Allotopic expression

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Allotopic expression (AE) refers to expression of genes in the cell nucleus that normally are expressed only from the mitochondrial genome. Biomedically engineered AE has been suggested as a possible future tool in gene therapy of certain mitochondria-related diseases,[1] however this view is controversial.[2] While this type of expression has been successfully carried out in yeast, the results in mammals have been conflicting.[3]


In the cells of extant organisms, the vast majority of the proteins present in the mitochondria are coded for by nuclear DNA. Those genes are thought to have transferred to the eukaryotic nucleus during evolution, suggesting that genes transferred not only survived but are expressed in the cell nucleus.[4]

Use in therapy[edit]

In 2014, Gensight Biologics began a clinical program of allotopic expressing the MT-ND4 gene in the nucleus as therapies for Leber's hereditary optic neuropathy.[5][6] In 2020, Gensight released Phase III clinical trial results, which showed a notable improvements against the normal progression of the disease but statistical insignificance in all areas. The company suspected the outcome was due to the transferal of viral vector DNA from the treated eye to the untreated eye of each patient, and thus a full control group trial in which the control group have no exposure to the drug may be needed if requested by the Food and Drug Administration.[7][8][9]

Gensight plans to initiate pre-clinical studies of allotopic expressing the MT-ND1 gene after the GS010 phase 3 trial.[10]


The SENS Research Foundation has reported success in expressing the ATP6 gene allotopically in vitro.[11]

As of 6 September 2016 and as a result of funds raised at, the SENS Research Foundation showed ATP6 and ATP8 could be successfully expressed with their published research appearing in Nucleic Acids Research[12] providing proof of concept for the MitoSENS repair approach for repairing age related damage.


  1. ^ de Grey AD (September 2000). "Mitochondrial gene therapy: an arena for the biomedical use of inteins". Trends Biotechnol. 18 (9): 394–9. doi:10.1016/S0167-7799(00)01476-1. PMID 10942964.
  2. ^ Oca-Cossio J, Kenyon L, Hao H, Moraes CT (October 2003). "Limitations of allotopic expression of mitochondrial genes in mammalian cells". Genetics. 165 (2): 707–20. PMC 1462783. PMID 14573482.
  3. ^ Perales-Clemente, Ester; et al. (January 2011). "Allotopic expression of mitochondrial-encoded genes in mammals: achieved goal, undemonstrated mechanism or impossible task?". Nucleic Acids Res. 39 (1): 225–234. doi:10.1093/nar/gkq769. PMC 3017613. PMID 20823090.
  4. ^ Johnston IG, Williams BP (February 2016). "Evolutionary Inference across Eukaryotes Identifies Specific Pressures Favoring Mitochondrial Gene Retention". Cell Systems. 2 (2): 101–11. doi:10.1016/j.cels.2016.01.013. PMID 27135164.
  5. ^ "Immune Response and Intraocular Inflammation in Patients With Leber Hereditary Optic Neuropathy Treated With Intravitreal Injection of Recombinant Adeno-Associated Virus 2 Carrying the ND4 Gene: A Secondary Analysis of a Phase 1/2 Clinical Trial". Retrieved 25 December 2020.
  6. ^ "Results from the Gensight Biologics Trial of ND4 Allotopic Expression". Retrieved 25 December 2020.
  7. ^ "Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy". Retrieved 25 December 2020.
  8. ^ "Gene Therapy Trial Successfully Improves Vision Mitochondrial gene therapy restores vision in landmark human trial". Retrieved 25 December 2020.
  9. ^ "Gene therapy injection in one eye surprises scientists by improving vision in both". Retrieved 25 December 2020.
  10. ^ Diseases We Target
  11. ^ "MitoSENS Project Results to be Published in the journal Nucleic Acids Research!". 18 August 2016. Retrieved 28 November 2016.
  12. ^ "Stable nuclear expression of ATP8 and ATP6 genes rescues a mtDNA Complex V null mutant". Nucleic Acids Research. Oxford Journals. Archived from the original on 9 September 2016. Retrieved 28 November 2016.