Marshall's "Gene Therapy on Trial" 2000

From Biol557

• 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