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Gene therapy in animal models of autosomal dominant retinitis pigmentosa.

Rossmiller B, Mao H, Lewin AS - Mol. Vis. (2012)

Bottom Line: Gene therapy for dominantly inherited genetic disease is more difficult than gene-based therapy for recessive disorders, which can be treated with gene supplementation.Treatment of dominant disease may require gene supplementation partnered with suppression of the expression of the mutant gene either at the DNA level, by gene repair, or at the RNA level by RNA interference or transcriptional repression.We conclude that combinatorial approaches have the greatest promise for success.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32611, USA.

ABSTRACT
Gene therapy for dominantly inherited genetic disease is more difficult than gene-based therapy for recessive disorders, which can be treated with gene supplementation. Treatment of dominant disease may require gene supplementation partnered with suppression of the expression of the mutant gene either at the DNA level, by gene repair, or at the RNA level by RNA interference or transcriptional repression. In this review, we examine some of the gene delivery approaches used to treat animal models of autosomal dominant retinitis pigmentosa, focusing on those models associated with mutations in the gene for rhodopsin. We conclude that combinatorial approaches have the greatest promise for success.

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Related in: MedlinePlus

Gene suppression. A: Zinc finger artificial transcription factors (ZF-ATF) use suppressor transcription factors to silence gene transcription. B: Zinc finger nucleases (ZFN) causes a double-stranded break leading to correction of the mutation through recombination. C: miRNA and shRNA degrade the endogenous target transcript while sparing the introduced resistant mRNA (hardened) with an altered sequence. D: Ribozymes catalytically cleave the target transcript, but insertion of a guanosine at the target site dramatically reduces cleavage of the hardened target.
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f3: Gene suppression. A: Zinc finger artificial transcription factors (ZF-ATF) use suppressor transcription factors to silence gene transcription. B: Zinc finger nucleases (ZFN) causes a double-stranded break leading to correction of the mutation through recombination. C: miRNA and shRNA degrade the endogenous target transcript while sparing the introduced resistant mRNA (hardened) with an altered sequence. D: Ribozymes catalytically cleave the target transcript, but insertion of a guanosine at the target site dramatically reduces cleavage of the hardened target.

Mentions: Therapeutic RNA interference (RNAi) employs three types of small RNA molecules: microRNA (miRNA), short hairpin RNA (shRNA), and short interfering RNA (siRNA). RNA interference with siRNA usually takes the form of direct treatment with modified double-stranded RNA (dsRNA) molecules, and requires repeated administration [90]. Therefore, this approach is not optimal for treating a chronic genetic disease, such as ADRP, though siRNAs are in clinical trials for age-related macular degeneration. Several groups are developing the use of RNAi for therapy for ADRP [91-97]. RNA interference was shown effective at knocking down the mutant mRNA and aiding in replacement with the wild-type gene [91,98] (Figure 3C).


Gene therapy in animal models of autosomal dominant retinitis pigmentosa.

Rossmiller B, Mao H, Lewin AS - Mol. Vis. (2012)

Gene suppression. A: Zinc finger artificial transcription factors (ZF-ATF) use suppressor transcription factors to silence gene transcription. B: Zinc finger nucleases (ZFN) causes a double-stranded break leading to correction of the mutation through recombination. C: miRNA and shRNA degrade the endogenous target transcript while sparing the introduced resistant mRNA (hardened) with an altered sequence. D: Ribozymes catalytically cleave the target transcript, but insertion of a guanosine at the target site dramatically reduces cleavage of the hardened target.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472929&req=5

f3: Gene suppression. A: Zinc finger artificial transcription factors (ZF-ATF) use suppressor transcription factors to silence gene transcription. B: Zinc finger nucleases (ZFN) causes a double-stranded break leading to correction of the mutation through recombination. C: miRNA and shRNA degrade the endogenous target transcript while sparing the introduced resistant mRNA (hardened) with an altered sequence. D: Ribozymes catalytically cleave the target transcript, but insertion of a guanosine at the target site dramatically reduces cleavage of the hardened target.
Mentions: Therapeutic RNA interference (RNAi) employs three types of small RNA molecules: microRNA (miRNA), short hairpin RNA (shRNA), and short interfering RNA (siRNA). RNA interference with siRNA usually takes the form of direct treatment with modified double-stranded RNA (dsRNA) molecules, and requires repeated administration [90]. Therefore, this approach is not optimal for treating a chronic genetic disease, such as ADRP, though siRNAs are in clinical trials for age-related macular degeneration. Several groups are developing the use of RNAi for therapy for ADRP [91-97]. RNA interference was shown effective at knocking down the mutant mRNA and aiding in replacement with the wild-type gene [91,98] (Figure 3C).

Bottom Line: Gene therapy for dominantly inherited genetic disease is more difficult than gene-based therapy for recessive disorders, which can be treated with gene supplementation.Treatment of dominant disease may require gene supplementation partnered with suppression of the expression of the mutant gene either at the DNA level, by gene repair, or at the RNA level by RNA interference or transcriptional repression.We conclude that combinatorial approaches have the greatest promise for success.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32611, USA.

ABSTRACT
Gene therapy for dominantly inherited genetic disease is more difficult than gene-based therapy for recessive disorders, which can be treated with gene supplementation. Treatment of dominant disease may require gene supplementation partnered with suppression of the expression of the mutant gene either at the DNA level, by gene repair, or at the RNA level by RNA interference or transcriptional repression. In this review, we examine some of the gene delivery approaches used to treat animal models of autosomal dominant retinitis pigmentosa, focusing on those models associated with mutations in the gene for rhodopsin. We conclude that combinatorial approaches have the greatest promise for success.

Show MeSH
Related in: MedlinePlus