Three Cases of Leber's Hereditary Optic Neuropathy with Rapid Increase in Visual Acuity After Gene Therapy

Yong Zhang, Jia-Jia Yuan, Hong-Li Liu, Zhen Tian, Si-Wei Liu, Bin Li, Yong Zhang, Jia-Jia Yuan, Hong-Li Liu, Zhen Tian, Si-Wei Liu, Bin Li

Abstract

Background: During the first few trials of gene therapy for Leber's hereditary optic neuropathy performed by our group, the visual acuity of the patients increased gradually over several months, or even years. However, in the current round of gene therapy for Leber's hereditary optic neuropathy, we noted that the visual acuity of three patients increased rapidly, within a few days after treatment.

Case presentation: Three patients who were diagnosed with mitochondrial gene 11778 mutation (associated with a G-to-A transition at Mt-11778 in the ND4 subunit gene of complex I of mitochondrial DNA that changes an arginine to histidine at amino acid 340) by genetic diagnosis were followed up three times before gene therapy, which lasted for 1 year, without spontaneous improvement of vision. Visual acuity in one or both eyes of each of the three patients increased rapidly after the initial gene therapy treatment.

Conclusion: We suspect that in some patients with Leber's hereditary optic neuropathy, a portion of the retinal ganglion cells might remain in a "dormant" state for a certain period of time; these may be activated, within an optimal timeframe, during gene therapy for Leber's hereditary optic neuropathy.

Trial registration: ClinicalTrials.gov NCT03153293.

Keywords: Leber's hereditary optic neuropathy; dormant; gene therapy; retinal ganglion cells; time window; visual acuity..

Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.

Figures

Fig. (1)
Fig. (1)
Fundus photographs from Cases 1, 2, and 3, before and after intravitreal injection of rAAV2-ND4. (Left) Fundus photographs of the three patients before surgery. (Right) Fundus photographs of the three patients after surgery. No structural abnormalities of the retina were found in any of the patients.
Fig. (2)
Fig. (2)
Visual acuity (logMAR) before, 4 days, 1 month(Case 2) and 3 months(Case 1 and Case 3) after injection of rAAV2-ND4 in three patients.

References

    1. Y-Wai-Man P. Turnbull DM. Chinnery PF. Leber hereditary optic neuropathy. J. Med. Genet. 2002;39:162–169. doi: 10.1136/jmg.39.3.162.
    1. Peragallo J.H., Newman N.J. Is there treatment for Leber hereditary optic neuropathy? Curr. Opin. Ophthalmol. 2015;26(6):450–457. doi: 10.1097/ICU.0000000000000212.
    1. Pilz Y.L., Bass S.J., Sherman J. A review of mitochondrial optic neuropathies: from inherited to acquired forms. J. Optom. 2017;10(4):205–214. doi: 10.1016/j.optom.2016.09.003.
    1. Wan X., Pei H., Zhao M.J., et al. Efficacy and safety of rAAV2-ND4 treatment for Leber’s hereditary optic neuropathy. Sci. Rep. 2016;6:21587. doi: 10.1038/srep21587.
    1. Guy J., Feuer W.J., Davis J.L., et al. Gene therapy for Leber hereditary optic neuropathy: Low- and medium-dose visual results. Ophthalmology. 2017;124(11):1621–1634. doi: 10.1016/j.ophtha.2017.05.016.
    1. Yang S., Ma S.Q., Wan X., et al. Long-term outcomes of gene therapy for the treatment of Leber’s hereditary optic neuropathy. EBioMedicine. 2016;10:258–268. doi: 10.1016/j.ebiom.2016.07.002.
    1. Brandt U. Energy converting NADH: Quinone oxidoreductase (complex I). Annu. Rev. Biochem. 2006;75:69–92. doi: 10.1146/annurev.biochem.75.103004.142539.
    1. Bi R., Zhang A.M., Yu D., Chen D., Yao Y.G. Screening the three LHON primary mutations in the general Chinese population by using an optimized multiplex allele-specific PCR. Clin. Chim. Acta. 2010;411(21-22):1671–1674. doi: 10.1016/j.cca.2010.06.026.
    1. Yang S., He H., Zhu Y., et al. Chemical and material communication between the optic nerves in rats. Clin. Exp. Ophthalmol. 2015;43(8):742–748. doi: 10.1111/ceo.12547.
    1. Luo X., Salgueiro Y., Beckerman S.R., Lemmon V.P., Tsoulfas P., Park K.K. Three-dimensional evaluation of retinal ganglion cell axon regeneration and pathfinding in whole mouse tissue after injury. Exp. Neurol. 2013;247:653–662. doi: 10.1016/j.expneurol.2013.03.001.
    1. Cen L.P., Ng T.K., Liang J.J., et al. Human periodontal ligament-derived stem cells promote retinal ganglion cell survival and axon regeneration after optic nerve injury. Stem Cells. 2018;36(6):844–855. doi: 10.1002/stem.2812.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren