Gene therapy holds much promise, but the field remains in its infancy. The potential for cure is not matched by either technology or understanding. Key challenges remain in characterizing mutations of genes for major diseases, understanding the pathogenic relevance of identified genes, and developing proper delivery systems for curative gene constructs (the main long-term gene therapy vehicle—viruses—is currently limited by the size of the gene, inflammatory effects, and the risk of oncogenesis).
Replacement of Absent Gene Product in X-Linked and Recessive Diseases
For genetic diseases in which the mutant allele produces either no message or an ineffective gene product (called a null allele), correction of the disorder may be possible by simple replacement of the gene in the deficient cells or tissues. It is theoretically possible to transfer normal genes into human cells that harbor either null or mutant genes not producing a stable, translated product. Vectors used to carry the genetic material into the cells include adenoviruses, retroviruses (especially adeno-associated viruses [AAVs]), and plasmid–liposome complexes. AAV vector gene therapy has been successful in curing many disorders in animal models, such as the RPE65 gene mutation that causes RP in the Briard dog.
Figure 5-9 Forest plots (at right) of meta-analyses for single nucleotide polymorphisms (SNPs) near LOX1 in pseudoexfoliation syndrome (XFS) and pseudoexfoliation glaucoma (XFG). A forest plot is a graphical display designed to illustrate the relative strength of effects found in different quantitative scientific studies that address the same question; essentially, it graphically represents a meta-analysis of the results. A, Meta-analysis of the association of SNP rs1048661 with a combined group of XFS and XFG cases. Subgroup metaanalysis indicated that the odds ratios (ORs) of SNP rs1048661 G allele are reversed in Caucasian and Japa nese populations. B, Meta-analysis of the association of SNP rs3825942 with a combined group of XFS and XFG cases. Subgroup meta-analysis indicated that the ORs of SNP rs3825942 G allele are consistent in Caucasian and Japa nese populations. Square = study-specific OR, with the size of the square proportional to the weight of the study; horizontal line = 95% confidence interval (CI); diamond = summary OR with its corresponding 95% CI.
(Reproduced with permission from Chen H, Chen LJ, Zhang M, et al. Ethnicity-based subgroup meta-analysis of the association of LOXL1 polymorphisms with glaucoma. Mol Vis. 2010;16:167–177.)
Table 5-1 Does a Change in a Gene Really Cause Disease?
Human gene therapy trials with RPE65 suggest no major early adverse effects and some improvement in visual function. In 2017, the US Food and Drug Administration approved the use of voretigene neparvovec (AAV2-hRPE65v2) in patients with confirmed biallelic RPE65-mediated retinal dystrophy (ie, Leber congenital amaurosis [LCA] and RP). The current cost of treating both eyes is $850,000. Also, mutations in RPE65 account for only a small percentage of LCA (see Chapter 6, Fig 6-4); thus, this therapy is not suitable for all patients with LCA. Studies in younger subjects (<3 years) are also under way, and several other retinal dystrophy genes are under investigation for human gene therapy trials.
Carvalho LS, Vandenberghe LH. Promising and delivering gene therapies for vision loss. Vision Res. 2015;111(Pt B):124–133.
Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849–860.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.