Abstract
The gene Prph2 encodes a photoreceptor-specific membrane glycoprotein1, peripherin-2 (also known as peripherin/rds), which is inserted into the rims of photoreceptor outer segment discs in a complex with rom-1 (ref. 2). The complex is necessary for the stabilization of the discs, which are renewed constantly throughout life, and which contain the visual pigments necessary for photon capture3. Mutations in Prph2 have been shown to result in a variety of photoreceptor dystrophies, including autosomal dominant retinitis pigmentosa and macular dystrophy4. A common feature of these diseases is the loss of photoreceptor function, also seen in the retinal degeneration slow (rds or Prph2 Rd2/Rd2) mouse, which is homozygous for a null mutation in Prph2. It is characterized by a complete failure to develop photoreceptor discs and outer segments5, downregulation of rhodopsin6,7 and apoptotic loss of photoreceptor cells8,9. The electroretinograms (ERGs) of Prph2Rd2/Rd2 mice have greatly diminished a-wave and b-wave amplitudes, which decline to virtually undetectable concentrations by two months10. Subretinal injection of recombinant adeno-associated virus (AAV) encoding a Prph2 transgene results in stable generation of outer segment structures and formation of new stacks of discs containing both perpherin-2 and rhodopsin, which in many cases are morphologically similar to normal outer segments. Moreover, the re-establishment of the structural integrity of the photoreceptor layer also results in electrophysiological correction. These studies demonstrate for the first time that a complex ultrastructural cell defect can be corrected both morphologically and functionally by in vivo gene transfer.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Travis, G.H., Brennan, M.B., Danielson, P.E., Kozak, C.A. & Sutcliffe, J.G. Identification of a photoreceptor-specific mRNA encoded by the gene responsible for retinal degeneration slow (rds ). Nature 338, 70–73 (1989).
Bascom, R.A. et al. Cloning of the cDNA for a novel photoreceptor membrane protein (rom-1) identifies a disk rim protein family implicated in human retinopathies . Neuron 8, 1171–1184 (1992).
Molday, R.S. Peripherin/rds and rom-1: molecular properties and role in photoreceptor cell degeneration. Prog. Ret. Eye Res. 13, 271 –299 (1994).
Gregory-Evans, K. & Bhattacharya, S.S. Genetic blindness: current concepts in the pathogenesis of human outer retinal dystophies . Trends Genet. 14, 103– 108 (1998).
Sanyal, S. & Jansen, H. Absence of receptor outer segments in the retina of rds mutant mice. Neurosci. Lett. 21, 23–26 (1981).
Shalken, J.J., Janssen, J.J., DeGrip, W.J., Hawkins, R.K. & Sanyal, S. Immunoassay of rod visual pigment (opsin) in the eyes of rds mutant mice lacking photoreceptor outer segments. Biochim. Biophys. Acta 839, 122 –126 (1985).
Nir, I., Agrawal, N. & Papermaster, D.S. Opsin gene expression during early and late phases of retinal degeneration in rds mice. Exp. Eye Res. 51, 257–267 (1983).
Chang, G.-Q., Hao, Y. & Wong, F. Apoptosis: final common pathway of photoreceptor death in rd, rds , and rhodopsin mutant mice. Neuron 11, 595–605 (1993).
Portera-Cailliau, C., Sung, C.H., Nathans, J. & Adler, R. Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa. Proc. Natl Acad. Sci. USA 91, 974–978 (1994).
Reuter, J.H. & Sanyal, S. Development and degeneration of retina in rds mutant mice: the electroretinogram. Neurosci. Lett. 48, 231–237 ( 1984).
Travis, G.H., Groshan, K.R., Lloyd, M. & Bok, D. Complete rescue of photoreceptor dysplasia and degeneration in transgenic retinal degeneration slow (rds) mice. Neuron 9, 113– 119 (1992).
Takahashi, M., Miyoshi, H., Verma, I.M. & Gage, F.H. Rescue from photoreceptor degeneration in the rd mouse by human immunodeficiency virus vector-mediated gene transfer. J. Virol. 73, 7812– 7816 (1999).
Lewin, A.S. et al. Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal retinitis pigmentosa. Nature Med. 4, 967–971 (1998).
Boursnell, M.E. et al. A genetically inactivated herpes simplex virus type 2 (HSV-2) vaccine provides effective protection against primary and recurrent HSV-2 disease. J. Infect. Dis. 175, 16– 25 (1997).
Zhang, X., O'Shea, H., Boursnell, M., Efstathiou, S. & Inglis, S. An efficient selection system for packaging herpes simplex virus amplicons. J. Gen. Virol. 79, 125–131 (1998).
Hill, T.J., Field, H.J. & Blyth, W.A. Acute and recurrent infection with herpes simplex virus in the mouse: a model for studying latency and recurrent disease. J. Gen. Virol. 28, 341–353 (1975).
Zhang, X. et al. High titre recombinant adeno-associated virus production from replicating amplicons and herpes vectors deleted for glycoprotein H. Hum. Gene Ther. 10, 2527–2537 (1999).
Ali, R.R. et al. Gene transfer into the mouse retina mediated by an adeno-associated viral vector. Hum. Mol. Genet. 5, 591– 594 (1996).
Acknowledgements
We thank G. Holder, C. Hogg and M. Seeliger for advice on ERG and X. Zhang for supplying the original vector plasmids. This work was supported by grants from the Foundation Fighting Blindness (USA), the Wellcome Trust, Fight for Sight, and DAAD/British Council. Personal support for GS from Ausbildungsstiftung für den Kanton Schwyz; EMDO Stiftung, Schweiz. Fonds zurVerhütung und Bekämpfung der Blindheit and Holderbank-Stiftung.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ali, R., Sarra, GM., Stephens, C. et al. Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy. Nat Genet 25, 306–310 (2000). https://doi.org/10.1038/77068
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/77068
This article is cited by
-
Potential therapeutic strategies for photoreceptor degeneration: the path to restore vision
Journal of Translational Medicine (2022)
-
Focused Update on AAV-Based Gene Therapy Clinical Trials for Inherited Retinal Degeneration
BioDrugs (2020)
-
Peripherin-2 and Rom-1 have opposing effects on rod outer segment targeting of retinitis pigmentosa-linked peripherin-2 mutants
Scientific Reports (2017)
-
Mutation screening in genes known to be responsible for Retinitis Pigmentosa in 98 Small Han Chinese Families
Scientific Reports (2017)
-
Genetic characterization and disease mechanism of retinitis pigmentosa; current scenario
3 Biotech (2017)