cure for CF?  Explain your answer.
3. What level of risk should be acceptable for a patient involved in a clinical trial?  In other words, under what circumstances should Nancy feel comfortable enrolling Joshua in a gene therapy clinical trial?
4. In the current clinical trials for gene therapy treatments of CF, participants must be over 12, so Joshua could not be helped by the trials that are currently being run at this time.  Why might there be an age restriction such as this?  Is an age restriction such as this fair?
5. Should Joshua be enrolled in a clinical trial on cystic fibrosis gene therapy?

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