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Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model
Sindhu Velmurugan1, Tsung-Han Chou1, Jeremy D Eastwood1
1Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States.
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.
Insights
Mitochondrial gene therapy shows promise for Leber hereditary optic neuropathy (LHON). Mitochondrial-targeted therapy was more effective than allotopic therapy in a mouse model, preserving vision and optic nerve axons.
Area of Science:
- Ophthalmology
- Genetics
- Neurology
Background:
- Leber hereditary optic neuropathy (LHON) is a mitochondrial DNA disorder with inadequate therapies.
- LHON leads to retinal ganglion cell (RGC) degeneration and vision loss.
Purpose of the Study:
- To develop and compare two gene therapy strategies for LHON: mitochondrial-targeted and allotopic expression.
- To evaluate the efficacy of these therapies in a pre-clinical LHON mouse model.
Main Methods:
- A LHON mouse model was created using an adeno-associated virus (AAV) carrying the mutant human NADH dehydrogenase 4 (ND4) gene.
- Mice were treated with either mitochondrial-targeted or allotopic wildtype human ND4 gene therapy via intravitreal injection.
- Retinal function and optic nerve preservation were assessed using pattern electroretinogram (PERG) and transmission electron microscopy.
Main Results:
- Both gene therapy strategies significantly preserved PERG amplitude in LHON mice over 15 months compared to controls.
- Mitochondrial-targeted ND4 therapy demonstrated a more significant rescue effect than allotopic therapy (p=0.0128).
- Post-mortem analysis revealed superior preservation of small axons, which are preferentially lost in human LHON, with mitochondrial-targeted therapy.
Conclusions:
- Mitochondrial-targeted AAV gene therapy is more efficient than allotopic AAV gene therapy for rescuing the LHON phenotype in a pre-clinical mouse model.
- These findings support the potential of mitochondrially-targeted gene therapy for treating LHON.
