Gene therapy for the treatment of mitochondrial DNA disorders

Expert Opinion on Biological Therapy

Volumn 5, Issue 2, 2005, Pages 183-194

  Taylor, Robert W ^a  

^a NEWCASTLE UNIVERSITY   (United Kingdom)

Author keywords

Complementation; Exercise training; Gene therapy; Heteroplasmy; Mitochondrial DNA; Treatment

Indexed keywords

BUPIVACAINE; OLIGOMYCIN;

AGING; CELL CULTURE; CHRONIC PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; DEGENERATIVE DISEASE; DNA REPLICATION; DNA TRANSFECTION; EXERCISE; FERTILIZATION IN VITRO; GENE DELETION; GENE REARRANGEMENT; GENETIC COUNSELING; GENETIC DISORDER; GENOME; HETEROPLASMY; IN VITRO STUDY; KEARNS SAYRE SYNDROME; MITOCHONDRIAL DNA DISORDER; MITOCHONDRIAL GENETICS; MITOCHONDRIAL RESPIRATION; MUTATION; NONHUMAN; PATHOGENESIS; PEARSON SYNDROME; POINT MUTATION; RESPIRATORY CHAIN; REVIEW;

ANIMALS; DNA, MITOCHONDRIAL; GENE THERAPY; HUMANS; MITOCHONDRIAL DISEASES;

EID: 15244354458     PISSN: 14712598     EISSN: None     Source Type: Journal    
DOI: 10.1517/14712598.5.2.183     Document Type: Review

References (101)

1. DIMAURO S, SCHON EA: Mitochondrial respiratory-chain diseases. N. Engl. J. Med. (2003) 348:2656-2668. An excellent overview of mitochondrial dysfunction and human disease.
2. MCFARLAND R, TAYLOR RW, TURNBULL DM: The neurology of mitochondrial DNA disease. Lancet Neurol. (2002) 1:345-351.
3. ZEVIANI M, DIDONATO S: Mitochondrial disorders. Brain (2004) 127:2153-2172.
4. SHOUBRIDGE EA: Nuclear genetic defects of oxidative phosphorylation. Hum. Mol. Genet. (2001) 10:2277-2284.
5. SCHWARTZ M, VISSING J: Paternal inheritance of mitochondrial DNA. N. Engl. J. Med. (2002) 347:576-580.
6. LIGHTOWLERS RN, CHINNERY PF, TURNBULL DM, HOWELL N: Mammalian mitochondrial genetics: heredity, heteroplasmy and disease. Trends Genet. (1997) 13:450-455.
7. CHOMYN A, MARTINUZZI A, YONEDA M et al.: MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts. Proc. Natl. Acad. Sci. USA (1992) 89:4221-4225.
8. SCIACCO M, BONILLA E, SCHON EA, DIMAURO S, MORAES CT: Distribution of wild-type and common deletion forms of mtDNA in normal and respiration-deficient muscle fibers from patients with mitochondrial myopathy. Hum. Mol. Genet. (1994) 3:13-19.
9. PETRUZZELLA V, MORAES CT, SANO MC, BONILLA E, DIMAURO S, SCHON EA: Extremely high levels of mutant mtDNAs co-localize with cytochrome c oxidase-negative ragged-red fibers in patients harboring a point mutation at nt 3243. Hum. Mol. Genet. (1994) 3:449-454.
10. CHINNERY PF, HOWELL N, LIGHTOWLERS RN, TURNBULL DM: Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes. Brain (1997) 120:1713-1721.
11. MICHIKAWA Y, MAZZUCCHELLI F, BRESOLIN N, SCARLATO G, ATTARDI G: Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science (1999) 286:774-779.
12. TRIFUNOVIC A, WREDENBERG A, FALKENBERG M et al.: Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature (2004) 429:417-423. First in vivo data in mammals to establish a causative link between mtDNA mutations and ageing phenotypes.
13. SCHON EA: Mitochondrial genetics and disease. Trends Biochem. Sci. (2000) 25:555-560.
14. CHINNERY PF, JOHNSON MA, WARDELL TM et al.: The epidemiology of pathogenic mitochondrial DNA mutations. Ann. Neurol. (2000) 48:188-193.
15. SCHAEFER AM, TAYLOR RW TURNBULL DM, CHINNERY PF: The epidemiology of mitochondrial disorders-past, present and future. Biochim. Biohys. Acta (2004) 1659(2-3):115-120.
16. CHINNERY PF, DIMAURO S, SHANSKE S et al.: Risk of developing a mitochondrial DNA deletion disorder. Lancet (2004) 364:592-596.
17. SUOMALAINEN A, KAUKONEN J: Diseases caused by nuclear genes affecting mtDNA stability. Am. J. Med. Genet. (2001) 106:53-61.
18. KIRBY DM, BONEH A, CHOW CW et al.: Low mutant load of mitochondrial DNA G13513A mutation can cause Leigh's disease. Ann. Neurol. (2003) 54:473-478.
19. HOLT IJ, WARDING AE, PETTY RK, MORGAN-HUCHES JA: A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am. J. Hum. Genet. (1990) 46:428-433.
20. WALLACE DC, SINGH G, LOTT MT et al.: Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science (1988) 242:1427-1430.
21. PULKES T, EUNSON L, PATTERSON V et al.: The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS overlap syndrome and may be a frequent cause of MELAS. Ann. Neurol. (1999) 46:916-919.
22. KIRBY DM, MCFARLAND R, OHTAKE A et al.: Mutations of the mitochondrial ND1 gene as a cause of MELAS. J. Med. Genet. (2004) 41:784-789.
23. MCFARLAND R, KIRBY DM, FOWLER KJ et al.: De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency. Ann. Neurol. (2004) 55:58-64.
24. ANDREU AL, HANNA MG, REICHMANN H et al.: Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N. Engl. J. Med. (1999) 341:1037-1044.
25. MCFARLAND R, ELSON JL, TAYLOR RW, HOWELL N, TURNBULL DM: Assigning pathogenicity to mitochondrial tRNA mutations: when 'definitely maybe' is not good enough. Trends Genet. (2004) 20:591-596.
26. Leu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature (1990) 348:651-653.
27. Lys mutation. Cell (1990) 61:931-937.
28. MCFARLAND R, CLARK KM, MORRIS AA et al.: Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation. Nat. Genet. (2002) 30:145-146.
29. TAYLOR RW GIORDANO C, DAVIDSON MM et al.: A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. (2003) 41:1786-1796.
30. Ile homoplasmic mutation in the mitochondrial genome. J. Med. Genet. (2004) 41:342-349.
31. MATTIAZZI M, VIJAYVERGIYA C, GAJEWSKI CD et al.: The mtDNA T8993G (NARP) mutation results in an impairment of oxidative phosphorylation that can be improved by antioxidants. Hum. Mol. Genet. (2004) 13:869-879.
32. DIMAURO S, MANCUSO M, NAINI A: Mitochondrial encephalomyopathies: therapeutic approach. Ann. NY Acad. Sci. (2004) 1011:232-245.
33. CHINNERY PF, BINDOFF LA: 116th ENMC international workshop: the treatment of mitochondrial disorders, 14th-16th March 2003, Naarden, The Netherlands. Neuromuscul. Disord. (2003) 13:757-764. Consensus paper outlining current best practice for the treatment of patients with mitochondrial disease.
34. LEWIS W, DALAKAS MC: Mitochondrial toxicity of antiviral drugs. Nat. Med. (1995) 1:417-422.
35. DALAKAS M, ILLA I, PEZESHKPOUR GH, LAUKAITIS JP, COHEN B, GRIFFIN JL: Mitochondrial myopathy caused by long-term zidovudine therapy. N. Engl. J. Med. (1990) 322:1098-1105.
36. ESTIVILL X, GOVEA N, BARCELO E et al.: Familial progressive sensorineral deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment with aminoglycosides. Am. J. Hum. Genet. (1997) 62:27-35.
37. TAYLOR RW, CHINNERY PF, CLARK KM, LIGHTOWLERS RN, TURNBULL DM: Treatment of mitochondrial disease. J. Bioenerg. Biomembr. (1997) 29:195-205.
38. D'SOUZA GG, WEISSIG V: Approaches to mitochondrial gene therapy. Curr. Gene Ther. (2004) 4:317-328.
39. NAGLEY P, FARRELL LB, GEARING DP, NERO D, MELTZER S, DEVENISH RJ: Assembly of functional proton-translocating ATPase complex in yeast mitochondria with cytoplasmically synthesized subunit 8, a polypeptide normally encoded within the organelle. Prof. Natl. Acad. Sci. USA (1988) 85:2091-2095. Proof of principle experiments demonstrating allotopic expression of a mtDNA-encoded protein in yeast.
40. MANFREDI G, FU J, OJAIMI J et al.: Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus. Nat. Genet. (2002) 30:394-399. First successful description of allotopic expression of a mtDNA-encoded protein in human cells.
41. GUY J, QI X, PALLOTTI F et al.: Rescue of a mitochondrial deficiency causing Leber Hereditary Optic Neuropathy. Ann. Neurol. (2002) 52:534-542.
42. OCA-COSSIO J, KENYON L, HAO H, MORAES CT: Limitations of allotopic expression of mitochondrial genes in mammalian cells. Genetics (2003) 165:707-720.
43. 0-ATPase is encoded by a nuclear gene in Chlamydomonas reinhardtii. J. Biol. Chem. (2002) 277:6051-6058.
44. OJAIMI J, PAN J, SANTRA S, SNELL WJ, SCHON EA: An algal nucleus-encoded subunit of mitochondrial ATP synthase rescues a defect in the analogous human mitochondrial-encoded subunit. Mol. Biol. Cell (2002) 13:3836-3844. Demonstration that ATPase 6 from C. reinhardtii could function and rescue a biochemical defect in human cells.
45. SEO BB, WANG J, FLOTTE TR, YAGI T, MATSUNO-YAGI A: Use of the NADH-quinone oxidoreductase (NDI1) gene of Saccharomyces cerevisiae as a possible cure for complex I defects in human cells. J. Biol. Chem. (2000) 275:37774-37778.
46. BAI Y, HAJEK P, CHOMYN A et al.: Lack of complex I activity in human cells carrying a mutation in MtDNA-encoded ND4 subunit is corrected by the Saccharomyces cerevisiae NADH-quinone oxidoreductase (NDI1) gene. J. Biol. Chem. (2001) 276:38808-38813.
47. SEO BB, NAKAMARU-OGISO E, CRUZ P, FLOTTE TR, YAGI T, MATSUNO-YAGI A: Functional expression of the single subunit NADH dehydrogenase in mitochondria in vivo: a potential therapy for complex I deficiencies. Hum. Gene. Ther. (2004) 15:887-895. One of a series of reports outlining the potential of expressing the yeast NDI1 gene to treat human complex I deficiency.
48. MAHAPATRA S, ADHYA S: Import of RNA into Leishmania mitochondria occurs through direct interaction with membrane-bound receptors. J. Biol. Chem. (1996) 271:20432-20437. One of a series of papers describing cytoplasmic tRNA import into kinetoplast mitochondria.
49. LEBLANC AJ, YERMOVSKY-KAMMERER AE, HAJDUK SL: A nuclear encoded and mitochondrial imported dicistronic tRNA precursor in Trypanosoma brucei. J. Biol. Chem. (1999) 74:21071-21077.
50. SMALL I, MARECHAL-DROUARD L, MASSON J et al.: In vivo import of a normal or mutagenized heterologous transfer RNA into the mitochondria of transgenic plants: towards novel ways of influencing mitochondrial gene expression? EMBO J. (1992) 11:1291-1296. One of a series of papers describing cytoplasmic tRNA import into plant mitochondria.
51. DELAGE L, DIETRICH A, COSSET A, MARECHAL-DROUARD L: In vitro import of a nuclearly encoded tRNA into mitochondria of Solanum tuberosum. Mol. Cell. Biol. (2003) 23:4000-4012.
52. Lys(CUU) of Saccharomyces cerevisiae: in vivo and in vitro targetting systems. Nucleic Acids Res. (1992) 20:1277-1281.
53. TARASSOV I, ENTELIS N, MARTIN R: Mitochondrial import of a cytoplasmic lysine-tRNA in yeast is mediated by cooperation of cytoplasmic and mitochondrial lysyl-tRNA syntherases. EMBO J. (1995) 14:3461-3471.
54. ENTELIS NS, KOLESNIKOVA OA, DOGAN S, MARTIN RP, TARASSOV IA: 5 S rRNA and tRNA Import into Human Mitochondria. Comparison of in vitro requirements. J Biol. Chem. (2001) 276:45642-45653.
55. MAGALHAES PJ, ANDREU AL, SCHON EA: Evidence for the presence of 5S rRNA in mammalian mitochondria. Mol. Biol. Cell (1998) 9:2375-82.
56. PURANAM RS, ATTARDI G: The RNase P associated with HeLa cell mitochondria contains an essential RNA component identical in sequence to that of the nuclear RNase P. Mol. Cell. Biol. (2001) 21:548-561.
57. KOLESNIKOVA OA, ENTELIS NS, MIREAU H, FOX TD, MARTIN RP, TARASSOV IA: Suppression of mutations in mirochondrial DNA by tRNAs imported from the cytoplasm. Science (2000) 289:1931-1933. Report showing that human mitochondria are able to internalise yeast tRNA derivatives in vitro.
58. KOLESNIKOVA OA, ENTELIS NS, JACQUIN-BECKER C et al.: Nuclear DNA-encoded tRNAs targeted into mitochondria can rescue a mitochondrial DNA mutation associated with the MERRF syndrome in cultured human cells. Hum. Mol. Genet. (2004) 13:2519-2534. Paper documenting the rescue of a biochemical defect in human MERRF cells following targeting of yeast cytoplasmic tRNA derivatives to mitochondria.
59. HOLT IJ, LORIMER HE, JACOBS HT: Coupled leading- and lagging-strand synthesis of mammalian mitochondrial DNA. Cell (2000) 100:515-524.
60. BOGENHAGEN DF, CLAYTON DA: The mitochondrial DNA replication bubble has not burst. Trends Biochem. Sci. (2003) 28:357-360.
61. CHRZANOWSKA-LIGHTOWLERS ZM, LIGHTOWLERS RN, TURNBULL DM: Gene therapy for mitochondrial DNA defects: is it possible? Gene Ther. (1995) 2:311-316.
62. TAYLOR RW, WARDELL TM, CONNOLLY BA, TURNBULL DM, LIGHTOWLERS RN: Linked oligodeoxynucleotides show binding cooperativity and can selectively impair replication of deleted mitochondrial DNA templates. Nucleic Acids Res. (2001) 29:3404-3012.
63. EGHOLM M, BUCHARDT O, CHRISTENSEN L et al.: PNA hybridizes to complementary oligonucleotides obeying the Watson-Crick hydrogen-bonding rules. Nature (1993) 365:566-568.
64. TAYLOR RW, CHINNERY PF, TURNBULL DM, LIGHTOWLERS RN: Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids. Nat. Genet. (1997) 15:212-215. In vitro proof of principle experiments documenting PNA-mediated selective inhibition of mtDNA replication of human templates with pathogenic mutations.
65. CHINNERY PF, TAYLOR RW, DIEKERT K, LILL R, TURNBULL DM, LIGHTOWLERS RN: Peptide nucleic acid delivery to human mitochondria. Gene Ther. (1999) 6:1919-1928.
66. MURATOVSKA A, LIGHTOWLERS RN, TAYLOR RW et al.: Targeting peptide nucleic acid (PNA) oligomers to mitochondria within cells by conjugation to lipophilic cations: implications for mitochondrial DNA replication, expression and disease. Nucleic Acids Res. (2001) 29:1852-1863.
67. MCGREGOR A, SMITH PM, ROSS GF, TAYLOR RW, TURNBULL DM, LIGHTOWLERS RN: Bridging PNAs can bind preferentially to a deleted mitochondrial DNA template but replication by mitochondrial DNA polymerase gamma in vitro is not impaired. Biochim. Biophys. Acta (2003) 1629:73-83.
68. ROSS GR SMITH PM, MCGREGOR A, TURNBULL DM, LIGHTOWLERS RN: Synthesis of trifunctional PNA-benzophenone derivatives for mitochondrial targeting, selective DNA binding, and photo-cross-linking. Bioconjug. Chem. (2003) 14:962-966.
69. SMITH PM, ROSS GF, TAYLOR RW, TURNBULL DM, LIGHTOWLERS RN: Strategies for treating disorders of the mitochondrial genome. Biochim. Biohys. Acta (2004) 1659:232-239.
70. FLIERL A, JACKSON C, COTTRELL B, MURDOCK D, SEIBEL P, WALLACE DC: Targeted delivery of DNA to the mitochondrial compartment via import sequence-conjugated peptide nucleic acid. Mol. Ther. (2003) 7:550-557.
71. TANAKA M, BORGELD HJ, ZHANG J et al.: Gene therapy for mitochondrial disease by delivering restriction endonuclease Smal into mitochondria. J. Biomed. Sci. (2002) 9:534-541.
72. SRIVASTAVA S, MORAES CT: Manipulating mitochondrial DNA heteroplasmy by a mitochondrially targeted restriction endonuclease. Hum. Mol. Genet. (2001) 10:3093-3099. One of two papers describing the manipulation of mtDNA heteroplasmy in human cells by restriction endonucleases expressed within the organelle.
73. BAYONA-BAFALUY MP, BATTERSBY BJ, SHOUBRIDGE EA, MORAES CT: Shifting mitochondrial DNA heteroplasmy by mitochondrially-targeted restriction endonucleases. Am. J. Hum. Genet. (2003) 73(Suppl.):627.
74. MANFREDI G, GUPTA N, VAZQUEZ-MEMIJE ME et al.: Oligomycin induces a decrease in the cellular content of a pathogenic mutation in the human mitochondrial ATPase 6 gene. J. Biol. Chem. (1999) 274:9386-9391.
75. SANTRA S, GILKERSON RW, DAVIDSON M, SCHON EA: Ketogenic treatment reduces deleted mitochondrial DNAs in cultured human cells. Ann. Neurol. (2004) 56:662-669. One of two papers from this group describing pharmacological approaches to shifting mtDNA heteroplasmy.
76. leu(CUN) mtDNA point mutation in a sporadic patient with mitochondrial encephalomyopathy segregates rapidly in skeletal muscle and suggests an approach to therapy. Hum. Mol. Genet. (1996) 5:1835-1840.
77. WEBER K, WILSON JN, TAYLOR L et al.: A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle. Am. J. Hum. Genet. (1997) 60:373-380.
78. CLARK KM, BINDOFF LA, LIGHTOWLERS RN et al.: Reversal of a mitochondrial DNA defect in human skeletal muscle. Nat. Genet. (1997) 16:222-224. 'Gene shifting' using the anaesthetic bupivacaine to induce muscle damage and stimulate satellite cell incorporation.
79. ANDREWS RM, GRIFFITHS PG, CHINNERY PF, TURNBULL DM: Evaluation of bupivacaine-induced muscle regeneration in the treatment of ptosis in patients with chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome. Eye (1999) 13:769-772.
80. SHOUBRIDGE EA, JOHNS T, KARPATI G: Complete restoration of a wild-type mtDNA genotype in regenerating muscle fibres in a patient with a tRNA point mutation and mitochondrial encephalomyopathy. Hum. Mol. Genet. (1997) 6:2239-2242. 'Gene shifting' using surgery (muscle biopsy) to induce muscle damage and stimulate satellite cell incorporation.
81. TAIVASSALO T, FU K, JOHNS T, ARNOLD D, KARPATI G, SHOUBRIDGE EA: Gene shifting: a novel therapy for mitochondrial myopathy. Hum. Mol. Genet. (1999) 8:1047-1052. Practical method of inducing satellite cell incorporation into mature muscle and 'gene shifting' - resistance exercise training.
82. TAIVASSALO T, SHOUBRIDGE EA, CHEN J et al.: Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects. Ann. Neurol. (2001) 50:133-141.
83. TAIVASSALO T, HALLER RG: Implications of exercise training in mtDNA defects-use it or lose it? Biochim. Biohys. Acta (2004) 1659:221-231.
84. THORBURN DR, DAHL HHM: Mitochondrial disorders: genetics, counseling, prenatal diagnosis and reproductive options. Am. J. Med. Genet. (2001) 106:102-114.
85. POULTON J, TURNBULL DM: 74th ENMC International workshop: Mitochondrial diseases. Neuromuscul. Disord. (2000) 10:460-462.
86. BROWN DT, SAMUELS DC, MICHAEL EM, TURNBULL DM, CHINNERY PF: Random genetic drift determines the level of mutant mtDNA in human primary oocytes. Am. J. Hum. Genet. (2000) 68:533-536.
87. 8993T>G disease. Am. J. Hum. Genet. (1992) 50:629-633.
88. WHITE SL, COLLINS VR, WOLFE R et al.: Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am. J. Hum. Genet. (1999) 65:474-482.
89. LESHINSKY-SILVER E, PERACH M, BASILEVSKY E et al.: Prenatal exclusion of Leigh syndrome due to T8993C mutation in the mitochondrial DNA. Prenat. Diagn. (2003) 23:31-33.
90. DEAN NL, BATTERSBY BJ, AO A, GOSDEN RG, TAN SL, SHOUBRIDGE EA: Prospect of preimplantation genetic diagnosis for heritable mitochondrial DNA diseases. Mol. Hum. Reprod. (2003) 9:631-638.
91. ROBERTS RM: Prevention of human mitochondrial (mtDNA) disease by nucleus transplantation into an enucleated donor oocyte. Am. J. Med. Genet. (1999) 87:265-266.
92. MEIRELLES F, SMITH LC: Mitochondrial genotype segregation in a mouse heteroplasmic lineage produced by embyonic karyoplast transplantation. Genetics (1997) 145:445-451.
93. FEUERMANN M, FRANCISCI S, RINALDI T et al.: The yeast counterparts of human 'MELAS' mutations cause mitochondrial dysfunction that can be rescued by overexpression of the mitochondrial translation factor EF-Tu. EMBO Rep. (2003) 4:53-58. Report demonstrating the suppression of mitochondrial dysfunction in yeast harbouring mtDNA mutations by EF-Tu, a nuclear elongation factor.
94. WEISSIG V LIZANO C, TORCHILIN VP: Selective DNA release from DQAsome/DNA complexes at mitochondria-like membranes. Drug Deliv. (2000) 7:1-5. One of several reports documenting the potential of the canonic lipid DQAsomes to deliver DNA toward mitochondria.
95. D'SOUZA GG, RAMMOHAN R, CHENG SM, TORCHILIN VP, WEISSIG V: DQAsome-mediated delivery of plasmid DNA toward mitochondria in living cells. J. Control. Release (2003) 92:189-197.
96. KOULINTCHENKO M, KONSTANTINOV Y, DIETRICH A: Plant mitochondria actively import DNA via the permeability transition pore complex. EMBO J. (2003) 22:1245-1254.
97. COLLOMBET JM, WHEELER VC, VOGEL F, COUTELLE C: Introduction of plasmid DNA into isolated mitochondria by electroporation. A novel approach toward gene correction for mitochondrial disorders. J. Biol. Chem. (1997) 272:5342-5347.
98. BIGGER B, TOLMACHOV O, COLLOMBET JM, FRAGKOS M, PALASZEWSKI I, COUTELLE C: An araC-controlled bacterial cre expression system to produce DNA minicircle vectors for nuclear and mitochondrial gene therapy. J. Biol. Chem. (2001) 276:23018-23027.
99. MCGREGOR A, TEMPERLEY R, CHRZANOWSKA-LIGHTOWLERS ZM, LIGHTOWLERS RN: Absence of expression from RNA internalised into electroporated mammalian mitochondria. Mol. Genet. Genomics (2001) 265:721-729.
100. BIGGER B, TAYLOR RW, TURNBULL DM, LIGHTOWLERS RN: Gene therapy for mitochondrial DNA disorders. In: Genetics of Mitochondrial Diseases. Holt IJ (Ed.), Oxford University Press, Oxford, UK (2003):327-344.
101. KHAN SM, BENNETT JP: Development of mitochondrial gene replacement therapy. J. Bioenerg. Biomembr. (2004) 36:387-393. Paper outlining 'protofection' as a potential mechanism for delivering genes to mitochondria.