Effect of gene therapy on visual function in Leber's congenital amaurosis.
James W B Bainbridge,Alexander J. Smith,Susie S Barker,Scott J Robbie,Robert H. Henderson,Kamaljit S. Balaggan,Ananth C. Viswanathan,Graham E. Holder,Andrew Stockman,Nick Tyler,Simon M. Petersen-Jones,Shomi S. Bhattacharya,Adrian J. Thrasher,Fred W. Fitzke,Barrie J Carter,Gary S. Rubin,Anthony T. Moore,Robin R. Ali +17 more
TL;DR: Three young adult patients with early-onset, severe retinal dystrophy were administered subretinal injections of recombinant adeno-associated virus vector 2/2 expressing RPE65 complementary DNA (cDNA) under the control of a human R PE65 promoter.
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Abstract: Early-onset, severe retinal dystrophy caused by mutations in the gene encoding reti- nal pigment epithelium-specific 65-kDa protein (RPE65) is associated with poor vi- sion at birth and complete loss of vision in early adulthood. We administered to three young adult patients subretinal injections of recombinant adeno-associated virus vector 2/2 expressing RPE65 complementary DNA (cDNA) under the control of a human RPE65 promoter. There were no serious adverse events. There was no clinically significant change in visual acuity or in peripheral visual fields on Gold- mann perimetry in any of the three patients. We detected no change in retinal re- sponses on electroretinography. One patient had significant improvement in visual function on microperimetry and on dark-adapted perimetry. This patient also showed improvement in a subjective test of visual mobility. These findings provide support for further clinical studies of this experimental approach in other patients with mutant RPE65. (ClinicalTrials.gov number, NCT00643747.)
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Citations
Validation of a Vision-Guided Mobility Assessment for RPE65-Associated Retinal Dystrophy.
Neruban Kumaran,Neruban Kumaran,Neruban Kumaran,Robin R. Ali,Robin R. Ali,Nick Tyler,James W B Bainbridge,James W B Bainbridge,Michel Michaelides,Michel Michaelides,Gary S. Rubin,Gary S. Rubin +11 more
TL;DR: A novel, quantifiable, repeatable, and valid assessment of mobility designed specifically for subjects with RPE65-RD, which is sensitive to the visual impairment of individuals with R PE65- RD in low illumination, identifies the known phenotypic heterogeneity and will furthermore provide an important outcome measure for RPE 65-RD.
27
Fetal gene therapy: Opportunities and risks☆☆☆
TL;DR: Gene therapy using genetically modified autologous HSC circumvents allogeneic HLA barriers and constitutes one of the most promising new approaches to correct genetic deficits in the fetus.
27
Expression of wild-type Rp1 protein in Rp1 knock-in mice rescues the retinal degeneration phenotype.
Qin Liu,Rob W.J. Collin,Frans P.M. Cremers,Anneke I. den Hollander,L. Ingeborgh van den Born,Eric A. Pierce +5 more
TL;DR: It is reported that a frameshift mutation in the 3rd exon of RP1 is found in a patient with recessive RP1 disease, which causes RP in the homozygous state, whereas the heterozygous carriers are unaffected, confirming that haploinsufficiency is not the causative mechanism.
Efficacy and Safety of Glycosidic Enzymes for Improved Gene Delivery to the Retina following Intravitreal Injection in Mice
Jasmina Cehajic-Kapetanovic,Jasmina Cehajic-Kapetanovic,Nina Milosavljevic,Robert A. Bedford,Robert J. Lucas,Paul N. Bishop,Paul N. Bishop +6 more
TL;DR: The efficacy and safety of this intravitreal approach in enhancing retinal transduction efficiency by AAV in rodents are confirmed and Translating this method into other species, such as non-human primates, or for clinical applications will have challenges and require further studies.
27
AAV Biology, Infectivity and Therapeutic Use from Bench to Clinic
Melisa Vance,Angela M. Mitchell,Richard Jude Samulski +2 more
- 26 Nov 2015
TL;DR: This chapter reviews current information on rAAV clinical trials and the potential for combining rAAv platform with other technologies, such as induced pluripotent cells and gene editing.
References
Gene therapy restores vision in a canine model of childhood blindness.
Gregory M. Acland,Gustavo D. Aguirre,Jharna Ray,Qi Zhang,Tomas S. Aleman,Artur V. Cideciyan,Susan E. Pearce-Kelling,Vibha Anand,Yong Zeng,Albert M. Maguire,Samuel G. Jacobson,William W. Hauswirth,Jean Bennett +12 more
TL;DR: The results indicate that visual function was restored in this large animal model of childhood blindness, and gene therapy directed at photoreceptors and RPE in a large-animal model of human disease has not been reported.
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Rpe65 is necessary for production of 11- cis-vitamin A in the retinal visual cycle
T. Michael Redmond,Shirley Yu,Eric Lee,Dean Bok,D. I. Hamasaki,Ning Chen,Patrice Goletz,Jian Xing Ma,Rosalie K. Crouch,Karl Pfeifer +9 more
TL;DR: Disruption of the RPE-based metabolism of all-trans-retinyl esters to 11-cis-retinal thus appears to underlie the Rpe65-/- phenotype, although cone pigment regeneration may be dependent on a separate pathway.
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Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy.
Sumin Gu,Debra A. Thompson,C. R.Srisailapathy Srikumari,Birgit Lorenz,Ulrich Finckh,Aileen Nicoletti,K. R. Murthy,Michaela Rathmann,Govindasamy Kumaramanickavel,Michael J. Denton,Andreas Gal +10 more
TL;DR: The analysis of RPE65 in a collection of about 100 unselected retinal-dystrophy patients of different ethnic origin revealed five that are likely to be pathogenic mutations, including a missense mutation, two point mutations affecting splicing and two small re-arrangements on a total of nine alleles of five patients with arCSRD.
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RPE65 is the isomerohydrolase in the retinoid visual cycle
TL;DR: It is demonstrated that recombinant RPE65, when expressed in QBI-293A and COS-1 cells, has robust enzymatic activity of the previous unidentified isomerohydrolase, an enzyme converting all-trans retinyl ester to 11-cis retinol in the visual cycle.
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