Human Molecular Genetics, Vol 6, 1415-1426, Copyright © 1997 by Oxford University Press
S Millington-Ward, B O'Neill, G Tuohy, N Al-Jandal, AS Kiang, PF Kenna, A Palfi, P Hayden, F Mansergh, A Kennan, P Humphries and GJ Farrar
A major difficulty associated with the design of gene therapies for
autosomal dominant diseases is the immense intragenic heterogeneity often
encountered in such conditions. In order to overcome such difficulties we
have designed, and evaluated in vitro, three strategies which avoid a
requirement to target individual mutations for genetic suppression. In the
first, normal and mutant alleles are suppressed by targeting sequences in
transcribed but untranslated regions of transcript (UTRs), enabling
introduction of a replacement gene with the correct coding sequencing but
altered UTRs to prevent suppression. A second approach involves suppression
in coding sequence and concurrent introduction of a replacement gene by
exploiting the degeneracy of the genetic code. A third strategy utilises
intragenic polymorphism to suppress the disease allele specifically, the
advantage being that a proportion of patients with different disease
mutations have the same polymorphism. These approaches provide a wider
choice of target sequence than those directed to single disease mutations
and are appropriate for many mutations within a given gene. General methods
for suppression may be directed towards the primary defect or a secondary
effect associated with the disease process, such as apoptosis. Three
general methods targeting the primary defect which circumvent problems of
allelic genetic heterogeneity are explored in vitro using hammerhead
ribozymes designed to target transcripts from the rhodopsin, peripherin and
collagen 1A1 and 1A2 genes, extensive genetic heterogeneity being a feature
of associated disease pathologies.
ARTICLES
Strategems in vitro for gene therapies directed to dominant mutations
Genetics Department, Trinity College Dublin, Ireland.
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