Nature Medicine
4, 967 - 971 (1998)
doi:10.1038/nm0898-967
There is an Erratum (September 1998) associated with this Article.
Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosaAlfred S. Lewin1, 2, 6, Kimberly A. Drenser1, William W. Hauswirth1, 2, 3, Shimpei Nishikawa4, Douglas Yasumura4, John G. Flannery5
& Matthew M. LaVail4
1Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida 32610
2Gene Therapy Center, University of Florida College of Medicine, Gainesville, Florida 32610
3Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida 32610
4Departments of Anatomy and Ophthalmology, Beckman Vision Center, University of California School of Medicine, San Francisco, California 94143
5Departments of Vision Science and Neuroscience, University of California, Berkeley, California 94720
6Correspondence should be addressed to A.S.L.; e-mail: lewin@college.med.ufl.edu Ribozymes, catalytic RNA molecules that cleave a complementary mRNA sequence, have potential as therapeutics for dominantly inherited disease. Twelve percent of American patients with the blinding disease autosomal dominant retinitis pigmentosa (ADRP) carry a substitution of histidine for proline at codon 23 (P23H) in their rhodopsin gene1, resulting in photoreceptor cell death from the synthesis of the abnormal gene product. Ribozymes can discriminate and catalyze the in vitro destruction of P23H mutant mRNAs from a transgenic rat model of ADRP (ref. 2). Here, we demonstrate that in vivo expression of either a hammerhead or hairpin ribozyme in this rat model considerably slows the rate of photoreceptor degeneration for at least three months. Catalytically inactive control ribozymes had less effect on the retinal degeneration. Intracellular production of ribozymes in photoreceptors was achieved by transduction with a recombinant adeno-associated virus (rAAV) incorporating a rod opsin promoter. Ribozyme-directed cleavage of mutant mRNAs, therefore, may be an effective therapy for ADRP and also may be applicable to other inherited diseases.
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