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Gene Therapy

A step toward mitochondrial gene therapy

Peptide-based system delivers DNA into mitochondria

by Melissa Pandika, special to C&EN
November 23, 2016 | A version of this story appeared in Volume 94, Issue 47

Illustration of peptide-DNA complex formation.
Credit: Biomacromolecules
A mitochondrial gene delivery system uses a self-assembling, dual-domain peptide to bundle DNA into a spherical particle.

Mutations in DNA that resides in cells’ energy-producing mitochondria underlie many diseases, including cancer, diabetes, heart disease, and age-related neurodegenerative disorders. But a safe, reliable method to deliver therapeutic DNA to mitochondria to correct these mutations doesn’t currently exist.

Now, Keiji Numata of Japan’s RIKEN research institute and colleagues have developed a peptide-based system that delivers a functional gene to human mitochondria without toxic effects. The system could pave the way to gene therapy for mitochondrial diseases (Biomacromolecules 2016, DOI: 10.1021/acs.biomac.6b01056).

Earlier attempts to develop mitochondria-targeted gene delivery systems posed limitations. Many were toxic, and although researchers had shown that mitochondria took up peptides used in various delivery systems, no one had shown whether mitochondria actually expressed the genes delivered.

Numata’s team built and tested a dual-domain peptide designed to penetrate cell membranes and then trigger transport receptors on the surface of mitochondria. The peptide is made of a subunit of a yeast enzyme, cytochrome c oxidase (Cytcox), fused to another peptide containing only lysine and histidine residues. The residues enable the peptide to pass through a cell’s membrane, while the Cytcox helps trigger the mitochondrial transporters. The researchers packaged DNA with this modified Cytcox by mixing plasmid DNA encoding a green fluorescent protein (GFP) with the modified peptide and allowing the components to self-assemble into spherical particles.

To see if the system could deliver the DNA, the researchers added the peptide-DNA complexes to human embryonic cells whose mitochondria they stained with red fluorescent dye. Confocal microscopy revealed that the glow from the GFP and the red dye overlapped, indicating that 82% of the mitochondria had taken up and expressed the plasmid DNA. The researchers observed gene expression for about a week and saw that the cells remained viable throughout.

But the system requires further analysis, experts say. Michael A. Teitell of UCLA says successful delivery of a gene involved in mitochondrial disease would confirm the system’s clinical usefulness.



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