An antigenomic strategy for treating heteroplasmic mtDNA disorders

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 es sential components of the mitochondrial respiratory chain. Defects of the m itochondrial genome can cause severe neurological and multi-systemic disord ers. As the genetic defect causes a dysfunction in the terminal stage of ox idative metabolism, there is little potential for pharmacological intervent ion. Thus, there is currently no effective therapy for these chronic progre ssive disorders. In the disease state, pathogenic mtDNA molecules often coh abit the same cell and tissue with wild type mtDNA, a situation termed hete roplasmy. Manifestation of biochemical and clinical defects occur only when a threshold level of heteroplasmy has been passed. The mitochondrial genom e must be continually turned over. Consequently, if a pathogenic mtDNA mole cule were to be targeted to prevent it from replicating, the wild type copy would be given a propagative advantage. Over time, therefore, the biochemi cal and, potentially, the clinical deficiency could be reversed. This manus cript 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 d isorders of the mitochondrial genome. (C) 2001 Elsevier Science B.V. All ri ghts reserved.