EMERGING THERAPEUTIC APPROACHES TO MITOCHONDRIAL DISEASES Tina Wenz, 1 Sion L. Williams, 1 Sandra R. Bacman, 1 and Carlos T. Moraes 1,2 * 1 Department of Neurology, University of Miami School of Medicine, Miami, Florida 2 Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, Florida Mitochondrial diseases are very heterogeneous and can affect dif- ferent tissues and organs. Moreover, they can be caused by genetic defects in either nuclear or mitochondrial DNA as well as by environmen- tal factors. All of these factors have made the development of therapies difficult. In this review article, we will discuss emerging approaches to the therapy of mitochondrial disorders, some of which are targeted to specific conditions whereas others may be applicable to a more diverse group of patients. ' 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:219–229. Key Words: mitochondrial diseases; gene therapy; heteroplasmy; oxida- tive phosphorylation defects M itochondrial disorders are no longer considered to be rare diseases. Recent estimates predict that 1 in 5,000 children will develop a mitochondrial disease [Schaefer et al., 2004]. Moreover, a recent study found that 1 in 200 adults carry a common mtDNA mutation and thus can potentially transmit a mitochondrial disease [Cree et al., 2009]. In the last decade, diagnosing and deciphering the mechanism of the broad spectrum of mitochondrial disorders has proceeded at a fast pace. However, this heterogeneous group of disorders is still faced with limited therapeutic options. It is therefore exciting that in recent years several dif- ferent strategies to overcome the initial defect and alleviate its up- and downstream effects have been developed and tested in cell and animal models of different mitochondrial disorders. In this review, we will discuss these emerging therapeutic advances. ENTRY POINTS FOR THERAPEUTIC STRATEGIES Defects in the oxidative phosphorylation system (OXPHOS) can be caused by mutations in the nuclear (n) and the mitochondrial (mt) DNA. Mutations in mtDNA are mostly heteroplasmic, meaning that there is a mixture of wild- type and mutated mtDNA molecules. Depending on the per- centage of mutated DNA, human subjects are either asymp- tomic or develop a mitochondrial disease when the number of mutated mtDNA molecules exceeds a certain threshold (threshold effect). Alterations in both genomes ultimately result in stalled electron transfer within the respiratory chain and disrupted ATP synthesis. These effects also influence other cellular metabolic process, which are linked to OXPHOS such as citric acid cycle and glycolysis. Hence, novel therapeutic strategies target genomic, protein or cellular metabolic levels to overcome the mitochondrial defect: 1. Preventing transmission of mtDNA defects. 2. Shifting the heteroplasmy level. 3. Replacement of the defective mitochondrial genes, tRNAs and proteins. 4. Scavenging of toxic intermediates. 5. Optimizing ATP synthetic capacity. 6. Bypassing defective OXPHOS components. Different strategies focusing on these issues will be dis- cussed in the following text. PREVENTING TRANSMISSION OF mtDNA DEFECTS—GERMLINE THERAPY Mutations in mtDNA are transmitted through the maternal lineage by women who, despite being asymptomatic, are carriers of mtDNA mutations. Asymmetrical cell division results in oocytes with different mutational load (ratio muta- ted—wild-type mtDNA), which theoretically can result in children with different degrees of mitochondrial dysfunction. This unpredictability contrasts to the Mendelian pattern of in- heritance for nuclear gene mutation and makes genetic coun- seling difficult for women with a mtDNA mutation. Substitu- tion of the mutated mtDNA by wild-type mtDNA is the best therapeutic option to prevent transmission of mitochondrial disease caused by mtDNA mutation from mother to child. Two options are conceptually possible to perform this substi- tution: Cytoplasmic transfer and pronuclear transfer. Present address of Tina Wenz: Institute for Genetics, University of Cologne, Zu ¨ lpicher Str. 47, 50674 Cologne, Germany. Grant sponsor: PHS; Grant numbers: EY10804, NS041777, CA85700.; Grant sponsors: The Parkinson Disease Foundation, the Muscular Dystrophy Associa- tion, United Mitochondria Disease Foundation. *Correspondence to: Carlos Moraes, Department of Neurology, University of Miami School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136. E-mail: cmoraes@med.miami.edu Received 16 April 2010; Accepted 29 June 2010 View this article online at wileyonlinelibrary.com. DOI: 10.1002/ddrr.109 DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS 16: 219 – 229 (2010) ' 2010 Wiley -Liss, Inc.