Retrospectacle: A Neuroscience Blog

Gene therapy is the isolation of a gene, which is then packaged into a vector for introduction into the body in hopes that it can correct some aspect of genetic disease. Often this “vector” is a type of virus which had been specifically engineered to be safer than its original version. This usually involves removing the exons responsible for its transmission through all cell types, effectively “disabling” it. The virus will infect target cells and force them to produce the protein of interest, effectively replacing (or overexpressing) the protein in the body–which can be perpetuated.

Gene therapy human trials have been suffering from bad press, as there have been a few high-profile deaths during a clinical trial (very few though, in respect to how many people have received the therapy). These deaths are huge setbacks in the public perception of gene therapy as well as the ability to secure funding for future trials. However, the most recent death during a gene therapy trial, that of Jolee Mohr, was just reported to be unrelated to the gene therapy itself. Mohr was involved in a clinical trial testing gene therapy for rheumatoid arthritis in her knee, and died 3 weeks after receiving the injected virus (an adeno-associated virus) and after her death the entire study was halted.

“At a September meeting of the federal Recombinant DNA Advisory Committee (RAC), experts noted that Mohr apparently died mainly from a fungal infection called histoplasmosis that her immune system was unable to fight off.”

Initially, it was hypothesized that the therapy may have contributed to her susceptibility to the infection. She was taking Humira for her arthritis which blocks tumor necrosis factor alpha (TNFa). This is the same protein expressed by the gene therapy, and if the virus had spread beyond her knee, the combination of both might have compromised her immune system. But it is now known for sure that that did not happen, according to the gene therapy company Targeted Genetics.

The level of TNF-α blocker detected in Mohr’s blood with a binding assay was “well within the normal range expected” from the dose of Humira she was taking, says President and CEO H. Stewart Parker. The new tests also ruled out the idea that the gene-therapy vector, adeno-associated virus, replicated in Mohr’s body. Although DNA from the vector turned up in other tissues, the amounts were extremely low.

This finding resulted in the FDA lifting the halt on the clinical trial, which can now resume (and those interested in gene therapy can breathe a sigh of relief.)


  1. #1 Kristen Suthers
    November 28, 2007

    Ms. Batts blog title is misleading. As she states herself, in her column, it is still not clear what exactly killed Mrs. Mohr; so claiming that it was not the gene therapy at this point is premature. Also, her use of the term “breathe a sigh of relief” at the end of her column is inappropriate and insensitive to the patient’s family – as if the needs of scientists trump those of a bereaved family. In the NY Times article today, Mr. Mohr seems only to be asking to wait to determine the cause of death before re-starting the trial.

  2. #2 Shelley Batts
    November 28, 2007

    No one is breathing a sigh of relief over the patient’s status, of course that is tragic. That was in no way implied (I certainly didn’t mean to).

    The relief is that future patients might be able to benefit from a promising therapy, and that the correct cause (which is definitively reported by Targeted Genetics and verified by the FDA) has been pinpointed. The FDA has reflected its satisfaction in their data by lifting the ban, which they would not do lightly. I have linked to Targeted Genetics press release and the Science article, I suggest you read them and then come back to comment on the cause.

  3. #3 Shelley Batts
    November 28, 2007

    Here’s the relevant portion of the summary at Targeted Genetics site (last link above):

    “The data obtained during the investigation indicates that tgAAC94 did not contribute to the patient’s death, which was due to disseminated histoplasmosis. Final molecular test results presented earlier this month at the 71st annual meeting of the American College of Rheumatology (ACR), supported initial observations that no amplification of viral vector occurred in the patient’s body as a result of the investigational therapy, that only trace amounts of vector DNA were detected in tissues outside the treated joint, and that the amount of circulating TNF-alpha antagonist protein was as expected from the background therapy. The subject was on adalimumab, methotrexate and prednisone, which are known to be immunosuppressive and a risk factor for histoplasma infection.”

  4. #4 qetzal
    November 28, 2007

    Thanks for posting this. I used to do gene therapy, but don’t follow as closely any more, so I hadn’t seen the latest on this case.

    I do want to comment on this passage:

    Gene therapy human trials have been suffering from bad press, as it has not been uncommon for a patient to die during the trial.

    The implication, perhaps unintended, is that death due to the gene therapy is not uncommon. Actually, that’s only happened twice that I know of: Jesse Gelsinger and one of the French children treated for X-SCID. I don’t know how many people have received gene therapy to date, but it’s surely in the thousands.

    Is 2 out of X thousand “not uncommon?” Is it higher than the rate for other experimental drugs in similar patients? I don’t know.

  5. #5 Shelley Batts
    November 28, 2007

    Qetzal, thanks for pointing that out. My meaning was that a death during the trial was commonly pointed out in the media, I’ll make it clearer.

  6. #6 SAM
    November 28, 2007

    Shelley, thank you for this blog.

    I’ve recently found it, and have already become a fan.
    I am linking it to my own blog, hoping that others may find it as stimulating as I do.

    Thank you!

  7. #7 Bryce M
    November 29, 2007

    I’m no expert by any means, but aren’t some of the side effects of gene therapy considered trade secrets so they don’t have to be revealed to the public? I’m in no way saying gene therapy isn’t useful, but the laws governing it are what give it a black eye in my opinion.

New comments have been disabled.