Severe combined immune deficiency

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Discussion Overview

The discussion revolves around severe combined immune deficiency (SCID) and the implications of retroviral gene therapy, particularly concerning the development of leukemia in some patients. Participants explore the safety and mechanisms of gene therapy, the distribution of viral integration sites, and the identification of faulty genes in SCID patients.

Discussion Character

  • Exploratory
  • Technical explanation
  • Debate/contested

Main Points Raised

  • One participant notes that out of 15 SCID patients cured by retroviral gene therapy, 2 developed leukemia due to the integration of the virus into a pro-oncogene (LMO-2), raising safety concerns about gene therapy.
  • Another participant references Derek Lowe's article, suggesting that the attachment points of viral vectors are not randomly distributed in chromosomes, which may explain the proximity to leukemia sites.
  • A participant questions how researchers determined that viral integration is not uniformly distributed and expresses skepticism about the conclusions drawn from the occurrence of mutations in specific blood cells.
  • There is curiosity about the methods used to identify the faulty gene in SCID patients and whether there may be other defective genes involved.

Areas of Agreement / Disagreement

Participants express differing views on the randomness of viral integration sites and the implications for gene therapy safety. The discussion remains unresolved regarding the mechanisms of integration and the identification of faulty genes.

Contextual Notes

Limitations include uncertainty about the mechanisms of viral integration, the distribution of integration sites, and the methods used to identify specific genetic defects in SCID patients.

Monique
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I thought it was interesting to note that out of 15 SCID (severe combined immune deficiency) patients cured by retroviral gene therapy, 2 developed leukemia.

This as a direct integration of the virus into a pro-oncogene, the interesting thing is that both patients had an insert in the same gene! (LMO-2)

This poses questions on the safety of gene therapy. Ofcourse, not all virusses integrate themselves into the genome (like adeno, or adeno-associated virusses) but those other ones bring severe immunological risks with them..


I wonder, wouldn't it be possible to target a virus to a specific 'junk region' of the genome? I am not sure how virusses integrate themselves, they probably depend on regions with less dense histone packing..
 
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Derek Lowe's article

http://www.corante.com/pipeline/ had an article about this a month or so ago - you might have to look in his archives for it. Basically what he said is that the attachment links are not randomly distributed in the chromosome, and that the probablility that your vector will attach near a leukemia site cannot be estimated by uniform distribution, which is what the experimentalists did. How the attachment points really are distributed, and why they seem to nestle close to leukemia sites is material for future research.
 
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I looked in the archives, but didn't find anything.

So how did these researchers know it is not uniformly distributed and is not random? I agree that lightning striking the same spot twice is suspicious, but since these are specific blood cells which will require a specific growth hormone, it might not be that striking that cells with this particular mutation have a growth advantage.

How did they find this gene in particular to be faulty anyway? Maybe there are a dozen more of the same genes defective in the same patients?
 
I'll see if I can find the paper/
 

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