title: Approaches to mitochondrial gene therapy.
abstract: Since their discovery during the end of the 80's the number of diseases found to be associated with defects in the mitochondrial genome has grown significantly. Organs affected by mutations in mitochondrial DNA (mtDNA) include in decreasing order of vulnerability the brain, skeletal muscle, heart, kidney and liver. Hence neuromuscular and neurodegenerative diseases represent the two largest groups of mtDNA diseases. Despite major advances in understanding mtDNA defects at the genetic and biochemical level, there is however no satisfactory treatment available to the vast majority of patients. This is largely due to the fact that most of these patients have respiratory chain defects, i.e. defects that involve the final common pathway of oxidative metabolism, making it impossible to bypass the defect by administering alternative metabolic carriers of energy. Conventional biochemical treatment having reached an impasse, the exploration of gene therapeutic approaches for patients with mtDNA defects is warranted. For now mitochondrial gene therapy appears to be only theoretical and speculative. Any possibility for gene replacement is dependent on the development of an efficient mitochondrial transfection vector. In this review we describe the current state of the development of mitochondria-specific DNA delivery systems. We summarize our own efforts in exploring the properties of dequalinium and other similar cationic bolaamphiphiles with delocalized charge centers, for the design of a vector suited for the transport of DNA to mitochondria in living cells. Further, we outline some unique hurdles that need to be overcome if the development of such delivery systems is to progress.
authors.affiliation: Department of Pharmaceutical Sciences, Bouve College of Health Sciences, Northeastern University, Boston, MA 02115, USA. dsouza.g@neu.edu
authors.forename: Gerard G M
authors.initials: GG
authors.lastname: D'Souza
authors.forename: Volkmar
authors.initials: V
authors.lastname: Weissig
mesh_terms: D004272:DNA, Mitochondrial / Q000235:genetics*; D016503:Drug Delivery Systems; D004579:Electron Transport / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D017240:Mitochondrial Myopathies / Q000235:genetics / Q000628:therapy*
chemical_list: D004272:DNA, Mitochondrial