Effect of Gene Therapy on Visual Function in Leber's Congenital Amaurosis

Bainbridge, James; Smith, Alexander J.; Barker, Susie S; Robbie, Scott; Henderson, Robert H.; Balaggan, Kamaljit S.; Viswanathan, Ananth C.; Holder, Graham E.; Stockman, Andrew; Tyler, Nick; Petersen‐Jones, Simon M.; Bhattacharya, Siladitya; Thrasher, Adrian J.; Fitzke, Fred W.; Carter, Barrie J.; Rubin, Gary S.; Moore, Anthony T.; Ali, Robin R.

doi:10.1056/nejmoa0802268

Cited by 1,736 publications

(1,448 citation statements)

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“…[3][4][5][6][7][8][9][10][11][12][13][14] On the basis of the success of some of these animal studies, clinical trials with AAV vectors have recently been initiated in humans with genetically linked ophthalmic diseases. 15,16 Human AAV serotype 2 was originally found as a contaminant in adenovirus preparations 17 and has not been associated with any human pathogenicity. Since then, several other AAV serotypes have been identified with slight variations in amino-acid capsid identity.…”

Section: Introductionmentioning

confidence: 99%

Cellular tropism and transduction properties of seven adeno-associated viral vector serotypes in adult retina after intravitreal injection

et al. 2008

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Recombinant adeno-associated virus (rAAV) vectors are increasingly being used as tools for gene therapy, and clinical trials have begun in patients with genetically linked retinal disorders. Intravitreal injection is optimal for the transduction of retinal ganglion cells (RGCs), although complete selectivity has not been achieved. There may also be advantages in using intravitreal approaches for the transduction of photoreceptors. Here we compared the cellular tropism and transduction efficiency of rAAV2/1, -2/2, -2/3, -2/4, -2/5, -2/6 and -2/8 in adult rat retina after intravitreal injection. Each vector encoded green fluorescent protein (GFP), and the number, laminar distribution and morphology of transduced GFP + cells were determined using fluorescent microscopy. Assessment of transduced cell phenotype was based on cell morphology and immunohistochemistry. rAAV2/2 and rAAV2/6 transduced the greatest number of cells, whereas rAAV2/5 and rAAV2/8 were least efficient. Most vectors primarily transduced RGCs; however, rAAV2/6 had a more diverse tropism profile, with 46% identified as amacrine or bipolar cells, 23% as RGCs and 22% as Mü ller cells. Mü ller cells were also frequently transduced by rAAV2/4. The highest photoreceptor transduction was seen after intravitreal rAAV2/3 injection. These data facilitate the design and selection of rAAV vectors to target specific retinal cells, potentially leading to an improved gene therapy for various human retinal pathologies.

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Section: Introductionmentioning

confidence: 99%

Cellular tropism and transduction properties of seven adeno-associated viral vector serotypes in adult retina after intravitreal injection

et al. 2008

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“…Last but not least, the knowledge of the molecular defect is a prerequisite for gene-specific therapy, as recently established for LCA. [3][4][5][6][7][8] This study appointed mutations in AIPL1, GUCY2D, and RDH12 as the molecular cause of LCA in three patients. For both AIPL1 and GUCY2D, proof-of-concept studies in animal models have shown beneficial effects of subretinal delivery of adeno-associated vectors containing the wild-type coding sequence.…”

Section: Discussionmentioning

confidence: 99%

“…However, in 2008, three independent phase I clinical trials achieved a major breakthrough following gene-replacement therapy in three young adults with RPE65-related LCA, which was shown to be safe and resulted in visual improvement in a subset of patients. [3][4][5] A follow-up study including children demonstrated even more beneficial effects at a younger age. 6 The efficacy and safety persisted through up to 2 years.…”

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confidence: 99%

Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis

Coppieters

Wilde

Lefever

et al. 2012

Genetics in Medicine

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Purpose: Leber congenital amaurosis (LCA) is a rare congenital retinal dystrophy associated with 16 genes. Recent breakthroughs in LCA gene therapy offer the first prospect of treating inherited blindness, which requires an unequivocal and early molecular diagnosis. While present genetic tests do not address this due to a tremendous genetic heterogeneity, massively parallel sequencing (MPS) strategies might bring a solution. Here, we developed a comprehensive molecular test for LCA based on targeted MPS of all exons of 16 known LCA genes. methods:We designed a unique and flexible workflow for targeted resequencing of all 236 exons from 16 LCA genes based on quantitative PCR (qPCR) amplicon ligation, shearing, and parallel sequencing of multiple patients on a single lane of a short-read sequencer. Twenty-two prescreened LCA patients were included, five of whom had a known molecular cause.Results: Validation of 107 variations was performed as proof of concept. In addition, the causal genetic defect and a single heterozygous mutation were identified in 3 and 5, respectively, of 17 patients without previously identified mutations. conclusion:We propose a novel targeted MPS-based approach that is suitable for accurate, fast, and cost-effective early molecular testing in LCA, and easily applicable in other genetic disorders.Genet Med 2012:14(6):576-585

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“…The hope is that the working gene will repair malfunctioning cells and keep them alive, preserving and even improving vision. Trials by three different groups [1][2][3][4] have shown not only that the procedure is safe, but also that it boosts vision in most participants -and that most improvements seem to be maintained for up to seven years. The biotechnology company Spark Therapeutics in Philadelphia, Pennsylvania, is now testing gene therapy for LCA2 in an advanced trial, and it hopes to file for regulatory approval in the United States as early as 2016.…”

Section: S M a L L S T E P Smentioning

confidence: 99%

“…Robin Ali, a geneticist at University College London who led one of the early LCA2 trials 3 , is more confident about the promise of these treatments: the careful animal work that preceded human trials showed that gene therapy, if given at the right dose and the right time, can slow degeneration. "We're still at the very start of the optimization process in humans, " he says.…”

Section: S M a L L S T E P Smentioning

confidence: 99%

Curing blindness: Vision quest

Lok¹

2014

Nature

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Effect of Gene Therapy on Visual Function in Leber's Congenital Amaurosis

Cited by 1,736 publications

References 21 publications

Cellular tropism and transduction properties of seven adeno-associated viral vector serotypes in adult retina after intravitreal injection

Cellular tropism and transduction properties of seven adeno-associated viral vector serotypes in adult retina after intravitreal injection

Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis

Curing blindness: Vision quest

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