Intravitreal Delivery of AAV-NDI1 Provides Functional Benefit in a Murine Model of Leber Hereditary Optic Neuropathy

Overview

Journal Eur J Hum Genet

Specialty Genetics

Date 2012 Jun 7

PMID 22669418

Citations 43

Authors

Naomi Chadderton

Arpad Palfi

Sophia Millington-Ward

Oliverio Gobbo

Nora Overlack

Matthew Carrigan

Mary OReilly

Matthew Campbell

Carsten Ehrhardt

Uwe Wolfrum

Peter Humphries

Paul F Kenna

G Jane Farrar

Affiliations

Soon will be listed here.

Abstract

Leber hereditary optic neuropathy (LHON) is a mitochondrially inherited form of visual dysfunction caused by mutations in several genes encoding subunits of the mitochondrial respiratory NADH-ubiquinone oxidoreductase complex (complex I). Development of gene therapies for LHON has been impeded by genetic heterogeneity and the need to deliver therapies to the mitochondria of retinal ganglion cells (RGCs), the cells primarily affected in LHON. The therapy under development entails intraocular injection of a nuclear yeast gene NADH-quinone oxidoreductase (NDI1) that encodes a single subunit complex I equivalent and as such is mutation independent. NDI1 is imported into mitochondria due to an endogenous mitochondrial localisation signal. Intravitreal injection represents a clinically relevant route of delivery to RGCs not previously used for NDI1. In this study, recombinant adenoassociated virus (AAV) serotype 2 expressing NDI1 (AAV-NDI1) was shown to protect RGCs in a rotenone-induced murine model of LHON. AAV-NDI1 significantly reduced RGC death by 1.5-fold and optic nerve atrophy by 1.4-fold. This led to a significant preservation of retinal function as assessed by manganese enhanced magnetic resonance imaging and optokinetic responses. Intraocular injection of AAV-NDI1 overcomes many barriers previously associated with developing therapies for LHON and holds great therapeutic promise for a mitochondrial disorder for which there are no effective therapies.

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References

OReilly M, Palfi A, Chadderton N, Millington-Ward S, Ader M, Cronin T . RNA interference-mediated suppression and replacement of human rhodopsin in vivo. Am J Hum Genet. 2007; 81(1):127-35. PMC: 1950918. DOI: 10.1086/519025. View

Wolfrum U . Cytoskeletal elements in arthropod sensilla and mammalian photoreceptors. Biol Cell. 1992; 76(3):373-81. DOI: 10.1016/0248-4900(92)90441-3. View

Williams R, Strom R, Rice D, Goldowitz D . Genetic and environmental control of variation in retinal ganglion cell number in mice. J Neurosci. 1996; 16(22):7193-205. PMC: 6578945. View

Cideciyan A, Aleman T, Boye S, Schwartz S, Kaushal S, Roman A . Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci U S A. 2008; 105(39):15112-7. PMC: 2567501. DOI: 10.1073/pnas.0807027105. View

Jarrett S, Lin H, Godley B, Boulton M . Mitochondrial DNA damage and its potential role in retinal degeneration. Prog Retin Eye Res. 2008; 27(6):596-607. DOI: 10.1016/j.preteyeres.2008.09.001. View

Doshi R, Bakri S, Fung A . Intravitreal injection technique. Semin Ophthalmol. 2011; 26(3):104-13. DOI: 10.3109/08820538.2010.541318. View

Watanabe T, Michaelis T, Frahm J . Mapping of retinal projections in the living rat using high-resolution 3D gradient-echo MRI with Mn2+-induced contrast. Magn Reson Med. 2001; 46(3):424-9. DOI: 10.1002/mrm.1209. View

Zhang X, Jones D, Gonzalez-Lima F . Neurodegeneration produced by rotenone in the mouse retina: a potential model to investigate environmental pesticide contributions to neurodegenerative diseases. J Toxicol Environ Health A. 2006; 69(18):1681-97. DOI: 10.1080/15287390600630203. View

Ullrich C, Humpel C . Rotenone induces cell death of cholinergic neurons in an organotypic co-culture brain slice model. Neurochem Res. 2009; 34(12):2147-53. PMC: 4311144. DOI: 10.1007/s11064-009-0014-9. View

10.

Levitt N, Briggs D, Gil A, Proudfoot N . Definition of an efficient synthetic poly(A) site. Genes Dev. 1989; 3(7):1019-25. DOI: 10.1101/gad.3.7.1019. View

11.

Qi X, Lewin A, Sun L, Hauswirth W, Guy J . SOD2 gene transfer protects against optic neuropathy induced by deficiency of complex I. Ann Neurol. 2004; 56(2):182-91. DOI: 10.1002/ana.20175. View

12.

Yamashita T, Nakamaru-Ogiso E, Miyoshi H, Matsuno-Yagi A, Yagi T . Roles of bound quinone in the single subunit NADH-quinone oxidoreductase (Ndi1) from Saccharomyces cerevisiae. J Biol Chem. 2007; 282(9):6012-20. DOI: 10.1074/jbc.M610646200. View

13.

Bearer E, Falzone T, Zhang X, Biris O, Rasin A, Jacobs R . Role of neuronal activity and kinesin on tract tracing by manganese-enhanced MRI (MEMRI). Neuroimage. 2007; 37 Suppl 1:S37-46. PMC: 2096707. DOI: 10.1016/j.neuroimage.2007.04.053. View

14.

Hayworth C, Rojas J, Gonzalez-Lima F . Transgenic mice expressing cyan fluorescent protein as a reporter strain to detect the effects of rotenone toxicity on retinal ganglion cells. J Toxicol Environ Health A. 2008; 71(24):1582-92. DOI: 10.1080/15287390802414190. View

15.

Harvey A, Kamphuis W, Eggers R, Symons N, Blits B, Niclou S . Intravitreal injection of adeno-associated viral vectors results in the transduction of different types of retinal neurons in neonatal and adult rats: a comparison with lentiviral vectors. Mol Cell Neurosci. 2002; 21(1):141-57. DOI: 10.1006/mcne.2002.1168. View

16.

Marella M, Seo B, Flotte T, Matsuno-Yagi A, Yagi T . No immune responses by the expression of the yeast Ndi1 protein in rats. PLoS One. 2011; 6(10):e25910. PMC: 3185062. DOI: 10.1371/journal.pone.0025910. View

17.

Dudus L, Anand V, Acland G, Chen S, Wilson J, Fisher K . Persistent transgene product in retina, optic nerve and brain after intraocular injection of rAAV. Vision Res. 1999; 39(15):2545-53. DOI: 10.1016/s0042-6989(98)00308-3. View

18.

Seo B, Chan E, Scheffler I, Yagi T . Molecular remedy of complex I defects: rotenone-insensitive internal NADH-quinone oxidoreductase of Saccharomyces cerevisiae mitochondria restores the NADH oxidase activity of complex I-deficient mammalian cells. Proc Natl Acad Sci U S A. 1998; 95(16):9167-71. PMC: 21310. DOI: 10.1073/pnas.95.16.9167. View

19.

Qi X, Sun L, Lewin A, Hauswirth W, Guy J . The mutant human ND4 subunit of complex I induces optic neuropathy in the mouse. Invest Ophthalmol Vis Sci. 2007; 48(1):1-10. DOI: 10.1167/iovs.06-0789. View

20.

Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M . A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain. 2011; 134(Pt 9):2677-86. PMC: 3170530. DOI: 10.1093/brain/awr170. View