Marshall's "Gene Therapy on Trial" 2000

From Biol557

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===Abstract===
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*Dusty Miller wants to find gene therapy for CF after death of Penn voluneer
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*Just put an asterisk as the first character to make a bullet point.
+
**says we lack a good vector
-
**Put two asterices to make a sub point.
+
**There is a general fear that nobody will do gene therapy reseach for a while because of the “crackdown” and recent negative media coverage
-
*Put three single quote marks around text you want to be '''bold''', perhaps for '''new terminology'''.
+
*FDA cracking down hard on gene therapy trials
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*Put two single quotes around ''things that should be italicized''.
+
**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 in 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.
 +
**!995 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 out 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
===Introduction===
===Introduction===

Revision as of 18:37, 3 March 2010

  • Dusty Miller wants to find gene therapy for CF after death of Penn voluneer
    • 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 in 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.
    • !995 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 out 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

Introduction

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