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An antigenomic strategy for treating heteroplasmic mtDNA disorders

Lookup NU author(s): Professor Robert Taylor, Dr Theresa Wardell, Dr Paul Smith, Emeritus Professor Doug Turnbull, Professor Robert Lightowlers


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In mammals, mitochondrial DNA (mtDNA) is the only autonomously replicating source of DNA outside the nucleus. Housed in the mitochondrial matrix, this molecule encodes thirteen polypeptides, all of which are believed to be essential components of the mitochondrial respiratory chain. Defects of the mitochondrial genome can cause severe neurological and multi-systemic disorders. As the genetic defect causes a dysfunction in the terminal stage of oxidative metabolism, there is little potential for pharmacological intervention. Thus, there is currently no effective therapy for these chronic progressive disorders. In the disease state, pathogenic mtDNA molecules often cohabit the same cell and tissue with wild type mtDNA, a situation termed heteroplasmy. Manifestation of biochemical and clinical defects occur only when a threshold level of heteroplasmy has been passed. The mitochondrial genome must be continually turned over. Consequently, if a pathogenic mtDNA molecule were to be targeted to prevent it from replicating, the wild type copy would be given a propagative advantage. Over time, therefore, the biochemical and, potentially, the clinical deficiency could be reversed. This manuscript summarises our attempts to identify such an antigenomic molecule, to localise this molecule to mitochondria and to assess its function in whole cells. Finally, we discuss the importance of identifying and designing new antigenomic molecules which may prove effective in treating patients with disorders of the mitochondrial genome. © 2001 Elsevier Science B.V.

Publication metadata

Author(s): Smith PM; Wardell TM; Lightowlers RN; Taylor RW; Turnbull DM; Muratovska A; Murphy MP

Publication type: Review

Publication status: Published

Journal: Advanced Drug Delivery Reviews

Year: 2001

Volume: 49

Issue: 1-2

Pages: 121-125

ISSN (print): 0169-409X

ISSN (electronic): 1872-8294


DOI: 10.1016/S0169-409X(01)00130-2

PubMed id: 11377807