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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Contribution of noncoding pathogenic variants to RPGRIP1-mediated inherited retinal degeneration.
Farzad Jamshidi,Emily Place,Sudeep Mehrotra,Daniel Navarro-Gomez,Mathew Maher,Kari Branham,Elise Valkanas,Timothy J. Cherry,Monkol Lek,Monkol Lek,Daniel G. MacArthur,Daniel G. MacArthur,Eric A. Pierce,Kinga M. Bujakowska +13 more
TL;DR: The results suggest that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and RPGRIP1-mediated IRDs are more common than previously thought.
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A Single Intravenous AAV9 Injection Mediates Bilateral Gene Transfer to the Adult Mouse Retina
Alexis-Pierre Bemelmans,Sandra Duque,Christel Rivière,Stéphanie Astord,Melissa Desrosiers,Melissa Desrosiers,Melissa Desrosiers,Thibaut Marais,José-Alain Sahel,Thomas Voit,Martine Barkats +10 more
TL;DR: This study provides the first demonstration that a single intravenous scAAV9 injection can deliver transgenes to the retinas of both eyes in adult mice, suggesting that this vector serotype is able to cross mature blood-eye barriers.
A clinical molecular genetic service for United Kingdom families with choroideraemia.
Simon C Ramsden,Anna O'Grady,Tracy Fletcher,James O'Sullivan,Nikki Hart-Holden,Stephanie Barton,Georgina Hall,Anthony T. Moore,Andrew R. Webster,Graeme C.M. Black +9 more
TL;DR: Clinical molecular testing for CHM is available clinically and can be used to support the clinical diagnosis and management of patients with choroideraemia as well as their families and the potential clinical utility of testing is demonstrated.
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Manipulating Immune Tolerance with Micro-RNA Regulated Gene Therapy.
TL;DR: The application of using miR transgene regulation to generate tolerogenic responses and speculate on possible mechanisms used by the liver to induce the transgenes-specific regulatory T cells are discussed.
Birth of a new therapeutic platform: 47 years of adeno-associated virus biology from virus discovery to licensed gene therapy.
TL;DR: Glybera is a recombinant adeno-associated virus vector with AAV2 inverted terminal repeats encapsidated into AAV1 capsids, which, when administered intramuscularly, can result in expression of sufficient levels of lipoprotein lipase (LPL) to be considered a safe and effective treatment of LPL deficiency.
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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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