Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model.
Front Neurosci
; 17: 1119724, 2023.
Article
em En
| MEDLINE
| ID: mdl-37051151
ABSTRACT
Introduction:
Therapies for Leber hereditary optic neuropathy (LHON), in common with all disorders caused by mutated mitochondrial DNA, are inadequate. We have developed two gene therapy strategies for the disease mitochondrial-targeted and allotopic expressed and compared them in a mouse model of LHON.Methods:
A LHON mouse model was generated by intravitreal injection of a mitochondrialtargeted Adeno-associated virus (AAV) carrying mutant human NADH dehydrogenase 4 gene (hND4/m.11778G>A) to induce retinal ganglion cell (RGC) degeneration and axon loss, the hallmark of the human disease. We then attempted to rescue those mice using a second intravitreal injection of either mitochondrial-targeted or allotopic expressed wildtype human ND4. The rescue of RGCs and their axons were assessed using serial pattern electroretinogram (PERG) and transmission electron microscopy.Results:
Compared to non-rescued LHON controls where PERG amplitude was much reduced, both strategies significantly preserved PERG amplitude over 15 months. However, the rescue effect was more marked with mitochondrial-targeted therapy than with allotopic therapy (p = 0.0128). Post-mortem analysis showed that mitochondrial-targeted human ND4 better preserved small axons that are preferentially lost in human LHON.Conclusions:
These results in a pre-clinical mouse model of LHON suggest that mitochondrially-targeted AAV gene therapy, compared to allotopic AAV gene therapy, is more efficient in rescuing the LHON phenotype.
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Bases de dados:
MEDLINE
Idioma:
En
Revista:
Front Neurosci
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos