Genomic DNA Nanoparticles Rescue Rhodopsin-associated Retinitis Pigmentosa Phenotype

Overview

Journal FASEB J

Specialties Biology
Physiology

Date 2015 Feb 26

PMID 25713057

Citations 30

Authors

Zongchao Han

Marcellus J Banworth

Rasha Makkia

Shannon M Conley

Muayyad R Al-Ubaidi

Mark J Cooper

Muna I Naash

Affiliations

Soon will be listed here.

Abstract

Mutations in the rhodopsin gene cause retinal degeneration and clinical phenotypes including retinitis pigmentosa (RP) and congenital stationary night blindness. Effective gene therapies have been difficult to develop, however, because generating precise levels of rhodopsin expression is critical; overexpression causes toxicity, and underexpression would result in incomplete rescue. Current gene delivery strategies routinely use cDNA-based vectors for gene targeting; however, inclusion of noncoding components of genomic DNA (gDNA) such as introns may help promote more endogenous regulation of gene expression. Here we test the hypothesis that inclusion of genomic sequences from the rhodopsin gene can improve the efficacy of rhodopsin gene therapy in the rhodopsin knockout (RKO) mouse model of RP. We utilize our compacted DNA nanoparticles (NPs), which have the ability to transfer larger and more complex genetic constructs, to deliver murine rhodopsin cDNA or gDNA. We show functional and structural improvements in RKO eyes for up to 8 months after NP-mediated gDNA but not cDNA delivery. Importantly, in addition to improvements in rod function, we observe significant preservation of cone function at time points when cones in the RKO model are degenerated. These results suggest that inclusion of native expression elements, such as introns, can significantly enhance gene expression and therapeutic efficacy and may become an essential option in the array of available gene delivery tools.

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References

Piechaczek C, Fetzer C, Baiker A, Bode J, Lipps H . A vector based on the SV40 origin of replication and chromosomal S/MARs replicates episomally in CHO cells. Nucleic Acids Res. 1998; 27(2):426-8. PMC: 148196. DOI: 10.1093/nar/27.2.426. View

Flannery J, Zolotukhin S, Vaquero M, LaVail M, Muzyczka N, Hauswirth W . Efficient photoreceptor-targeted gene expression in vivo by recombinant adeno-associated virus. Proc Natl Acad Sci U S A. 1997; 94(13):6916-21. PMC: 21259. DOI: 10.1073/pnas.94.13.6916. View

Jacobson S, Acland G, Aguirre G, Aleman T, Schwartz S, Cideciyan A . Safety of recombinant adeno-associated virus type 2-RPE65 vector delivered by ocular subretinal injection. Mol Ther. 2006; 13(6):1074-84. DOI: 10.1016/j.ymthe.2006.03.005. View

Fink T, Klepcyk P, Oette S, Gedeon C, Hyatt S, Kowalczyk T . Plasmid size up to 20 kbp does not limit effective in vivo lung gene transfer using compacted DNA nanoparticles. Gene Ther. 2006; 13(13):1048-51. DOI: 10.1038/sj.gt.3302761. View

Jackson D, Juranek S, Lipps H . Designing nonviral vectors for efficient gene transfer and long-term gene expression. Mol Ther. 2006; 14(5):613-26. DOI: 10.1016/j.ymthe.2006.03.026. View

Farjo R, Skaggs J, Quiambao A, Cooper M, Naash M . Efficient non-viral ocular gene transfer with compacted DNA nanoparticles. PLoS One. 2006; 1:e38. PMC: 1762345. DOI: 10.1371/journal.pone.0000038. View

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

Nicoud M, Kong J, Iqball S, Kan O, Naylor S, Gouras P . Development of photoreceptor-specific promoters and their utility to investigate EIAV lentiviral vector mediated gene transfer to photoreceptors. J Gene Med. 2007; 9(12):1015-23. DOI: 10.1002/jgm.1115. View

Wen X, Shen L, Brush R, Michaud N, Al-Ubaidi M, Gurevich V . Overexpression of rhodopsin alters the structure and photoresponse of rod photoreceptors. Biophys J. 2009; 96(3):939-50. PMC: 2716671. DOI: 10.1016/j.bpj.2008.10.016. View

10.

Chadderton N, Millington-Ward S, Palfi A, OReilly M, Tuohy G, Humphries M . Improved retinal function in a mouse model of dominant retinitis pigmentosa following AAV-delivered gene therapy. Mol Ther. 2009; 17(4):593-9. PMC: 2835099. DOI: 10.1038/mt.2008.301. View

11.

Smith A, Bainbridge J, Ali R . Prospects for retinal gene replacement therapy. Trends Genet. 2009; 25(4):156-65. DOI: 10.1016/j.tig.2009.02.003. View

12.

Ding X, Quiambao A, Fitzgerald J, Cooper M, Conley S, Naash M . Ocular delivery of compacted DNA-nanoparticles does not elicit toxicity in the mouse retina. PLoS One. 2009; 4(10):e7410. PMC: 2756629. DOI: 10.1371/journal.pone.0007410. View

13.

Yurek D, Flectcher A, Kowalczyk T, Padegimas L, Cooper M . Compacted DNA nanoparticle gene transfer of GDNF to the rat striatum enhances the survival of grafted fetal dopamine neurons. Cell Transplant. 2009; 18(10):1183-96. PMC: 3031110. DOI: 10.3727/096368909X12483162196881. View

14.

Palfi A, Millington-Ward S, Chadderton N, OReilly M, Goldmann T, Humphries M . Adeno-associated virus-mediated rhodopsin replacement provides therapeutic benefit in mice with a targeted disruption of the rhodopsin gene. Hum Gene Ther. 2009; 21(3):311-23. DOI: 10.1089/hum.2009.119. View

15.

Cai X, Conley S, Nash Z, Fliesler S, Cooper M, Naash M . Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa. FASEB J. 2009; 24(4):1178-91. PMC: 2845431. DOI: 10.1096/fj.09-139147. View

16.

Amado D, Mingozzi F, Hui D, Bennicelli J, Wei Z, Chen Y . Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness. Sci Transl Med. 2010; 2(21):21ra16. PMC: 4169124. DOI: 10.1126/scitranslmed.3000659. View

17.

Bode J, Benham C, Knopp A, Mielke C . Transcriptional augmentation: modulation of gene expression by scaffold/matrix-attached regions (S/MAR elements). Crit Rev Eukaryot Gene Expr. 2000; 10(1):73-90. View

18.

Tan E, Wang Q, Quiambao A, Xu X, Qtaishat N, Peachey N . The relationship between opsin overexpression and photoreceptor degeneration. Invest Ophthalmol Vis Sci. 2001; 42(3):589-600. View

19.

Hachet O, Ephrussi A . Drosophila Y14 shuttles to the posterior of the oocyte and is required for oskar mRNA transport. Curr Biol. 2001; 11(21):1666-74. DOI: 10.1016/s0960-9822(01)00508-5. View

20.

Proudfoot N, Furger A, Dye M . Integrating mRNA processing with transcription. Cell. 2002; 108(4):501-12. DOI: 10.1016/s0092-8674(02)00617-7. View