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

Autor: Wang Y; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China., Hu LF; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China., Cui PF; School of Pharmacy, Changzhou University, Changzhou, 213164, China., Qi LY; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China., Xing L; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.; Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing, 210009, China.; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China., Jiang HL; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.; Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing, 210009, China.; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China.
Jazyk: angličtina
Zdroj: Advanced materials (Deerfield Beach, Fla.) [Adv Mater] 2021 Oct; Vol. 33 (41), pp. e2103307. Date of Electronic Publication: 2021 Aug 25.
DOI: 10.1002/adma.202103307
Abstrakt: 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.
(© 2021 Wiley-VCH GmbH.)
Databáze: MEDLINE
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