Immune responses to AAV in a phase I study for Canavan disease

McPhee, Scott; Janson, Christopher G.; Li, Chengwen; Samulski, R. Jude; Camp, Angelique S.; Francis, Jeremy S.; Shera, David; Lioutermann, L.; Feely, Michael; Freese, Andrew; Leone, Paola

doi:10.1002/jgm.885

Cited by 208 publications

(147 citation statements)

References 33 publications

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“…Owing to its safe profile, AAV is considered to be the most suitable viral vector for human application, and is currently being tested in a phase I clinical trial. 34 Integration of newly formed cartilage with and neighbouring, undamaged tissue has always been a major issue in cartilage repair. Poor integration causes uneven distribution of mechanical loading, and predisposes the joint surface to the development of early degenerative changes.…”

Section: Discussionmentioning

confidence: 99%

Articular cartilage repair by genetically modified bone marrow aspirate in sheep

et al. 2010

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Section: Discussionmentioning

confidence: 99%

Articular cartilage repair by genetically modified bone marrow aspirate in sheep

et al. 2010

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“…These data also contrast with those from a study of adeno-associated virus in Canavan disease, in which selective induction of the Th2 cytokine IL-10 was seen. 15 In summary, we have analysed the immune responses to intravenous administration of an oncolytic agent in a highly valuable, and relevant, population of patients. Our data indicate that future protocols should be biased towards rapid, repeated administrations of virus before the full force of the NARA response is developed.…”

Section: Immune Responses To Reovirus CL White Et Almentioning

confidence: 99%

“…In addition to adaptive humoral responses, viral administration may also affect circulating populations of T lymphocytes and NK cells and may have effects on circulating cytokine profiles. 15 Such alterations to components of the adaptive and innate immune systems may, in turn, affect the antiviral and antitumour immune milieu. 16 A knowledge of the effects of viral administration on immune parameters will be an important component of the future development of viral vectors as cancer therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the adaptive and innate immune response to intravenous oncolytic reovirus (Dearing type 3) during a phase I clinical trial

et al. 2008

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“…29 However, a much more limited systemic response to vector has been observed when rAAV was administered to the brain, which is an immune privileged site, with no anti-vector antibodies detected in the CNS itself and only a minority of patients developing circulating NAb. 30 The eye is also a site of immune privilege, and thus is a good target for gene delivery. Three clinical trials for LCA II have been initiated, in which one eye of each patient has been treated with rAAV2.…”

Section: Introductionmentioning

confidence: 99%

Gene therapy in the second eye of RPE65-deficient dogs improves retinal function

Annear

Bartoe

Barker³

et al. 2010

Gene Ther

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The purpose of this study was to evaluate whether immune responses interfered with gene therapy rescue using subretinally delivered recombinant adeno-associated viral vector serotype 2 carrying the RPE65 cDNA gene driven by the human RPE65 promoter (rAAV2.hRPE65p.hRPE65) in the second eye of RPE65À/À dogs that had previously been treated in a similar manner in the other eye. Bilateral subretinal injection was performed in nine dogs with the second eye treated 85-180 days after the first. Electroretinography (ERG) and vision testing showed rescue in 16 of 18 treated eyes, with no significant difference between first and second treated eyes. A serum neutralizing antibody (NAb) response to rAAV2 was detected in all treated animals, but this did not prevent or reduce the effectiveness of rescue in the second treated eye. We conclude that successful rescue using subretinal rAAV2.hRPE65p.hRPE65 gene therapy in the second eye is not precluded by prior gene therapy in the contralateral eye of the RPE65À/À dog. This finding has important implications for the treatment of human LCA type II patients. Gene Therapy (2011) The condition is characterized by severe visual impairment in dim light, typically progressing to complete blindness in the second decade of life. LCA type II results from mutations in the RPE65 gene, and accounts for 10-15% of LCA cases. 2,3 RPE65 encodes a protein that forms an essential component of the visual cycle and is expressed within the retinal pigment epithelium. 3 The visual cycle is responsible for the supply of the chromophore, 11-cis-retinal, to the photoreceptor cells for combination with the rod and cone opsins to form the visual pigments. RPE65 is an isomerohydrolase that converts esters of vitamin A to 11-cis-retinol for subsequent oxidation to 11-cis-retinal prior to transport to the photoreceptors. A spontaneous 4 basepair deletion in RPE65 in the Briard breed of dog results in a premature stop codon and an absence of RPE65 gene product, resulting in a very similar phenotype to LCA type II. 4 Affected dogs have markedly reduced vision and an abnormal electroretinogram with greatly elevated threshold of responses. 4,5 The similarities between the human and canine disease resulting from RPE65 mutations, make the RPE65À/À Briard a valuable large animal model for LCA type II.Dramatic restoration of vision with gene therapy was first reported in the canine RPE65À/À model of LCA. 6 A number of studies have shown rod and cone photoreceptor rescue using rAAV vectors to deliver a normal copy of the RPE65 gene via a subretinal injection in the RPE65 mutant Briard. [6][7][8][9][10][11][12][13] On the basis of the great success of the canine trials, phase I/II clinical trials of rAAV-RPE65 gene replacement therapy in human LCA patients have started with the first reported results showing great promise. 14-16 Thus far in all human patients only one eye has been treated. A critical aspect of the management of LCA

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Immune responses to AAV in a phase I study for Canavan disease

Cited by 208 publications

References 33 publications

Articular cartilage repair by genetically modified bone marrow aspirate in sheep

Articular cartilage repair by genetically modified bone marrow aspirate in sheep

Characterization of the adaptive and innate immune response to intravenous oncolytic reovirus (Dearing type 3) during a phase I clinical trial

Gene therapy in the second eye of RPE65-deficient dogs improves retinal function

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