Gene Therapy III

Most of the approaches to gene therapy attempted to date — and described in other pages — involve the use of vectors to introduce a functioning gene into cells.

One problem with these approaches is that foreign DNA is inserted into the host genome. It is possible — and has been demonstrated — that the foreign DNA may be inserted into a chromosomal position that disturbs normal gene function there. In fact, several boys treated with vectors containing a gene to cure their X-linked severe combined immunodeficiency (X-linked SCID) developed cancer because of this. [Link]

But now Urnov, F. D. et al., report (in Nature, 6 June 2005) their success — with cultured cells — in correcting the molecular deficiency in X-linked SCID without the need for any vector.

X-linked SCID is caused by a mutated X-linked gene encoding a subunit — called γc (gamma-c) — of the receptor for several interleukins.

Their treatment consisted of an synthetic protein containing
  1. a zinc-finger transcription factor. This can be engineered to recognize and bind to any desired DNA sequence in the genome. It is coupled to
  2. a restriction enzyme that cuts through both strands of DNA near that location. The combination of 1 and 2 is a "zinc-finger nuclease".
  3. a separate plasmid containing the correct version of the γc gene.

The result: a double-stranded break (DSB) in the DNA at the γc locus.

Using the cells repaired their own defective gene with surprisingly-high efficiency (and often both copies). This procedure

It's a long way from something that works in cultured cells to something that works in human patients, but here at least is a promising procedure. Instead of adding a functioning gene anywhere in the genome, both copies of the cell's own defective genes are repaired.

Humans with single-gene disorders like

might have some of their cells
Clinical trials of this procedure on several AIDS patients — reported in February 2011 — showed promise. Samples of the patient's CD4+ T cells were treated with a zinc-finger nuclease so that their CCR5 gene became nonfunctional. HIV uses CCR5 as a coreceptor to gain entry into T cells [More]. Expanded in culture and then returned to the donor, five (of six) patients had their CD4+ T cell counts rebound.

But what of genetic diseases whose gene products are produced by immobile cells in organs like the liver?

Another tool that holds promise for gene therapy are TALENs — link to a discussion.


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9 January 2013