Marshall's "Gene Therapy Death Prompts Review of Adenovirus Vector" 1999

From Biol557

University of Pennsylvania’s Institute for Human Gene Therapy

• 18 year old (Jesse Gelsinger) participating in gene therapy study for an unspecified enzyme deficiency
• died 4 days after injection of a genetically altered virus into his liver
• first patient to die in the study
• highlighted a central problem: the difficulty of transferring genes to human cells and getting them expressed

Meeting with NIH

• Chief of Penn’s clincical team (James Wilson) appeared at a special meeting called by the NIH to discuss what went wrong in the case.
  • Penn team admitted they weren’t sure.

Details about Gelsinger’s Treatment

• injected vector: a crippled from of adenovirus combined with a gene to control Gelsinger’s ammonia metabolism.
• he was given the highest dose of anyone in the trial
• invaded the target (liver) but also other unintended organs
  • For completeness: liver, spleen, lung, thyroid, heart, kidney, testicles, brain, pancreas, lymph nodes, bone marrow, bladder, small intestine, muscle, skin.
• this activated an innate immune response and a systemic inflammatory response.
  • death due to lungs filling with fluid, could not oxygenate blood properly.
• only 1% of transferred genes were taken up by target cells.
  • animal studies have shown to be much more effective
  • not sure why transfer isn’t as efficient in humans

New findings about patient

• Gelsinger’s bone marrow was severely depleted of erythroid precursor blood cells
  • This suggested an undetected genetic condition or parvovirus
  • the only patients who have ever had a similar immune response to this therapy were patients with CF, although they did not make any mention of Gelsinger having CF

The article concluded with comments about the FDA suggesting that NIH improve monitoring of gene therapy.