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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

Improvement of electroretinography (ERG) response by single AAV injection of normal mouse rhodopsin cDNA (WT Rho) in P23H transgenic mice [89]. Bars represent the average of five scotopic ERG scans at 0 dB (2.6 cd (cd)-s/m2) a-wave response. A: and b-wave response. B: at 1 month and 6 months post injection. ERG amplitudes of 1 month uninjected P23H eyes were set as 100%. A: Compared with that of corresponding contralateral eyes, injection of AAV-Rho demonstrated a significant increase in a-wave amplitudes at both 1 month (122%) and 6 months (90%) time points. (*p<0.05, n=6). B: Compared with contralateral eyes, injection of WT Rho demonstrated the same significant increase in b-wave amplitudes as that of a-wave response at both 1 month (122%) and 6 months (90%) time points. (*p<0.05, ** p<0.005, n=6). Although injection injury can induce protective cytokines such as CNTF, this effect peaks within a few days of injection and is complete before the first measurements were made.
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f2: Improvement of electroretinography (ERG) response by single AAV injection of normal mouse rhodopsin cDNA (WT Rho) in P23H transgenic mice [89]. Bars represent the average of five scotopic ERG scans at 0 dB (2.6 cd (cd)-s/m2) a-wave response. A: and b-wave response. B: at 1 month and 6 months post injection. ERG amplitudes of 1 month uninjected P23H eyes were set as 100%. A: Compared with that of corresponding contralateral eyes, injection of AAV-Rho demonstrated a significant increase in a-wave amplitudes at both 1 month (122%) and 6 months (90%) time points. (*p<0.05, n=6). B: Compared with contralateral eyes, injection of WT Rho demonstrated the same significant increase in b-wave amplitudes as that of a-wave response at both 1 month (122%) and 6 months (90%) time points. (*p<0.05, ** p<0.005, n=6). Although injection injury can induce protective cytokines such as CNTF, this effect peaks within a few days of injection and is complete before the first measurements were made.

Mentions: Although neurotrophic factors are aimed at preserving the photoreceptors without addressing the underlying mutation, more direct treatments including gene suppression or replacement are also being tested. Photoreceptors are sensitive to changes in rhodopsin levels, and overabundance of this protein can lead to retinal degeneration in mouse models [23,85]. In a transgenic mouse line, an excess of rhodopsin of only 23% was enough to cause RP-like retinal degeneration [86]. However, heterozygous mutations in the mouse Rho gene result in a relatively normal retina at birth, with the length of rod outer segments approximately 60% that of Rho+/+ mice [87]. Similar to humans bearing heterozygous mutations, Rho+/− show a reduced response to light flash. Rhodopsin mutations, acting in a dominant negative manner, may be treatable simply through a DNA cassette expressing wild-type RHO [88,89]. With a single injection of AAV-transferred normal rhodopsin, 90% of the ERG response in a- and b-wave amplitudes can be preserved in P23H mice compared with P23H mice without treatment (Figure 2) [89]. Other mutations, however, may require suppression of the mutant gene plus provision of a wild-type replacement gene, especially since overexpression of rhodopsin can be toxic [86]. The methods for suppressing endogenous expression begin at the either the RNA or DNA level. RNA interference or ribozymes achieve suppression at the RNA level while advances in zinc finger transcription factors and endonucleases and transcription activator-like (TAL) effector nucleases could correct the mutations at the DNA level.


Gene therapy in animal models of autosomal dominant retinitis pigmentosa.

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

Improvement of electroretinography (ERG) response by single AAV injection of normal mouse rhodopsin cDNA (WT Rho) in P23H transgenic mice [89]. Bars represent the average of five scotopic ERG scans at 0 dB (2.6 cd (cd)-s/m2) a-wave response. A: and b-wave response. B: at 1 month and 6 months post injection. ERG amplitudes of 1 month uninjected P23H eyes were set as 100%. A: Compared with that of corresponding contralateral eyes, injection of AAV-Rho demonstrated a significant increase in a-wave amplitudes at both 1 month (122%) and 6 months (90%) time points. (*p<0.05, n=6). B: Compared with contralateral eyes, injection of WT Rho demonstrated the same significant increase in b-wave amplitudes as that of a-wave response at both 1 month (122%) and 6 months (90%) time points. (*p<0.05, ** p<0.005, n=6). Although injection injury can induce protective cytokines such as CNTF, this effect peaks within a few days of injection and is complete before the first measurements were made.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Improvement of electroretinography (ERG) response by single AAV injection of normal mouse rhodopsin cDNA (WT Rho) in P23H transgenic mice [89]. Bars represent the average of five scotopic ERG scans at 0 dB (2.6 cd (cd)-s/m2) a-wave response. A: and b-wave response. B: at 1 month and 6 months post injection. ERG amplitudes of 1 month uninjected P23H eyes were set as 100%. A: Compared with that of corresponding contralateral eyes, injection of AAV-Rho demonstrated a significant increase in a-wave amplitudes at both 1 month (122%) and 6 months (90%) time points. (*p<0.05, n=6). B: Compared with contralateral eyes, injection of WT Rho demonstrated the same significant increase in b-wave amplitudes as that of a-wave response at both 1 month (122%) and 6 months (90%) time points. (*p<0.05, ** p<0.005, n=6). Although injection injury can induce protective cytokines such as CNTF, this effect peaks within a few days of injection and is complete before the first measurements were made.
Mentions: Although neurotrophic factors are aimed at preserving the photoreceptors without addressing the underlying mutation, more direct treatments including gene suppression or replacement are also being tested. Photoreceptors are sensitive to changes in rhodopsin levels, and overabundance of this protein can lead to retinal degeneration in mouse models [23,85]. In a transgenic mouse line, an excess of rhodopsin of only 23% was enough to cause RP-like retinal degeneration [86]. However, heterozygous mutations in the mouse Rho gene result in a relatively normal retina at birth, with the length of rod outer segments approximately 60% that of Rho+/+ mice [87]. Similar to humans bearing heterozygous mutations, Rho+/− show a reduced response to light flash. Rhodopsin mutations, acting in a dominant negative manner, may be treatable simply through a DNA cassette expressing wild-type RHO [88,89]. With a single injection of AAV-transferred normal rhodopsin, 90% of the ERG response in a- and b-wave amplitudes can be preserved in P23H mice compared with P23H mice without treatment (Figure 2) [89]. Other mutations, however, may require suppression of the mutant gene plus provision of a wild-type replacement gene, especially since overexpression of rhodopsin can be toxic [86]. The methods for suppressing endogenous expression begin at the either the RNA or DNA level. RNA interference or ribozymes achieve suppression at the RNA level while advances in zinc finger transcription factors and endonucleases and transcription activator-like (TAL) effector nucleases could correct the mutations at the DNA level.

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