Institut National De La Sante Et De La Recherche Medicale

Inserm

Crystel Bonnet

Jose-Alain Sahel

José-Alain Sahel

Marisol Corral-Debrinski

Valerie Kaltimbacher

Valérie Kaltimbacher

An expression vector containing appropriate mitochondrion-targeting sequences (MTS) and appropriate 3'UTR sequences provides efficient and stable delivery of a mRNA encoding a protein (CDS) to the mitochondrion of a mammalian cell. The MTS and 3&#x2032;UTR sequences guide the CDS mRNA from the nuclear compartment of the cell to mitochondrion-bound polysomes, where the CDS is translated. This provides an efficient translocation of a mature functional protein into the mitochondria. A method of targeting mRNA expressed in the nuclear compartment of a mammalian cell to the mitochondrion is also provided. The vector and methods can be used to treat defects in mitochondrial function.

Importation of mitochondrial protein by an enhanced allotopic approach

The inventors demonstrate that mRNA sorting to the mitochondrial surface is an efficient way to proceed to such an allotopic expression, and that this mRNA sorting can be controlled by selecting appropriate mitochondrion-targeting sequence (MTS) and appropriate 3'UTR sequences. The CDS sequence which codes for the protein to be delivered into the mitochondrion is guided by these appropriate MTS and 3&#x2032;UTR sequences from the nuclear compartment to the mitochondrion-bound polysomes (where the CDS is translated), and aids in an efficient translocation of a mature functional protein into the mitochondria. Appropriate MTS and 3&#x2032;UTR sequences correspond to those of nuclearly-transcribed mitochondrially-targeted mRNAs. The inventors demonstrate that, to obtain a stable therapeutically-effective importation, both an appropriate MTS and an appropriate 3&#x2032;UTR should preferably be used.

Growing community of inventors

Montrouge, France

Crystel Bonnet