Novel therapeutic strategies for autosomal dominant retinitis pigmentosa
Citation:
Brian G. D. O'Neill, 'Novel therapeutic strategies for autosomal dominant retinitis pigmentosa', [thesis], Trinity College (Dublin, Ireland). School of Genetics and Microbiology, 2000, pp 307Download Item:
Abstract:
A major difficulty associated with the design of gene therapies for autosomal dominant diseases is the
immense intragenic heterogeneity often encountered in such conditions. Two strategies which circumvent
the difficulties associated with developing multiple mutation-specific therapies for dominant disorders and
with discriminating between disease and normal alleles have been explored in this thesis. In the first,
normal and mutant alleles are suppressed by targeting sequences in transcribed but untranslated regions
(UTRs) enabling introduction of a replacement gene with the correct coding sequence but altered UTRs to
prevent suppression. The second approach involves suppression in the coding sequence of a gene and
concurrent introduction of a replacement gene by exploiting the degeneracy of the genetic code. Both
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. The aim of this project was to examine the
feasibility of both therapeutic approaches using a group of genetically heterogeneous retinopathies termed
retinitis pigmentosa; for example, over 150 mutations have been identified in the genes encoding the
photoreceptor-specific proteins, rhodopsin and peripherin in patients with retinal degenerations. Notably,
the vast majority of these mutations are known to give rise to autosomal dominant retinitis pigmentosa. In
the context of general methods for gene suppression it is of note that such methods may be directed towards
the primary defect, in the case of RP for example the rhodopsin gene, or a secondary effect associated with
the disease process such as apoptosis. Two general methods targeting the primary defect which overcome
the problems of allelic heterogeneity are explored in this thesis using hammerhead ribozymes directed to
transcripts from the rhodopsin and peripherin genes. The ribozyme technologies explored in the study could
be used to develop therapies for retinopathies which are directed to therapeutic targets other than rhodopsin
or peripherin.
Author: O'Neill, Brian G. D.
Advisor:
Farrar, JaneHumphries, Peter
Kenna, Paul
Qualification name:
Doctor of Philosophy (Ph.D.)Publisher:
Trinity College (Dublin, Ireland). School of Genetics and MicrobiologyNote:
TARA (Trinity’s Access to Research Archive) has a robust takedown policy. Please contact us if you have any concerns: rssadmin@tcd.iePrint thesis water damaged as a result of the Berkeley Library Podium flood 25/10/2011
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thesisAvailability:
Full text availableKeywords:
Genetics, Ph.D., Ph.D. Trinity College DublinMetadata
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