Seeing Eye to Eye With Gene Therapy
Authors: Roland W Herzog
Journal: Molecular Therapy (2012)

In 2008, three independent clinical studies reported results of almost biblical proportions: gene therapy had restored sight to the blind. All three studies had targeted a rare inherited form of blindness called Leber's congenital amaurosis (LCA), which is caused by a deficiency in RPE65. This enzyme is normally expressed in retinal pigment endothelial cells and is required for recycling of 11-cis-retinal. Without this function, light transduction cannot be sustained and photoreceptors degenerate over time. Patients lose most of their sight early in life, and no treatment was available before these gene therapy protocols. Recently, subretinal administration of an adeno-associated viral (AAV) vector (serotype 2) has restored at least some visual function. In some cases, it has been documented that the degree of correction at the site of gene transfer was the maximum possible for the number of intact photoreceptors that had remained. This success in humans came approximately one decade after proof of principle in a canine model and provided an enormous boost for the gene therapy field in general. Many memorable statements from participating patients illustrated just how remarkable the outcome has been. Examples included “the sun is hurting my eye,” “seeing the blue sky for the first time,” and being able to read the digital clock in the dashboard of a car. Patients were able to master an obstacle course without bumping into objects, something they were not able to do before gene transfer. Although the initially treated patients were adults, the success story continued in a subsequent trial in children. Many of us have seen the YouTube video of an 8-year-old who went from going blind to attending school and playing Little League baseball after receiving gene therapy. Because of the novel and experimental nature of this treatment, all patients in the initial trials received gene therapy in only one eye. Many of them were now appealing to the doctors and scientists to have their second eye treated. But would that be possible? It is dogma in the gene therapy community that one cannot readminister a viral vector—at least systemically—because of neutralizing antibodies. However, the eye is an immune-privileged site. For example, the anterior chamber–associated immune deviation is a known immunosuppressive response in the eye. In addition, only small vector doses had been administered, and preclinical data in animals supported the conclusion that one can indeed readminister an AAV vector to the second eye. It has also been shown that intraocular administration of a viral vector to children with retinoblastoma did not cause a systemic immune response.1Ildefonso CJ Kong L Leen A Chai SJ Petrochelli V Chintagumpala M et al.Absence of systemic immune response to adenovectors after intraocular administration to children with retinoblastoma.Mol Ther. 2010; 18: 1885-1890Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Nonetheless, many humans have preexisting immunity to AAV due to natural infection, and the field had become wary of such conclusions from animal studies after, unexpectedly, it became clear that humans can mount CD8+ T-cell responses against the AAV capsid. Thus, the first gene transfer, even if it did not initially cause a detectable immune response, may have further sensitized the patients' immune systems to the vector. Still, Bennett and colleagues at the University of Pennsylvania and the Children's Hospital of Philadelphia cautiously proceeded with gene transfer to the contralateral eye in three adult patients whose first eye had been treated 2–3 years earlier.2Bennett J Ashtari M Wellman J Marshall KA Cyckowski LL Chung DC et al.AAV2 gene therapy readministration in three adults with congenital blindness.Sci Transl Med. 2012; 4: 120ra15Crossref PubMed Scopus (310) Google Scholar Not only was readministration found safe, without immune responses or toxicities, but visual function was clearly improved in the second eye in all three subjects. For example, two of the patients are now able to navigate in dim light much more accurately. The study reports several additional and surprising findings. Although light sensitivity, as expected, did not change in the first, previously treated eye, functional magnetic resonance imaging showed further improvement in visual cortex function in response to light signals to the first eye as well. This suggests that better synchrony in eye movement or plasticity of the brain allows for better processing of the light signals. In earlier studies, it had been noticed that a pseudo fovea could emerge over time at the site of gene transfer in humans with LCA and that correction of color blindness in monkeys resulted in processing of the novel information only long after gene transfer, illustrating the potential for plasticity and adjustments in transduction and processing of visual information. The new study provides the first evidence for restoration of cone function in humans, as evidenced by increased sensitivity to red light stimuli in at least one patient. Finally, two of the three patients received a higher dose of gene transfer to the second eye than they had to the first eye. Interocular comparison of light sensitivity and visual function demonstrated a possible dose response to vector treatment. In conclusion, these new findings on vector readministration are highly encouraging for the other patients, including children, who are hoping to finally see with both eyes thanks to gene therapy. Development of gene therapies for other eye diseases will also benefit from these findings.