Gene therapy in hereditary retinal degeneration and the tower of Babel

In the Western world hereditary retinal diseases are the most common cause of blindness in people under 70 years of age, affecting about 1.5 million individuals. Various attempts have been tried but none of the enumerated treatments had any scientifically confirmed beneficial effect.1 Gene therapy holds the promise of revolutionising the treatment of genetic diseases and might be an “ideal” approach to treat many forms of hereditary retinal diseases. Indeed, hereditary retinal diseases meet all of the major requirements for gene therapy.2 Firstly, their genetic basis is well characterised and the biochemical defects are known in several diseases (for example, Refsum disease, gyrate atrophy, Kearns-Sayre syndrome). Secondly, efficient gene delivery techniques that can be relatively well controlled are available and allow even local ocular application. Lastly, reliable animal models of hereditary retinal diseases are available that permit preclinical testing.

However, fundamental challenges in gene therapy are still present and it appears that clinical trials in non-life threatening disorders such as retinal dystrophies are far away from being conducted. One of the most significant hurdles preventing the clinical application of gene therapy is the lack of safe gene transfer systems. Of all gene delivery vectors available today, viral vectors, including replication defective adenoviruses, adeno associated viruses, herpes simplex 1, and lentiviruses, dominate the field. Replication defective adenoviral vehicles are probably the most versatile vectors to deliver plasmid DNA to retinal cells. Most importantly, at low multiplicity of infection they do not appear to interfere with RPE cell function or survival.3 However, adenoviral vectors remain episomal and cannot integrate into the host genome for long term gene expression. In addition, first generation E1 deleted adenoviruses express proteins of their own, resulting in an immune response against the cells that harbour the virus and lead to clearance of the infected cells with ultimately loss of the therapeutic effect. Indeed, a number of studies are showing a shortened term of expression due to a potent antiviral immune response.4

The paper presented by Reichel et al (p 341) in this issue of the BJO reports interesting observations, which in part contradict these concerns, and contributes to the growing literature on unexpected findings in ocular gene therapy. Following intravitreal injection of an adenoviral vector carrying a reporter gene, a significant rescue of photoreceptors was observed when injections were performed in T cell depletedrd mice. Although previous studies already reported that ocular injury, such as intravitreal injection itself, can inhibit photoreceptor cell degeneration, it is not considered as a significant factor. The results presented in this study indicate that the immune response may have a so far unexpected role following adenovirus mediated gene transfer. The authors substantiate their findings by experiments using depletion of either CD4+, CD8+ cells or a combined strategy that support the finding of an immune mediated protective effect. It is of interest that depletion of both CD4+ and CD8+ cells was necessary to obtain protection indicating that the afferent as well as the efferent arc of the immune response is involved.

Still the central question remains, how is this mechanisms generated? The authors hypothesise a role of growth factors and this is certainly a vivid explanation. There is growing evidence that neuroprotective factors such as basic fibroblast growth factor (bFGF) and ciliary neurotrophic factor (CNTF) are upregulated following injury.5 However, the finding that animals receiving sham injections did not demonstrate a beneficial effect strongly suggests that this is not yet an unspecific bystander effect. Instead, activated T cells seem to participate in retina protection. Interestingly, this may highlight another field of interest that recently has been coined as “protective autoimmunity”.6 Reactive T cells, usually considered as the “bad guys”, have been shown to have a protective role in neurodegeneration. Activated T cells are known to patrol the central nervous system including the neuroretina and an immune response may act as a protective mechanism.6

Another question that remains open is the relative immunogenicity of viral antigens compared with the transgene. It might be assumed that expression of the encoded proteins following transfection is more immunogenic than the intracellular reporter gene product, but no proof is provided. Since gene therapy for hereditary retinal diseases is an active field of interest, this has to be kept in mind and further investigations seem indicated. In particular the use of adequate controls including an inactive “functional” gene or immunosuppressive treatment seems mandatory and has also been suggested by the authors of this study.

Taken together, the findings of this report may at least bring to mind that more basic research is needed in gene therapy and no rush into clinical trials should be expected. This resumé already given 5 years ago still holds true.7 In the short term it seems more likely that advances in the treatment of hereditary retinal degenerations may come from other therapeutic options—for example, retinal implants.1 However, the ultimate goal of a definitive permanent treatment lies in the future of gene therapy.