Allotopic expression

Last updated

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]

Contents

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.

Related Research Articles

<span class="mw-page-title-main">Mitochondrial disease</span> Spontaneously occurring or inherited disorder that involves mitochondrial dysfunction

Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of food molecules into the ATP that powers most cell functions.

Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. Several ASOs have been approved in the United States, the European Union, and elsewhere.

<span class="mw-page-title-main">Homoplasmy</span> Identity of organellar DNA sequences in a cell

Homoplasmy is a term used in genetics to describe a eukaryotic cell whose copies of mitochondrial DNA are all identical. In normal and healthy tissues, all cells are homoplasmic. Homoplasmic mitochondrial DNA copies may be normal or mutated; however, most mutations are heteroplasmic. It has been discovered, though, that homoplasmic mitochondrial DNA mutations may be found in human tumors.

<span class="mw-page-title-main">Idebenone</span> Chemical compound

Idebenone is a drug that was initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer's disease and other cognitive defects. This has been met with limited success. The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of neuromuscular diseases. In 2010, early clinical trials for the treatment of Friedreich's ataxia and Duchenne muscular dystrophy have been completed. As of December 2013 the drug is not approved for these indications in North America or Europe. It is approved by the European Medicines Agency (EMA) for use in Leber's hereditary optic neuropathy (LHON) and was designated an orphan drug in 2007.

<span class="mw-page-title-main">Leber's hereditary optic neuropathy</span> Mitochondrially inherited degeneration of retinal cells in human

Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; it predominantly affects young adult males. LHON is transmitted only through the mother, as it is primarily due to mutations in the mitochondrial genome, and only the egg contributes mitochondria to the embryo. Men cannot pass on the disease to their offspring. LHON is usually due to one of three pathogenic mitochondrial DNA (mtDNA) point mutations. These mutations are at nucleotide positions 11778 G to A, 3460 G to A and 14484 T to C, respectively in the ND4, ND1 and ND6 subunit genes of complex I of the oxidative phosphorylation chain in mitochondria.

Neuro-ophthalmology is an academically-oriented subspecialty that merges the fields of neurology and ophthalmology, often dealing with complex systemic diseases that have manifestations in the visual system. Neuro-ophthalmologists initially complete a residency in either neurology or ophthalmology, then do a fellowship in the complementary field. Since diagnostic studies can be normal in patients with significant neuro-ophthalmic disease, a detailed medical history and physical exam is essential, and neuro-ophthalmologists often spend a significant amount of time with their patients.

Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain. [1].

Protofection is a protein-mediated transfection of foreign mitochondrial DNA (mtDNA) into the mitochondria of cells in a tissue to supplement or replace the native mitochondrial DNA already present. The complete mtDNA genome or just fragments of mtDNA generated by polymerase chain reaction can be transferred into the target mitochondria through the technique.

<span class="mw-page-title-main">MT-ND6</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND6 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 6 protein (ND6). The ND6 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in the human MT-ND6 gene are associated with Leigh's syndrome, Leber's hereditary optic neuropathy (LHON) and dystonia.

<span class="mw-page-title-main">MT-ND4</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND4 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 4 (ND4) protein. The ND4 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in the MT-ND4 gene are associated with age-related macular degeneration (AMD), Leber's hereditary optic neuropathy (LHON), mesial temporal lobe epilepsy (MTLE) and cystic fibrosis.

<span class="mw-page-title-main">MT-ND2</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND2 is a gene of the mitochondrial genome coding for the NADH dehydrogenase 2 (ND2) protein. The ND2 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variants of human MT-ND2 are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh's syndrome (LS), Leber's hereditary optic neuropathy (LHON) and increases in adult BMI.

<span class="mw-page-title-main">MT-ND4L</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND4L is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 4L (ND4L) protein. The ND4L protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variants of human MT-ND4L are associated with increased BMI in adults and Leber's Hereditary Optic Neuropathy (LHON).

<span class="mw-page-title-main">MT-ATP8</span> Mitochondrial protein-coding gene whose product is involved in ATP synthesis

MT-ATP8 is a mitochondrial gene with the full name 'mitochondrially encoded ATP synthase membrane subunit 8' that encodes a subunit of mitochondrial ATP synthase, ATP synthase Fo subunit 8. This subunit belongs to the Fo complex of the large, transmembrane F-type ATP synthase. This enzyme, which is also known as complex V, is responsible for the final step of oxidative phosphorylation in the electron transport chain. Specifically, one segment of ATP synthase allows positively charged ions, called protons, to flow across a specialized membrane inside mitochondria. Another segment of the enzyme uses the energy created by this proton flow to convert a molecule called adenosine diphosphate (ADP) to ATP. Subunit 8 differs in sequence between Metazoa, plants and Fungi.

<span class="mw-page-title-main">MT-ND3</span> Mitochondrial protein-coding gene whose product is involved in the respiratory chain

MT-ND3 is a gene of the mitochondrial genome coding for the NADH dehydrogenase 3 (ND3) protein. The ND3 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variants of MT-ND3 are associated with Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh's syndrome (LS) and Leber's hereditary optic neuropathy (LHON).

<span class="mw-page-title-main">MT-ATP6</span> Mitochondrial protein-coding gene whose product is involved in ATP synthesis

MT-ATP6 is a mitochondrial gene with the full name 'mitochondrially encoded ATP synthase membrane subunit 6' that encodes the ATP synthase Fo subunit 6. This subunit belongs to the Fo complex of the large, transmembrane F-type ATP synthase. This enzyme, which is also known as complex V, is responsible for the final step of oxidative phosphorylation in the electron transport chain. Specifically, one segment of ATP synthase allows positively charged ions, called protons, to flow across a specialized membrane inside mitochondria. Another segment of the enzyme uses the energy created by this proton flow to convert a molecule called adenosine diphosphate (ADP) to ATP. Mutations in the MT-ATP6 gene have been found in approximately 10 to 20 percent of people with Leigh syndrome.

<span class="mw-page-title-main">MT-ND5</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND5 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 5 protein (ND5). The ND5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in human MT-ND5 are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) as well as some symptoms of Leigh's syndrome and Leber's hereditary optic neuropathy (LHON).

<span class="mw-page-title-main">MT-ND1</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND1 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 1 (ND1) protein. The ND1 protein is a subunit of NADH dehydrogenase, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variants of the human MT-ND1 gene are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh's syndrome (LS), Leber's hereditary optic neuropathy (LHON) and increases in adult BMI.

<span class="mw-page-title-main">FOXRED1</span> Protein-coding gene in the species Homo sapiens

FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1), also known as H17, or FP634 is an enzyme that in humans is encoded by the FOXRED1 gene. FOXRED1 is an oxidoreductase and complex I-specific molecular chaperone involved in the assembly and stabilization of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in FOXRED1 have been associated with Leigh syndrome and infantile-onset mitochondrial encephalopathy.

Mitohondrial optic neuropathies are a heterogenous group of disorders that present with visual disturbances resultant from mitochondrial dysfunction within the anatomy of the Retinal Ganglion Cells (RGC), optic nerve, optic chiasm, and optic tract. These disturbances are multifactorial, their aetiology consisting of metabolic and/or structural damage as a consequence of genetic mutations, environmental stressors, or both. The three most common neuro-ophthalmic abnormalities seen in mitochondrial disorders are bilateral optic neuropathy, ophthalmoplegia with ptosis, and pigmentary retinopathy.

<span class="mw-page-title-main">Alfredo Sadun</span> American ophthalmologist

Alfredo Arrigo Sadun is an American ophthalmologist, academic, author and researcher. He holds the Flora L. Thornton Endowed Chair at Doheny Eye Centers-UCLA and is Vice-Chair of Ophthalmology at UCLA.

References

  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. doi:10.1093/genetics/165.2.707. 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. ↑ 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. (2019). "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". JAMA Ophthalmology. 137 (4): 399–406. doi:10.1001/jamaophthalmol.2018.6902. PMC   6459107 . PMID   30730541.
  6. ↑ "Results from the Gensight Biologics Trial of ND4 Allotopic Expression". 27 December 2016. Retrieved 25 December 2020.
  7. ↑ 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 (2020). "Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy". Science Translational Medicine. 12 (573). doi:10.1126/scitranslmed.aaz7423. hdl: 11585/794045 . PMID   33298565. S2CID   228076964 . 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". 10 December 2020. Retrieved 25 December 2020.
  10. ↑ Diseases We Target
  11. ↑ "MitoSENS Project Results to be Published in the journal Nucleic Acids Research!". lifespan.io. 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.