Integrative Biology

Biography

Biography: Haya Lorberboum-Galski

Abstract

Modern medicine offers no cure for genetic mitochondrial disorders and the usual treatment is mostly palliative. We developed a novel concept for the treatment of mitochondrial disorders using Cell/Organelle-Directed Protein Replacement Therapy; the delivery of a wild type mitochondrial protein/enzyme directly to its sub-cellular location and into its natural complexes, in the form of a fusion protein. Our approach is to fuse a wild type mitochondrial protein, including the Mitochondrial Targeting Sequence (MTS) with the delivery peptide TAT [HIV-transactivator of transcription (TAT) peptide], which will lead the protein/enzyme into the cells and their mitochondria, where it will substitute for the mutated endogenous protein. We tested this novel approach using a number of mitochondrial proteins, implicated in mitochondrial human diseases: Lipoamide Dehydrogenase (LAD), C6ORF66 and Frataxin were evaluated in vitro, in patients’ cells and in vivo, in mouse models. TAT-MTS-Mitochondrial fusion proteins are rapidly and efficiently internalizing into cells and their mitochondria both in patients’ cells and in mice tissues, including the brain. Treatment with the new TAT-MTS-Mitochondrial fusion proteins, improves mitochondrial functions and life span in animal models. Interestingly, when we replaced the MTS sequence of the exogenous protein with a heterogeneous MTS sequence, both mitochondrial penetration and biological activity significantly increased. This novel approach may open new inroads in the management of many incurable mitochondrial diseases.