Journal
SEMINARS IN NEUROLOGY
Volume 21, Issue 3, Pages 327-335Publisher
THIEME MEDICAL PUBL INC
DOI: 10.1055/s-2001-17949
Keywords
allotopic gene expression; mitochondrial DNA; gene therapy; ATPase6; Leigh syndrome; oxidative phosphorylation; mitochondrial disease; somatic mutations; mitochondrial targeting leader sequence; heteroplasmy
Categories
Ask authors/readers for more resources
Successful treatment of mitochondrial DNA (mtDNA) mutations might be possible by construction of mtDNA-encoded protein genes so that they can be inserted into the nuclear genome and the protein expressed in the mitochondria (allotopic expression). This technique would require individual assembly of all 13 mtDNA-encoded protein genes with an aminoterminal leader peptide that directs the cytoplasmic translated protein to the mitochondrial membrane. The 13 allotopic genes could be inserted into the nuclear genome of a patient's stem cell that had been cured of its nascent mtDNA via ethidium bromide treatment (tho-zero cell). The rho-zero cell would be a uridine auxotroph, and recovery from uridine auxotrophy would indicate successful transformation. The patient's own cells could then be returned to the patient's body. With a selective advantage of recovered oxidative phosphorylation, the transformed cells could replace cells with mtDNA mutations. Results of experiments by us on allotopically expressed CHO ATPase6 and of experiments by other workers suggest that there might be competition with endogenous mtDNA-encoded proteins if the particular protein gene is not removed from the endogenous mitochondrial genomes. Thus, it is likely that an 13 mtDNA-encoded protein genes will need to be allotopically expressed, with concomitant removal of all mtDNA genomes, in order for this form of mtDNA gene therapy to be successful.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available