Journal of IiME Volume 1 Issue 2 www.investinme.org Can "molecular addressing" correct mitochondrial diseases? Mitochondria are the power plants of the cell and perform most of the chemical reactions that transform sugars into usable energy. Mitochondrial diseases are estimated to affect at least 1 in 5000 people and can lead to a variety of serious diseases. Many of the genes responsible for energy production are made up of mitochondrial DNA, rather than DNA in the cell's nucleus - and an obvious solution to mitochondrial errors would be to introduce a normal copy of the defective gene into the mitochondrial DNA. Dr. Marisol Corral-Debrinski and her colleagues at the Pierre and Marie Curie University in Paris, France, picked two mitochondrial gene mutations. The team tagged normal versions of these genes with two separate cellular "address codes" and inserted them into the cytoplasm of cells grown in a lab dish. The first code directs the messenger RNA - the molecule that carries the instructions for making a protein - to the surface of the mitochondria, ensuring that the protein gets made at the mitochondrial membrane. The second address code, known as the mitochondrial targeting sequence, tells the protein to enter the mitochondria. These double-tagged genes were able to reverse the effect of both mitochondrial mutations in cell cultures for up to a year. Corral-Debrinski is now planning to test the gene therapy on laboratory mice. Although not directly affecting ME we felt that Marisol’s work on mitochondria might be of interest. Marisol allowed IiME to publish three of her research papers in the Journal but, unfortunately, we have been unable to get the permission to from the publishers to include them here. So instead Marisol has kindly produced the following article describing her work. Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface By Marisol Corral-Debrinski1 1 Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM U592, Université Pierre et Marie Curie (UPMC-Paris6), Hôpital St. Antoine–Bât. Kourilsky, Paris, France. 2 INSERM U676, Hôpital Robert Debré 48, Paris, France. Mitochondrial diseases encompass an extraordinary assemblage of clinical problems, commonly involving tissues that have high energy requirements, such as retina, brain, heart, muscle, and endocrine systems. The clinical presentations range from fatal infantile disease to muscle weakness and most of them are characterized by inexorable progression. Recent epidemiological studies have shown that mitochondrial disorders have a prevalence of at least one in 5000, making them probably the most common form of metabolic disorders. 300 mitochondrial DNA (mtDNA) alterations have been identified as the genetic cause of approximately 30 % of these diseases. Moreover, the spectrum of mitochondrial diseases has been expanded by the recognition that mutations in the genes for nuclear-encoded mitochondrial proteins cause not only a number of neurodegenerative diseases but also haematological and ophthalmological disorders. Hence, finding ways to fight these devastating disorders especially in the case of neuromuscular degeneration is the main objective of many laboratories worldwide. Since almost four years we are using the phenomenon of mRNA localization to the mitochondrial surface aimed at developing a therapeutic strategy for replacing inactive proteins inside the mitochondria. Hence, we have optimized the nuclear expression of ATP6, ND1 and ND4 genes, originally located in the organelle, by the addition of cis-acting elements which ensures the transport of their transcripts to the mitochondrial surface. The optimization of this approach, known as "allotopic expression" have led to the complete and long-lasting rescue of mitochondrial dysfunction in fibroblasts from patients harboring a deleterious mutation in either ATP6, ND1 or ND4 genes. Because of their highly sophisticated function in the visual process retinal cells contain a large number of mitochondria. Therefore, any impairment in mitochondrial function leads to retinal cell degeneration that arises from mutations in genes encoding mitochondrial proteins located in either nuclear or mitochondrial genomes, such as neurogenic muscle weakness Ataxia Retinitis Pigmentosa (NARP), Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA). As for the other mitochondrial disorders, no cure is available. Since, the eye is an excellent target organ for gene therapy, given its small size, its relative anatomical isolation and the ease with which vectors can be delivered to retinal cells we have decided to apply our optimized approach as a first step for treating neuromuscular diseases dues to mitochondrial dysfunction. Ultimately, our most important goal is to provide a gene therapy that will impede blindness of adults brutally affected by LHON or DOA, this therapy will subsequently become available for an array of neuromuscular degenerations caused by mutations in both nuclear and mitochondrial DNA genes encoding mitochondrial proteins. Invest in ME Charity Nr 1114035 (continued on page 22) Page 21/72

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