Gene Therapy for Leber's Congenital Amaurosis is Safe and Effective Through 1.5 Years After Vector Administration

Abstract

The safety and efficacy of gene therapy for inherited retinal diseases is being tested in humans affected with Leber's congenital amaurosis (LCA), an autosomal recessive blinding disease. Three independent studies have provided evidence that the subretinal administration of adeno-associated viral (AAV) vectors encoding RPE65 in patients affected with LCA2 due to mutations in the RPE65 gene, is safe and, in some cases, results in efficacy. We evaluated the long-term safety and efficacy (global effects on retinal/visual function) resulting from subretinal administration of AAV2-hRPE65v2. Both the safety and the efficacy noted at early timepoints persist through at least 1.5 years after injection in the three LCA2 patients enrolled in the low dose cohort of our trial. A transient rise in neutralizing antibodies to AAV capsid was observed but there was no humoral response to RPE65 protein. The persistence of functional amelioration suggests that AAV-mediated gene transfer to the human retina does not elicit immunological responses which cause significant loss of transduced cells. The persistence of physiologic effect supports the possibility that gene therapy may influence LCA2 disease progression. The safety of the intervention and the stability of the improvement in visual and retinal function in these subjects support the use of AAV-mediated gene augmentation therapy for treatment of inherited retinal diseases.

Optogenetic therapy for retinitis pigmentosa

“…63 The use of AAV-2 has been shown to be safe for human patients. 64 However, the more potent serotypes, for example, AAV-7 and AAV-8, have not yet been tested in the clinic. Preclinical trials should address carefully the immunogenic potential of the different optogenetic tools in combination with AAV serotypes.…”

“…Preclinical trials should address carefully the immunogenic potential of the different optogenetic tools in combination with AAV serotypes. Gene expression from AAVs has been reported to last for at least 1.5 years in humans, 64 but it is not yet known how long the sensitivity of optogenetic sensors will persist. Therefore, re-injection of AAVs 65 expressing optogenetic sensors should also be tested in preclinical trials.…”

Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis

“…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.…”

“…6 The efficacy and safety persisted through up to 2 years. [6][7][8] Despite this tremendous step forward, a major obstacle remains in identifying LCA patients eligible for gene-specific treatment due to a massive genetic heterogeneity. Sixteen disease genes are known to account for ~70% of LCA cases, leaving the remaining 30% unexplained (RetNet, http://www.sph.uth.tmc.edu/ massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis…”

Anticancer Gene Transfer for Cancer Gene Therapy

“…Clinical successes the last 5 years have breathed new air in the field of gene therapy like i.e. the treatment of X-linked SCID, ADA-SCID (Cartier and Aubourg, 2010;Aiuti et al, 2002), Xadrenoleukodystrophy (Cartier et al, 2009) and Wiskott-Aldrich Syndrome (WAS) (Boztug et al, 2010;Aiuti et al, 2013) metachromatic leukodystrophy by using ex vivo gene transfer into bone marrow hematopoietic stem cells and autologous transplantation or by direct gene transfer in vivo as in the cases of Leber congenital amaurosis (Bainbridge et al, 2008;Simonelli et al, 2010) and Parkinson's disease (LeWitt et al, 2011;Palfi et al, 2013) ONCOLYTIC VIRUSES AND VECTOR SYSTEMS FOR GENE DELIVERY There are several virus families and representatives of each family that are currently engaged in the battle with cancer. Oncolytic viruses have a native capacity of cell lysis and so innate ability of killing.…”