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Rajeshwari D Koilkonda, Hong Yu, Venu Talla, John Guy; Comparision of Allotopic and Mito targeted ND4 gene therapy for treating Leber Hereditary Optic Neuropathy (LHON) in mice. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3964.
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© ARVO (1962-2015); The Authors (2016-present)
To compare AAV mediated gene therapy using allotopic ND4 (P1ND4) and mito targeted ND4 to treat LHON in mice.
Pattern electroretinogram (PERG) data of four intravitreally injected mice groups were compared, Group 1) Mice injected with AAVGFP and AAVP1ND4(G11778A), Group 2) ND4 allotopic rescue mice, injected with AAVP1ND4(WT) and AAVP1ND4(G11778A), Group 3) mito targeted ND4 rescue mice, injected with AAVHSPND4(WT) and AAVP1ND4(G11778A) Group 4) aged matched un-injected mice. Mutant ND4(G11778A) was allotopically delivered to induce LHON in mice groups 1, 2, and 3. Serial PERG data recorded at 6m and 1 year post injections (ypi) were compared.
PERG data showed that at 6m and 1ypi, the average PERG amplitudes of Group-1 mice injected with AAVGFP and AAVP1ND4(G11778A) was significantly reduced (10.3±0.69μV and 8.5±0.72μV ; mean ± SE) compared to age-matched un-injected mice (20.4±1.9μV and 16.06±2.14μV; mean ± SE, p=2.89e-07, 0.00015). In addition, at 6mpi both rescue groups, i.e., Group-2, ND4 Allotopic rescue mice, treated with AAVP1ND4(WT) and AAVP1ND4(G11778A) and Group-3) ND4 modified mito AAV rescue mice, treated with HSPND4(WT) and AAVP1ND4(G11778A) showed significant rescue (17.68±2.3μV and 14.05±1.01μV, mean ± SE, p=0.00017, 0.00254,) compared to mock treated (Group 1, 10.3±0.69 μV, mean ± SE). Similarly, at 1ypi, Group-2, ND4 Allotopic rescue mice, treated with AAVP1ND4(WT) and AAVP1ND4(G11778A) and Group-3, ND4 modified mito AAV rescue mice, treated with HSPND4(WT) and AAVP1ND4(G11778A) showed significant rescue (13.23±1.9μV and 16.07±5μV, mean ± SE, p=0.0075, 0.0029) compared to mock group 1, 8.51±0.72μV (mean ± SE). Interestingly, while the allotopic ND4 rescue was seemingly higher at 6m (73%) that reduced slightly at one year (62.4%), the rescue using mito targeted ND4 on the other hand increased from 37% at 6months to 100% at one year.
While the allotopic ND4 rescues LHON disease, there could be a possible decrease in efficiency with time as was also shown in LCA clinical trial. Mitochondrially delivered DNA showed efficient and long term rescue of LHON mice compared to allotopic ND4 delivery possibly due to a higher stability of DNA within mitochondria and a positive selection of rescued mitochondria or could there be delivered DNA replication that need to be further explored.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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