Pathologically Responsive Mitochondrial Gene Therapy in an Allotopic Expression‐Independent Manner Cures Leber's Hereditary Optic Neuropathy

Abstract

Leber's hereditary optic neuropathy (LHON) is a rare inherited blindness caused by mutations in the mitochondrial DNA (mtDNA). The disorder is untreatable and tricky, as the existing chemotherapeutic agent Idebenone alleviates symptoms rather than overcoming the underlying cause. Although some studies have made progress on allotopic expression for LHON, in situ mitochondrial gene therapy remains challenging, which may simplify delivery procedures to be a promising therapeutic for LHON. LHON becomes more difficult to manage in the changed mitochondrial microenvironment, including increasing reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP). Herein, a pathologically responsive mitochondrial gene delivery vector named [triphenylphosphine‐terminated poly(sulfur‐containing thioketal undecafluorohexylamine histamine) and Ide‐terminated poly(sulfur‐containing thioketal undecafluorohexylamine histamine)] (TISUH) is reported to facilitate commendable in situ mitochondrial gene therapy for LHON. TISUH directly targets diseased mitochondria via triphenylphosphine and fluorination addressing the decreasing MMP. In addition, TISUH can be disassembled by high mitochondrial ROS levels to release functional genes for enhancing gene transfection efficiency and fundamentally correcting genetic abnormalities. In both traditional and gene‐mutation‐induced LHON mouse models, TISUH‐mediated gene therapy shows satisfactory curative effect through the sustained therapeutic protein expression in vivo. This work proposes a novel pathologically responsive in situ mitochondrial delivery platform and provides a promising approach for refractory LHON as well as other mtDNA mutated diseases treatments.

Proteomic Profiling Reveals Increased Glycolysis, Decreased Oxidoreductase Activity and Fatty Acid Degradation in Skin Derived Fibroblasts from LHON Patients Bearing m.G11778A

“…The results showed higher ROS in LHON fibroblasts compared to the control cells, indicating dysregulation of redox reactions ( Figure 5 C). The results were consistent with previous studies [ 29 , 30 , 31 ] and manifested the reliability of the data further.…”

Gene therapy restores mitochondrial function and protects retinal ganglion cells in optic neuropathy induced by a mito-targeted mutant ND1 gene

“…Even though the mitochondrial double membrane has proven to be a formidable barrier in targeting nucleic acids to the organelle, viruses, naked DNA, and RNA are observed to traverse the membranes 35 – 38 . To generate a mouse model carrying human mutated ND1 , we cloned the human ND1/m.3460G>A gene linked to a Myc epitope followed by a stop codon (without a tRNA) and mitochondrial encoded mCherry into a self-complementary AAV serotype 2 (AAV2) backbone (mut-hND1)( Fig 1A ), as described in the Materials and Methods section.…”

ECE2 is a prognostic biomarker associated with m6A modification and involved in immune infiltration of lung adenocarcinoma

“…GO/KEGG enrichment analysis indicated that the co-expressed genes of ECE2 were involved in mitochondrial expression, ATPase activity and cell cycle function. Some studies have found that the above-mentioned biological functions play an important role in the occurrence and development of tumors ( 27 – 29 ). These findings suggest that the co-expression network of ECE2 plays a key role in tumor initiation and progression.…”