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THE FOREVER FIX – GENE THERAPY AND THE BOY WHO SAVED IT
CHAPTER QUESTIONS
CHAPTER 2
1. Describe Corey’s symptoms leading up to his diagnosis?
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2. Theorize why Corey’s pediatrician didn’t know his condition was genetic?
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3. What did Corey’s ERG show and explain what it means?
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CHAPTER 3
1. Sketch an eye labeling – pupil, lens, iris, retina, and optic nerve.
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2. Distinguish where in the eye rhodopsin is located and discuss what is it?
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3. Explain the function of RPE65 protein?
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4. Where does the name for LCA come from?
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5. Construct a chart showing the causes doctors could eliminated for Corey’s blindness?
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6. Estimate how much a gene test cost at John and Marcia Carver Nonprofit Genetic
Testing Lab?
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7. Who started Project 3000 and describe its purpose.
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8. Discuss how you think Corey felt about sitting in the back of the classroom and support
your thoughts with an example from your life of a similar situation?
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9. Predict why Corey’s new found vision effected the field of gene therapy.
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CHAPTER 4
1. Organize and describe the advancements in bone marrow transplants since 1957.
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2. Organize and describe the advancements in cancer chemotherapy since 1948.
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3. Discuss how Edward Jenner used James Phipps in a human experiment in 1796. Support
whether you agree or disagree with his experiment.
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4. Do you believe the informed consent documents Barney Clark signed where complete?
Support your answer?
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5. What benefits came from Barney Clarks’ artificial heart transplant?
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6. Do you think parents of a desperately sick newborn can give informed consent? Support
your answer?
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7. Are experiments meant to help a particular patient or to advance a therapy that could
one day help many? Support your answer.
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CHAPTER 5
1. Describe Jesse Gelsinger’s genetic disorder.
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2. Jesse was mosaic for OTC. Describe what mosaic means and predict why this allowed
Jesse to live longer than most children with OTC.
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3. Jesse was only mildly affected by OTC. Support why he decide to do the gene therapy?
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4. Describe viruses and how they are used in gene therapy?
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5. Describe how Jesse’s clinical trial was supposed to happen.
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6. Describe Lesch-Nyhan syndrome.
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7. Describe familial hypercholesterolemia FH.
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8. What is a vector and compare that to how it is used in gene therapy?
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9. What is the worst characteristic of a viral vector in gene therapy? Support your answer.
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10. Why were the IRB’s set up in the 1960’s?
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11. Why was RAC set up in the 1970’s?
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12. Discuss the regulatory maze the OTC deficiency trial had to go through before it was
approved.
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CHAPTER 6
1. Reconstruct the events that led up to Jesse’s death.
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2. Order the major events that took place after Jesse’s death on Sept 17, 1999?
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3. What was determined at the 3 day RAC meeting about Jesse’s death?
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4. On Jan 19, 2000 the FDA completed its investigation of the OTC deficiency clinical trial
citing 18 specific violations. What were some of the violations?
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5. James Wilson had to write a paper “Lessons Learned”. Discuss the main points in the
paper?
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6. Jesse’s father was not happy with the punishment given to those responsible for the
clinical trial that led to his son’s death. What were the punishments and do you agree with
them? Support your answer.
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CHAPTER 7
1. Distinguish between SCID and SCID-X1?
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2. What did David Phillip Vetter, the bubble boy, die from?
*Cancer of the lymphatic system, lymphoma caused by Epstein-Barr virus in his sister’s bone
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3. Construct a list of genetic concepts a parent must suddenly master when their child is
diagnosed with a genetic disease.
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4. Explain “the code is universal” and why this is important for gene therapy.
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5. Explain what is wrong with a patient with CF.
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6. Describe the famous meeting in 1975 at the Asilomar conference.
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7. Distinguish between somatic gene therapy and germline gene therapy.
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8. What vector is now used the most?
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9. Analyze a few of the challenges with gene therapy for Beta-thalassemia?
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10. Describe ADA deficiency and how it was treated in the 80’s.
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11. Discuss some of the signs that Ashi’s gene therapy worked?
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12. Who was the second girl to receive gene therapy for ADA deficiency?
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13. Compare the gene therapy in Ashi and Cynthia verses Andrew and Zachary?
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CHAPTER 8
1. Defend why ADA deficiency was a good candidate for gene therapy?
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2. Describe the results in Dr. Alain Fischer gene therapy trial for SCID-X1?
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3. Detail how Dr. Donald Kohn’s researchers were more careful based on what they learned
from Dr. Alain Fischer’s clinical trials.
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4. In August 2011, the National Institutes of Health announced a new program in its
“Common Fund,” which Congress enacted in 2006 to encourage within-agency
collaborations. The new program is in “Gene-Based Therapeutics: Manipulating the Output
of the Genome to Treat Disease.” What do you think this will do to gene therapy? Support
your answer.
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5. Jolee Mohr had gene therapy for rheumatoid arthritis. She died shortly after her second
injection. Why did she die?
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6. Discuss how the failures in trials taught powerful lessons to those who plan and carry out
gene transfer experiments, in pursuit of gene therapies.
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CHAPTER 9
1. Describe how PKU was discovered, what it is, and how it is treated.
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2. How long should PKU patients have to stay on the special diet and why? Support your
answer.
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3. Describe what happens to patients with ALD.
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4. People with ALD have a type of neuroglia called microglia. Support why it makes ALD a
good candidate for gene therapy?
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5. Dr. Hugo Moser wrote “As a work of fiction, Lorenzo’s Oil is excellent, however as a
factual documentary it has three main flaws.” What were the flaws.
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6. What happened to Lorenzo Odone?
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7. After Oliver (Salzman) Lapin died of ALD his brother Elliott and his cousin Spencer
development symptoms. They had a new procedure done for patients that could not find
bone marrow transplants. Describe the new approach.
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8. What happened to Elliott and Spencer? Would you consider this a success?
Support your answer.
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9. What is IVF-PGD?
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10. Adam Nash was selected through IVF-PGD to save his six year old sister,
Molly to treat Fanconi anemia. His case was written about in “My sister’s Keeper”, which
depicted a teen suing her parents for intentionally conceiving her to save her sister’s
leukemia. How would you feel about it if you were conceived for the same reason?
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11. The Salzman sisters met with James Wilson. He was the doctor under investigation for
Jesse Gelsinger’s death. He helped them put together a team to do a clinical trial for ALD
gene therapy. Compose a list of what this gene therapy trial should include?
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12. What is the lentivirus? Why is it a great viral vector?
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CHAPTER 10
1. Describe the symptoms of GAN – Giant axon disease.
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2. In 2000 the mutated gene location was found for GAN. Describe where is it located and
what it does?
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3. Compose a description of what an ‘orphan genetic disorder’ is?
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CHAPTER 11
1. Lori and Matt Same, Hannah’s parents, did a lot of fund raising through Hannah’s Hope
Fund for GAN. Predict what the money was needed for?
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2. Describe pseudoxanthoma elasticum, or PXE.
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3. Describe spinal muscular atrophy, or SMA.
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4. Distinguish between a Phase I, II, and III clinical trial.
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5. How long and how much does it take to get a drug on the market?
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6. What are the biggest challenges for treatment of rare genetic disorders?
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CHAPTER 12
1. Describe Canavan disease.
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2. Canavan disease seemed a good candidate for gene therapy. What was the main
stumbling block?
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3. Why did Paola Leone take on gene therapy for canavan?
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CHAPTER 13
1. Construct a chart of genetic diseases that are higher in the Jewish population.
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2. Analyze why there are so many genetic diseases that are higher in the Jewish population.
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3. Describe how Dor Yeshorim, Hebrew for “upright generation”, got started and what it is.
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4. Labeling an inherited disease as “Jewish,” such as Tay-Sachs or Canavan disease, can
hampered diagnoses in patients of other backgrounds. Discuss why.
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CHAPTER 14
1. The Canavan gene patent conflict began in 1981. Daniel and Debbie Greenberg were
very involved and started the Chicago chapter of the National Tay-Sachs and Allied
Diseases Association. They recruited Dr. Matalon to develop a prenatal test for Canavan
disease so that couples could avoid having children as sick as their own. He later gets a
patent on the Canavan gene. Defend why the parents were so upset by this patent?
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2. Describe the consequences once the patent was given in 1997 for the Canavan Gene?
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3. Describe Henrietta Lacks and her cervical cancer (“ HeLa”) cells, and John Moore and his
celebrated spleen cases and discuss how you feel about what happened to them.
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CHAPTER 15
1. Describe the gene therapy procedure that Lindsay Karlin and Alyssa Mushin went through
for Canavan in 1996.
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2. Dr. During faced a lot of criticism for performing the Canavan gene therapy trial in New
Zealand. He said, “he might get approval there in a few months, where here it would take
years.” Do you think this was the right thing to do? Support your answer?
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3. Analyze the data that showed the, 1996, gene therapy was working in Lindsay and Alyssa.
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4. Distinguish between the gene therapy procedure that Jacob Sontag, Max Randell and
Lindsay Karlin, went through for Canavan in 1998 to the 1996 trial.
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5. By 1999 Paola Leone was developing a viral vector for a new trial. Why did she want to
use a virus and what stopped further trial until 2001-2002?
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6. Distinguish between the third gene therapy procedure done on Jacob Sontag, Max
Randell, Lindsay Karlin and 15 other children in 2001-2002 and the 1998 trial.
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7. After the third try, gene therapy for Canavan disease seems to have faded away. Why?
* The reasons are complex, but center around the severity of Canavan disease and the
limited, if lasting, improvement following gene therapy.
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8. What happens after gene therapy? Have the incremental changes justified the risk? The
parents think so. Describe how each family felt about their child having gene therapy for
Canavan. (Lindsay Karlin, Jacob Sontag, Lana Swancey, and Max Randell)
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9. The emotionally wrenching Canavan stories has raised the question of whether a partial
forever fix, a stalling or slowing of disease progression, is a worthwhile goal. What do you
think? Support your answer.
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CHAPTER 16
1. Explain what the exome is?
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2. The fact that the same mutation is found in all night-blind Briard dogs indicates a founder
effect. Explain what founder effect is and hypothesis as to how this happens.
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3. Dr. Narfström examined a breeder’s Briards. 5 of them had night blindness and they were
diagnosed with congenital stationary night blindness (CSNB), an older and broader
descriptive term that includes Corey’s disease. She predicted it was recessive inheritance.
What evidence did she use to make this decision?
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4. Compare the hybrid crosses Dr. Narfström did with dogs to the famous experiments of
Gregor Mendel
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5. Why do you think the discovery of the blind Briards was important to Corey’s gene
therapy? Support your answer.
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6. An animal model of intermediate size that has been important in the development of
gene therapy for LCA is Gallus gallus— the chicken. A flock of Rhode Island Reds at the
University of Florida is being studied. What was learned from the experiment being done on
birds and how is it useful in gene therapy trials for humans.
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CHAPTER 17
1. Construct a chart showing different breeds of dogs and they’re form of a human disorder.
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2. Describe the role of animals used in preclinical trials.
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3. Describe hemophilia B.
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4. In a clinical trial at CHOP for hemophilia B the virus (AAV) that carried the clotting factor
gene into a man’s liver took a detour to his semen. If the vector wound up inside sperm cells,
then its cargo could, theoretically, be ejaculated into the next generation. Such “germline
gene therapy” is a big enough ethical no-no. Discuss why it is a no-no.
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5. Describe what the doctors saw when they dissected 4 eyes from the blind dogs that
made them think they could restore vision.
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6. After dissecting more of the dog eyes at various ages the scientist could show the
progression of the disease. Describe their findings and what they meant.
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7. In 1997 and 1998, a convergence of research pathways confirmed the hypothesis that
the Braird dogs had LCA. What where these findings.
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8. Why was LCA2 a perfect candidate for gene therapy?
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9. Explain the gene therapy procedure done on Lancelot the first Briard dog.
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10. Kristina Narfström’s contribution to the discovery of RPE65 and her work on gene therapy
on LCA leading up to Corey’s gene therapy was left out of the records in the beginning. This
was mainly due to miscommunication by reporters. How would you feel if this was your life’s
work?
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11. Narfström’s group published a series of papers on dogs they’d treated with gene therapy
in 2001 and 2002 in The Journal of Heredity— a nice-enough publication, but one devoted to
“organismal genetics.” What did this allow her to do?
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12. What did Narfstrom hypothesis was happening when the dogs untreated eye also
started to improve.
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13. Dissecting the dog eyes reveals what is going on in a way that couldn’t happen in a
human clinical trial. What did the scientists learn?
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CHAPTER 18
1. There were many gene therapy trials for LCA at the same time. Why was that necessary?
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2. What did Hauswirth-Jacobson team learn from their patients treated in 2008?
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3. As time goes on it appears that the LCA2 gene therapy is indeed sustained, for an
impressive percentage of the patients. However no one has had full recovery. Why do you
think this is true? Support your answer.
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4. The NIH provides extensive guidelines on how to handle communication around informed
consent, for kids and adults. Their documents offer examples in seventh-grade-level
language. Give examples.
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5. What are the steps in a clinical trial.
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*Step 7
6. Jesse’s trial was a dose-escalation design. Explain how this works.
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CHAPTER 19
1. Corey Haas went to CHOP for his year check up after his gene therapy. Kathy Marshall,
clinical research coordinator and ophthalmologic technician ran various tests on Corey.
Explain each of the tests.
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2. The FDA the mobility course in the protocol because “Some people said, ‘Get rid of the
mobility test! It’s unscientific! It’s psychological, about learning and coordination!’. Do you
agree? What did Al Maguire say?
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3. After three days of tests Corey refused to do the last test. Hypothesize as to why?
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Chapter 20
1. Describe how Lucentis and Avastin work.
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2. The jump from Corey’s disease, LCA2, to wet age-related macular degeneration
elegantly demonstrates how a gene therapy strategy used to treat a very rare disease can
be applied to a very common one. Two million people have wet AMD in the United States
alone. Compare gene therapy for Corey’s genetic disorder to gene therapy for AMD.
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3. Hypothesize why pharmaceutical companies are not very willing to participate in gene
therapy.
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4. Medical breakthroughs from the past half century reveals not a series of cures, but the
creation of chronic conditions that lock in steady markets. List some examples of not curing
an illness but just treating it with a drug.
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5. If pharmaceutical companies are not during gene therapy who is?
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6. How much does gene therapy cost?
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7. Gene therapies that have already been complete are helping pave the way for treating
more common problems. Give examples.
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8. Gene therapy will be the forever fix. Do you believe this statement. Support your answer.
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