Marshall's "Gene Therapy on Trial" 2000
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| - | *Dusty Miller wants to find gene therapy for CF after death of Penn | + | *Dusty Miller wants to find gene therapy for CF after death of Penn volunteer |
**says we lack a good vector | **says we lack a good vector | ||
| - | **There is a general fear that nobody will do gene therapy reseach for a while because of the | + | **There is a general fear that nobody will do gene therapy reseach for a while because of the "crackdown" and recent negative media coverage |
*FDA cracking down hard on gene therapy trials | *FDA cracking down hard on gene therapy trials | ||
**shut down all trials at Penn after death | **shut down all trials at Penn after death | ||
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*Two lessons learned by Penn accident: | *Two lessons learned by Penn accident: | ||
**every vector has it’s limits | **every vector has it’s limits | ||
| - | **the nature of human clinical trials | + | **the nature of human clinical trials is dangerous |
'''Design By Committee''' | '''Design By Committee''' | ||
| - | *Penn’s Insitute for Bioethics defends trial by saying | + | *Penn’s Insitute for Bioethics defends trial by saying "they had the best intentions" |
| - | *Jesse Gelsinger had an enzyme deficiency | + | *Jesse Gelsinger had an [http://en.wikipedia.com/Ornithine_transcarbamylase_deficiency enzyme deficiency] |
**occurs when the X chromosome is missing or defective, producing to little of the liver enzyme OTC (ornithine transcarbamylase) | **occurs when the X chromosome is missing or defective, producing to little of the liver enzyme OTC (ornithine transcarbamylase) | ||
**OTC is needed to remove ammonia from the blood | **OTC is needed to remove ammonia from the blood | ||
**Most people die in infancy but if kept to a strict diet, can live a normal life. | **Most people die in infancy but if kept to a strict diet, can live a normal life. | ||
*Purpose of the study was to use the adenovirus vector to inject OTC into Jesse’s liver. | *Purpose of the study was to use the adenovirus vector to inject OTC into Jesse’s liver. | ||
| - | Adenovirus Vector Pros: | + | *Adenovirus Vector Pros: |
| - | *it was the only one that worked “rapidly enough” | + | **it was the only one that worked “rapidly enough” |
| - | *most vectors take 3-6 weeks, adenovirus starts to work in 24 hours. | + | **most vectors take 3-6 weeks, adenovirus starts to work in 24 hours. |
| - | Adenovirus Vector Cons: | + | *Adenovirus Vector Cons: |
| - | *gene expression with this vector has a limited duration | + | **gene expression with this vector has a limited duration |
| - | *could possibly lead to need for liver transplat | + | **could possibly lead to need for liver transplat |
*Initial patients would have almost no chance of benefitting: | *Initial patients would have almost no chance of benefitting: | ||
**vector can only be given once | **vector can only be given once | ||
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'''A meeting of experts decided to use adults rather than children''' | '''A meeting of experts decided to use adults rather than children''' | ||
| - | * | + | *"it’s wrong to do non-therapeutic research on someone who can’t consent." |
*Toxicity trial in primates gave a level of toxicity they thought was comparable to humans | *Toxicity trial in primates gave a level of toxicity they thought was comparable to humans | ||
*Their plan was to start with a dose that was 5% of what caused maximum toxicity in primates | *Their plan was to start with a dose that was 5% of what caused maximum toxicity in primates | ||
**5 three-fold increases after the initial 5% does | **5 three-fold increases after the initial 5% does | ||
| - | **FDA agreed and gave them the | + | **FDA agreed and gave them the "green light" in 1997 |
*17 patients were injected this way, all experienced minor symptoms but nothing severe. | *17 patients were injected this way, all experienced minor symptoms but nothing severe. | ||
*Gelsinger was the 18th patient. | *Gelsinger was the 18th patient. | ||
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*also had high IL-6 which contributes to inflammation | *also had high IL-6 which contributes to inflammation | ||
**1993 California gene therapy study showed a similar immune response when adenovirus was injected into CF patients. | **1993 California gene therapy study showed a similar immune response when adenovirus was injected into CF patients. | ||
| - | ** | + | **1995 study in North Carolina also showed inflammation in CF patients using adenovirus because the vector stimulated nerve fibers in the epithelium causing an inflammatory response. |
***said it was a capsid protein problem | ***said it was a capsid protein problem | ||
| - | ***caused by the | + | ***caused by the outer shell of the vector |
*reached the target cells very late in the process | *reached the target cells very late in the process | ||
**Coxsackie adenovirus receptor (CAR): is much more prevalent in mouse livers | **Coxsackie adenovirus receptor (CAR): is much more prevalent in mouse livers | ||
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*want to try and engineer the vector to not be so dangerous. | *want to try and engineer the vector to not be so dangerous. | ||
*high doses will always be necessary | *high doses will always be necessary | ||
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Current revision as of 19:44, 7 March 2010
- Dusty Miller wants to find gene therapy for CF after death of Penn volunteer
- says we lack a good vector
- There is a general fear that nobody will do gene therapy reseach for a while because of the "crackdown" and recent negative media coverage
- FDA cracking down hard on gene therapy trials
- shut down all trials at Penn after death
- warning letter to St. Elizabeth Medical Center in Boston
- Two lessons learned by Penn accident:
- every vector has it’s limits
- the nature of human clinical trials is dangerous
Design By Committee
- Penn’s Insitute for Bioethics defends trial by saying "they had the best intentions"
- Jesse Gelsinger had an enzyme deficiency
- occurs when the X chromosome is missing or defective, producing to little of the liver enzyme OTC (ornithine transcarbamylase)
- OTC is needed to remove ammonia from the blood
- Most people die in infancy but if kept to a strict diet, can live a normal life.
- Purpose of the study was to use the adenovirus vector to inject OTC into Jesse’s liver.
- Adenovirus Vector Pros:
- it was the only one that worked “rapidly enough”
- most vectors take 3-6 weeks, adenovirus starts to work in 24 hours.
- Adenovirus Vector Cons:
- gene expression with this vector has a limited duration
- could possibly lead to need for liver transplat
- Initial patients would have almost no chance of benefitting:
- vector can only be given once
- patients develop an immune response to the vector
A meeting of experts decided to use adults rather than children
- "it’s wrong to do non-therapeutic research on someone who can’t consent."
- Toxicity trial in primates gave a level of toxicity they thought was comparable to humans
- Their plan was to start with a dose that was 5% of what caused maximum toxicity in primates
- 5 three-fold increases after the initial 5% does
- FDA agreed and gave them the "green light" in 1997
- 17 patients were injected this way, all experienced minor symptoms but nothing severe.
- Gelsinger was the 18th patient.
Surprising Toxicity
- Trying to figure out why Gelsinger’s toxicity was so much more severe than other patients
- his RBC precursors had been wiped out in his bone marrow
- concluded it was due to a pre-existing parvovirus
- also had high IL-6 which contributes to inflammation
- 1993 California gene therapy study showed a similar immune response when adenovirus was injected into CF patients.
- 1995 study in North Carolina also showed inflammation in CF patients using adenovirus because the vector stimulated nerve fibers in the epithelium causing an inflammatory response.
- said it was a capsid protein problem
- caused by the outer shell of the vector
- reached the target cells very late in the process
- Coxsackie adenovirus receptor (CAR): is much more prevalent in mouse livers
- CAR is needed for uptake of vector.
A Mortal Blow for Adenovirus:
- want to try and engineer the vector to not be so dangerous.
- high doses will always be necessary
