Allotopic expression explained

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]

Evolution

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

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]

Research

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 Lifespan.io, 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.

Notes and References

  1. de Grey AD . Mitochondrial gene therapy: an arena for the biomedical use of inteins . Trends Biotechnol. . 18 . 9 . 394–9 . September 2000 . 10942964 . 10.1016/S0167-7799(00)01476-1 .
  2. Oca-Cossio J, Kenyon L, Hao H, Moraes CT . Limitations of allotopic expression of mitochondrial genes in mammalian cells . Genetics . 165 . 2 . 707–20 . October 2003 . 10.1093/genetics/165.2.707 . 14573482 . 1462783 .
  3. Allotopic expression of mitochondrial-encoded genes in mammals: achieved goal, undemonstrated mechanism or impossible task? . Perales-Clemente, Ester . Nucleic Acids Res. . Jan 2011 . 39 . 1 . 225–234 . 10.1093/nar/gkq769 . 20823090 . 3017613. etal.
  4. Johnston IG, Williams BP . Evolutionary Inference across Eukaryotes Identifies Specific Pressures Favoring Mitochondrial Gene Retention . Cell Systems . 2 . 2 . 101–11 . February 2016 . 27135164 . 10.1016/j.cels.2016.01.013 . free .
  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 . 2019 . 30730541 . Bouquet . C. . Vignal Clermont . C. . Galy . A. . Fitoussi . S. . Blouin . L. . Munk . M. R. . Valero . S. . Meunier . S. . Katz . B. . Sahel . J. A. . Thomasson . N. . JAMA Ophthalmology . 137 . 4 . 399–406 . 10.1001/jamaophthalmol.2018.6902 . 6459107 .
  6. Web site: Results from the Gensight Biologics Trial of ND4 Allotopic Expression . 27 December 2016 . 2020-12-25.
  7. Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy . 2020 . 10.1126/scitranslmed.aaz7423 . 2020-12-25 . Yu-Wai-Man . Patrick . Newman . Nancy J. . Carelli . Valerio . Moster . Mark L. . Biousse . Valerie . Sadun . Alfredo A. . Klopstock . Thomas . Vignal-Clermont . Catherine . Sergott . Robert C. . Rudolph . Günther . La Morgia . Chiara . Karanjia . Rustum . Taiel . Magali . Blouin . Laure . Burguière . Pierre . Smits . Gerard . Chevalier . Caroline . Masonson . Harvey . Salermo . Yordak . Katz . Barrett . Picaud . Serge . Calkins . David J. . Sahel . José-Alain . Science Translational Medicine . 12 . 573 . 33298565 . 228076964 . 11585/794045 . free .
  8. Web site: Gene Therapy Trial Successfully Improves Vision Mitochondrial gene therapy restores vision in landmark human trial. 2020-12-25.
  9. Web site: Gene therapy injection in one eye surprises scientists by improving vision in both . 10 December 2020 . 2020-12-25.
  10. https://www.gensight-biologics.com/diseases-we-target/ Diseases We Target
  11. Web site: MitoSENS Project Results to be Published in the journal Nucleic Acids Research!. 18 August 2016. lifespan.io. 28 November 2016 .
  12. Web site: Stable nuclear expression of ATP8 and ATP6 genes rescues a mtDNA Complex V null mutant . https://web.archive.org/web/20160909050218/http://nar.oxfordjournals.org/content/early/2016/09/04/nar.gkw756 . dead . 9 September 2016 . Oxford Journals . Nucleic Acids Research . 28 November 2016 .

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