THERAPEUTIC APPROACHES TO MITOCHONDRIAL ENCEPHALOMYOPATHIES

Therapy for mitochondrial diseases is woefully inadequate. However, lack of cure does not equate with lack of treatment. We consider sequentially different therapeutic approaches. Palliative therapy is dictated by good medical practice and includes anticonvulsant medication, control of endocrine dysfunction, and surgical procedures. Removal of noxious metabolites is centered on combating lactic acidosis, but extends to other metabolites, such as thymidine in patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome. Attempts to bypass blocks in the respiratory chain by means of administration of electron acceptors have not been successful, but this concept may be amenable to genetic engineering. Administration of metabolites and cofactors is the mainstay of real-life therapy, and includes both components of the respiratory chain and other natural compounds. This approach is especially important and may be lifesaving in disorders due to primary deficiencies of specific compounds, such as carnitine or coenzyme Q10 (CoQ10). There is increasing interest in the administration of reactive oxygen radicals (ROS) scavengers both in primary mitochondrial diseases and in neurodegenerative diseases directly or indirectly related to mitochondrial dysfunction. Gene therapy is a challenge because of polyplasmy and heteroplasmy, but interesting experimental approaches are being pursued. One important strategy is to decrease the ratio of mutant to wild-type mitochondrial genomes (“gene shifting”) by different means: (i) converting mutated mitochondrial DNA genes into normal nuclear DNA genes (“allotopic expression”); (ii) importing cognate genes from other species (xenotopic expression); (iii) correcting mtDNA mutations by importing specific restriction endonucleases; (iv) selecting for respiratory function; and (v) inducing muscle regeneration. Germline therapy raises ethical problems but is being seriously considered to prevent maternal transmission of mtDNA mutations. Preventive therapy through genetic counseling and prenatal diagnosis is still limited for mtDNA-related disorders but is becoming increasingly important for nDNA-related disorders.