Compound Called MITO-PIP May Have Potential as Gene Therapy for Mitochondrial Diseases

A compound that can silence a gene in a very specific manner was adapted by researchers to be used inside mitochondria — opening the possibility of manipulating genes linked to mitochondrial diseases.

MITO-PIP, as the scientists call the compound, binds to a stretch of mitochondrial DNA that is involved in several disorders, including Leber’s hereditary optic neuropathy and mitochondrial myopathy.

While their study “Creation of a Synthetic Ligand for Mitochondrial DNA Sequence Recognition and Promoter-Specific Transcription Suppression,” published in the Journal of the American Chemical Society, provided a proof-of-concept that it is possible to manipulate mitochondrial genes in this way, the researchers are intent on continuing to refine the compound.

They are now aiming to improve MITO-PIP so that it only enters mitochondria that are faulty, leaving the healthy ones to do their work, Ganesh Pandian Namasivayam, who led the research team with Kyoto University in Japan, said in a press release.

PIPs (Pyrrole-imidazole polyamides) have been used to target disease-causing genes in normal cell DNA. They act by binding to their target stretch to prevent so-called transcription factors from initiating the process of making a protein from a gene.

Transcription factors are molecules that control gene activity by directly interacting with DNA and the protein-making machinery.

But PIPs lacked the ability to penetrate the membranes surrounding mitochondria. To solve this, the team linked a PIP to a protein fragment that possessed the specific ability to cross mitochondrial membranes.

The team developed a MITO-PIP that bound to a DNA stretch normally occupied by a factor called TFAM. TFAM controls genes crucial for energy production. One of them is ND6 — a gene that contributes to Leber’s, a disease marked by vision loss, and mitochondrial myopathy, in which patients develop muscle weakness, seizures, and learning difficulties.

First, the researchers conducted experiments to make sure that MITO-PIP really ended up inside the mitochondria. Using a fluorescent dye, they traced the factor, and confirmed that it was, indeed, inside mitochondria, with no evidence of it in the cells’ nuclei.

Further experiments confirmed that the compound lowered the amount of ND6 by 60% to 90%, depending on the dose the team used.

“Our proof-of-concept study provides a fresh platform that opens new avenues for DNA-based functional ligands that are capable of altering the mitochondrial genome in a sequence-specific manner,” said Hiroshi Sugiyama, the study’s senior author.

The study was performed in lab-grown cells, and human tests are not even in the planning stage. Nevertheless, the findings show that the treatment has the potential to benefit people with a variety of mitochondrial diseases.

Next, “we plan to develop an advanced version of MITO-PIPs that can identify and localize only inside diseased mitochondria,” Ganesh said.