Allotopic expression (AE) refers to expression of

genes In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

in the

cell nucleus The cell nucleus (; : nuclei) is a membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have #Anucleated_cells, ...

that normally are expressed only from the mitochondrial genome. Biomedically engineered AE has been suggested as a possible future tool in

gene therapy Gene therapy is Health technology, medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells. The first attempt at modifying human DNA ...

of certain

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

-related diseases, however this view is controversial. While this type of expression has been successfully carried out in

yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom (biology), kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are est ...

, the results in mammals have been conflicting.

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.

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 Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited (transmitted from mother to offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; it predomin ...

. 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 The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

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

Research

The

SENS Research Foundation The SENS Research Foundation is a non-profit organization that does research programs and public relations work for the application of regenerative medicine to aging. It was founded in 2009, located in Mountain View, California, US. The organizat ...

has reported success in expressing the ATP6 gene allotopically ''in vitro''. 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 ''Nucleic Acids Research'' is an open-access peer-reviewed scientific journal published since 1974 by the Oxford University Press. The journal covers research on nucleic acids, such as DNA and RNA, and related work. According to the ''Journal Cita ...

providing proof of concept for the MitoSENS repair approach for repairing age related damage.

References

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