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Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids
Abstract
Mitochondrila DNA (mtDNA) is the only extrachromosomal DNA in humans. It is a small (16.5 kb) genome which encodes 13 essential peptides of the respiratory chain, two rRNAs and 22 tRNAs. Defects of this genome are now recognized as important causes of disease and may take the form of point mutations or rearrangements. There is no effective treatment for patients with mtDNA mutations. In the majority of patients with mtDNA defects, both mutant and wild-type molecules are present in the same cell-a phenomenon known as intracellular heteroplasmy. In addition, in the presence of heteroplasmy there is a threshold whereby a certain level of mutant mtDNA is necessary before the disease becomes biochemically and clinically apparent. Based on the presence of heteroplasmy and the recessive nature of these mutations, we believe it will be possible to treat patients by selectively inhibiting the replication of the mutant mtDNA, thereby allowing propagation of only the wild-type molecule. To confirm the validity of such an approach we synthesised peptide nucleic acids (PNAs) complementary to human mtDNA templates containing a deletion breakpoint or single base mutation, both mutations well documented to cause disease. Using an in vitro replication run-off assay under physiological conditions, the antigenomic PNAs specifically inhibited replication of mutant but not wild-type mtDNA templates. Furthermore, we have shown uptake of these PNAs into cultured human myoblasts. We believe that we have therefore established the potential value of antigenomic PNA therapy for patients with heteroplasmic mtDNA disorders.
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“Antigenomic therapy, which involves using sequence-specific nucleic acid derivatives that selectively target and inhibit the replication of mutated mtDNA thus allowing the wild-type genome to propagate, showed promising initial results in vitro with peptide nucleic acids (PNAs) [234].”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [234]
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Cited by
Sorted by citations
Mitochondrial DNA mutations in human disease
Taylor, R. W., & Turnbull, D. M. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1606 · Cited by 1,922
“The selective inhibition of mutated mtDNA replication by antigenomic agents has been applied to manipulate mtDNA heteroplasm”
Mitochondrial Energetics and Therapeutics
Wallace, D. C., Fan, W., & Procaccio, V. (2010) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev.pathol.4.110807.092314 · Cited by 747
“However, in vivo efficacy of this approach has yet to be established (104, 105).”
Mitochondrial DNA mutations and human disease
Tuppen, H. A. L., Blakely, E. L., Turnbull, D. M., & Taylor, R. W. (2010) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2009.09.005 · Cited by 676
“Antigenomic therapy, which involves using sequence-specific nucleic acid derivatives that selectively target and inhibit the replication of mutated mtDNA thus allowing the wild-type genome to propagate, showed promising initial results in vitro with peptide nucleic acids (PNAs) [234].”
BackgroundMammalian mitochondrial genetics: heredity, heteroplasmy and disease
Lightowlers, R. N., Chinnery, P. F., Turnbull, D. M., & Howell, N. (1997) · Trends in Genetics · doi:10.1016/s0168-9525(97)01266-3 · Cited by 469
Mitochondrial Diseases: Hope for the Future
Russell, O. M., Gorman, G. S., Lightowlers, R. N., & Turnbull, D. M. (2020) · Cell · doi:10.1016/j.cell.2020.02.051 · Cited by 480
Metadata
- Authors
- Taylor, R. W., Chinnery, P. F., Turnbull, D. M., & Lightowlers, R. N.
- Affiliations
- Newcastle University (GB)
- Corresponding author
- Turnbull, Douglass M.
- Venue
- Nature Genetics
- Published
- 1997-02
- Volume
- 15
- Issue
- 2
- Pages
- 212-215
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1964789697
- Cited by
- 249
- References
- 31
- Citations by year
- 2025: 5 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 9 · 2017: 2 · 2016: 6 · 2015: 8 · 2014: 6 · 2013: 2 · 2012: 10
- FWCI
- 5.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- mitochondrial DNA, mitochondrial DNA replication, peptide nucleic acid, heteroplasmy, myoblasts, mitochondrial disease, deletion breakpoints, single-base mutations
- MeSH terms
- Cell Line, Depression, Chemical, DNA Replication, DNA, Mitochondrial, DNA, Single-Stranded, Humans, Mitochondria, Muscle, Oligodeoxyribonucleotides, Peptides, Templates, Genetic, Drug Design, MERRF Syndrome
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