The use of PNAs and their derivatives in mitochondrial gene therapy |
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Authors: | P M Smith G F Ross T M Wardell R W Taylor D M Turnbull and R N Lightowlers |
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Institution: | (1) Department of Neurology, University of Newcastle upon Tyne, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, U.K |
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Abstract: | Human mitochondria contain their own genome, mtDNA. This small molecule encodes 24 RNA species and 13 polypeptides, which
are essential components of the mitochondrial respiratory chain. The mitochondrial genome is present in hundreds or thousands
of copies in each cell and is believed to turnover throughout the life of the cell. Defects of the mitochondrial genome (mtDNA)
cause a variety of multisystemic disorders routinely affecting the muscle and nervous system. There is currently no effective
treatment for patients with defects of the mitochondrial genome. In many patients, defective cells harbour two sub-populations
of mtDNA (a situation termed heteroplasmy), one being normal, the other containing the pathogenic mutation. The mutated copy
is often recessive, with biochemical and clinical defects only becoming apparent when the levels of mutated mtDNA outweigh
the normal copies. It has therefore been postulated that by selectively preventing replication of the mutated mtDNA, the normal
copy will propagate, restoring biochemical function. The search has therefore been on during recent years to identify an antigenomic
molecule that will fulfil this criterion. Following evidence that peptide nucleic acids could selectively inhibit replication
of templates carrying a known pathogenic mtDNA mutation in vitro,we report on the progress of this approach and the various modificationsthat are now being used to improve the efficacy of
PNA-based antigenomic inhibition. |
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Keywords: | antigenomic hypothesis mtDNA peptide nucleic acids |
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