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Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy

Gene Therapy volume 15, pages 1311–1320 (2008)Cite this article

Abstract

Autosomal recessive Stargardt disease (STGD1) is a macular dystrophy caused by mutations in the ABCA4 (ABCR) gene. The disease phenotype that is most recognized in STGD1 patients, and also in the Abca4−/− mouse (a disease model), is lipofuscin accumulation in retinal pigment epithelium. Here, we tested whether delivery of the normal (wt) human ABCA4 gene to the subretinal space of the Abca4−/− mice via lentiviral vectors would correct the disease phenotype; that is, reduce accumulation of the lipofuscin pigment A2E. Equine infectious anemia virus (EIAV)-derived lentiviral vectors were constructed expressing either the human ABCA4 gene or the LacZ reporter gene under the control of the constitutive (CMV) or photoreceptor-specific (Rho) promoters. Abca4−/− mice were injected subretinally with 1 μl (∼5.0 × 105 TU) of each EIAV vector in one eye at postnatal days 4 and 5. An injection of saline, an EIAV-null vector, or an uninjected contralateral eye served as a control. Mice were killed at various times after injection to determine photoreceptor (PR) transduction efficiency and A2E concentrations. EIAV-LacZ vectors transduced from 5 to 20% of the PRs in the injected area in mice. Most importantly, a single subretinal injection of EIAV-CMV-ABCA4 to Abca4−/− mouse eyes substantially reduced disease-associated A2E accumulation compared to untreated and mock-treated control eyes. Treated eyes of Abca4−/− mice accumulated 8–12 pmol per eye (s.d.=2.7) of A2E 1 year after treatment, amounts comparable to wt controls, whereas mock-treated or untreated eyes had 3–5 times more A2E (27–39 pmol per eye, s.d.=1.5; P=0.001–0.005). Although extrapolation to humans requires caution, the high transduction efficiency of both rod and cone photoreceptors and the statistically significant reduction of A2E accumulation in the mouse model of STGD1 suggest that lentiviral gene therapy is a potentially efficient tool for treating ABCA4-associated diseases.

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Acknowledgements

We thank Dr SP Goff, Dr EA Pierce, Dr I Verma, Dr P Leboulch, Dr R Pawliuk, Dr S Rose, Dr C Barber, Dr T Nagasaki and Dr T Schoen for helpful discussions. We are also grateful to Dr J Nathans, Dr H Sun, Dr R Pawliuk and Dr RS Molday for valuable reagents and advice. This work was supported in part by funds from Foundation Fighting Blindness, National Neurovision Research Institute, Manning Family Foundation, Mr and Mrs Michael Schneeweiss, NIH EY13435 (RA), EY12951 (JRS) and unrestricted grant to the Department of Ophthalmology, Columbia University from Research to Prevent Blindness Inc.

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  1. Department of Ophthalmology, Columbia University, New York, NY, USA

    J Kong, S-R Kim, I Pata, K Doi, J Mannik, J Zernant-Rajang, J R Sparrow, P Gouras & R Allikmets

  2. Oxford BioMedica (UK) Ltd, Oxford Science Park, Oxford, UK

    K Binley, O Kan, S Iqball & S Naylor

  3. Department of Pathology and Cell Biology, Columbia University, New York, NY, USA

    J R Sparrow & R Allikmets

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  1. J Kong
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Kong, J., Kim, SR., Binley, K. et al. Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy. Gene Ther 15, 1311–1320 (2008). https://doi.org/10.1038/gt.2008.78

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