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?

Read about two other techniques for gene editing:
  • the CRISPR-Cas9 system at this LINK
  • TALENs at this LINK

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17 April 2019