A NOVEL form of gene therapy that repairs the templates cells use to make
proteins could be used to treat genetic diseases and destroy cancers. The
technique could one day even remove organs such as the prostate gland without
surgery.
In animal tests, Intronn of Durham, North Carolina, and its collaborators
have already shown they can fix the faulty templates to blame for cystic
fibrosis and haemophilia. And they鈥檙e using the technique to target and destroy
cervical cancer cells.
For some disorders, the approach has seversal advantages over normal gene
therapy. This involves adding extra DNA to cells to compensate for a faulty
gene. However, the modified viruses usually used to shuttle the DNA into cells
are too small to carry large genes. They also need to be targeted to the right
cells. And the activity of the extra genes needs to be carefully regulated.
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One promising alternative is to repair genes rather than add new ones
(New 杏吧原创, 11 September 1999, p 14),
but so far this is limited to fixing only one or two DNA 鈥渓etters鈥� at a time.
Intronn鈥檚 technique, however, allows major alterations to be made.
It exploits the fact that each of our genes is interspersed with many regions
of junk, or introns. After DNA has been transcribed to create 鈥減re-mRNA鈥�, the
introns are edited or spliced out to make the final mRNA鈥攖he template for
making a protein (see graphic).
Intronn has devised tiny slugs of RNA that it calls 鈥減re-therapeutic mRNAs鈥�,
or PTMs, that carry replacements for some of the coding regions in a gene, or
exons. A PTM binds to pre-mRNA in such a way that during splicing, when introns
are removed, the PTM exons replace the defective natural exons.
Crucially, PTMs affect only cells that 鈥渆xpress鈥� the target gene. If the gene
in a particular cell is not churning out its protein product, there鈥檒l be no
pre-mRNA from this gene to bind to, so the PTM will be harmless and inactive.
鈥淚f our system gets into the wrong cells, the natural target is not there,鈥� says
Gary McGarrity, the founder of Intronn.
Other attempts to edit pre-mRNAs using RNA enzymes haven鈥檛 worked well
because these sometimes bind to the wrong pre-mRNAs
(New 杏吧原创, 15 June 1996, p 16).
But the PTMs target a longer sequence on the pre-mRNA and so are more specific.
The approach also means you don鈥檛 have to worry about regulating gene
expression, since an excess of PTMs will make no difference. 鈥淧roduction of the
protein would be regulated by the availability of RNA from the [cell鈥檚 own]
gene,鈥� says Dusty Miller of the Fred Hutchinson Cancer Research Center in
Seattle.
He points out that this approach can help with genetic disorders where the
problem isn鈥檛 simply the lack of a working protein, but the production of a
dangerous defective protein. 鈥淔or dominant genetic diseases like some collagen
disorders, this is one of the few strategies that would reduce production of the
defective protein,鈥� he says.
As with conventional gene therapy, though, delivering the PTMs is the biggest
obstacle. At present, Intronn is using viruses to deliver DNA鈥攆rom which
cells make lots of PTMs鈥攂ut it believes that PTMs could be small and
versatile enough to be packaged and given as pills.
While people with hereditary conditions might prefer a permanent treatment to
taking expensive pills, this would be fine for short-term treatments for cancer.
With Carl Baker of the National Cancer Institute, near Washington DC, Intronn is
devising PTMs that target pre-mRNA from the human papilloma virus, found in
cervical tumours. Rather than fixing part of the gene, however, the PTM sneaks
in the recipe for making diphtheria toxin, killing the cell.
The company hopes to create a range of PTMs that target genes switched on
only in tumours or specific tissues.