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Published at www.nejm.org April 27, 2008 (10.1056/NEJMoa0802268)

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SUMMARY

Early-onset, severe retinal dystrophy caused by mutations in the gene encoding retinal pigment epithelium–specific 65-kDa protein (RPE65) is associated with poor vision at birth and complete loss of vision in early adulthood. We administered to three young adult patients subretinal injections of recombinant adeno-associated virus vector 2/2 expressing RPE65 complementary DNA (cDNA) under the control of a human RPE65 promoter. There were no serious adverse events. There was no clinically significant change in visual acuity or in peripheral visual fields on Goldmann perimetry in any of the three patients. We detected no change in retinal responses on electroretinography. One patient had significant improvement in visual function on microperimetry and on dark-adapted perimetry. This patient also showed improvement in a subjective test of visual mobility. These findings provide support for further clinical studies of this experimental approach in other patients with mutant RPE65. (ClinicalTrials.gov number, NCT00643747 [ClinicalTrials.gov] .)

Although the retinal dystrophy caused by defects in RPE65 is severe, features of the disorder suggest that it may respond to gene-replacement therapy. There is useful visual function in childhood, and retinal imaging suggests that photoreceptor-cell death occurs late in the disease process.³ Gene transfer therefore has the potential to improve visual function as well as preserve existing vision. Gene-replacement therapy has been shown to improve visual function in the Swedish Briard dog, a naturally occurring animal model with mutated RPE65.¹⁷ Subretinal delivery of recombinant adeno-associated virus vector containing the RPE65 cDNA results in improved retinal function and improved vision, as determined by visual mobility in low light.^{18,19,20,21,22}

The purpose of this study was to determine whether gene therapy for retinal dystrophy caused by RPE65 mutations was associated with immediately obvious adverse events and whether efficacy could be demonstrated in humans. In this exploratory, open-label, single-center study involving three young adults, each of whom received a single subretinal injection of recombinant adeno-associated virus 2/2.hRPE65p.hRPE65, the primary outcome was safety, and the secondary outcome was evidence of efficacy in terms of visual function.

Methods

Patients and Study Design

In this study, we included young adults (17 to 23 years of age) with early-onset, severe retinal dystrophy caused by missense mutations in RPE65 (Table 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). We excluded persons with visual acuity in the study eye that was better than 20/120 on the Snellen visual acuity scale, null mutations, and contraindications to systemic immunosuppression, as well as women who were pregnant or lactating. A National Health Service diagnostic laboratory (Manchester Regional Genetics Laboratory) confirmed the genotypes of potential subjects. In each patient, the eye with the worse acuity was selected as the study eye. The contralateral eye was used as a control.

The study was approved by the U.K. Gene Therapy Advisory Committee, the Medicines and Health Products Regulatory Authority, the Moorfields Research Governance Committee, and the local research ethics committee. All patients gave written informed consent. The study was conducted in compliance with Good Clinical Practice guidelines according to the European Clinical Trials Directive (Directive 2001 EU/20/EC) and the Declaration of Helsinki.

Before administration of the vector, we evaluated the retinal structure and function by means of clinical assessment, retinal imaging, psychophysical techniques, and electrodiagnostic methods. Retinal imaging techniques included color fundus photography, fundus autofluorescence imaging, and optical coherence tomography to determine retinal thickness and integrity. We measured visual acuity, contrast sensitivity, color vision, and cone flicker sensitivities. We investigated the patients' visual fields by means of microperimetry (see the Supplementary Appendix), Goldmann dynamic perimetry, and photopic and scotopic (dark-adapted) automated static perimetry (see the Supplementary Appendix). All testing was performed according to standardized, detailed protocols, with controlled room lighting, a dark-adaptation period, and a fixed sequence of test patterns. Both microperimetry and dark-adapted perimetry are fully automated, so there was little opportunity for experimenter bias. We determined the visual mobility of the patients at different illumination levels by measuring their ability to navigate a simulated street scene (Fig. 1 in the Supplementary Appendix). Electrophysiological evaluation included full-field, pattern, and multifocal electroretinography performed to incorporate the standards and guidelines of the International Society for Clinical Electrophysiology of Vision.

We repeated assessments of visual function and immune status (see below) at 2, 4, 6, and 12 months (the latter for Patient 1 only; Patients 2 and 3 have not yet reached the 12-month point) after administration of the vector. The end point for toxic effects for each patient was a grade 3 adverse event, defined as loss of visual acuity by 15 or more letters according to the Early Treatment Diabetic Retinopathy Study scale (on which 20/20 denotes perfect vision), or severe, unresponsive intraocular inflammation. The end point for efficacy for each patient was defined as any improvement in visual function that was greater than the test–retest difference for each technique. The assay of immune response and detection of disseminated recombinant adeno-associated virus are described in the Supplementary Appendix.

Recombinant Adeno-Associated Virus and Subretinal Delivery

The tgAAG76 vector is a recombinant adeno-associated virus vector of serotype 2. The vector contains the human RPE65 coding sequence driven by a 1400-bp fragment of the human RPE65 promoter and terminated by the bovine growth hormone polyadenylation site, as described elsewhere.²¹ The vector was produced by Targeted Genetics Corporation according to Good Manufacturing Practice guidelines with the use of a B50 packaging cell line,²³ an adenovirus–adeno-associated virus hybrid shuttle vector containing the tgAAG76 vector genome, and an adenovirus 5 helper virus. The vector was filled in a buffered saline solution at a titer of 1x10¹¹ vector particles per milliliter and frozen in 1-ml aliquots at –70°C.

Patients 1, 2, and 3 underwent surgery on February 7, April 25, and July 11, 2007, respectively. After three-port vitrectomy, we administered up to 1 ml of recombinant adeno-associated virus vector by means of a subretinal cannula (de Juan, Synergetics) to the subretinal space of one eye, involving up to one third of the total retinal area, including the macula. To reduce the possibility of clinically significant intraocular inflammation, patients were given a 5-week course of oral prednisolone, at a dose of 0.5 mg per kilogram of body weight for 1 week before administration of the vector, 1 mg per kilogram for the first week after administration, 0.5 mg per kilogram for the second week, 0.25 mg per kilogram for the third week, and 0.125 mg per kilogram for the fourth week. Patients received betamethasone and cefuroxime subconjunctivally at the completion of surgery and topical treatment with 0.5% chloramphenicol four times a day for 7 days, 0.1% dexamethasone four times a day for 4 weeks, and 1% atropine twice a day for 7 days after surgery. We performed a clinical examination, fundus photography, and ocular coherence tomography (Stratus OCT, Carl Zeiss Meditec) at frequent intervals in the early postoperative period to monitor for retinal reattachment and to identify any intraocular inflammation.

Results

Each patient had little or no vision in low light from an early age but retained some limited visual function in good lighting conditions. We selected these patients because they retained a limited degree of residual retinal function despite advanced retinal degeneration, and they might therefore be expected to benefit from intervention.

We performed vitrectomy and subretinal injection of the vector without complication in each patient (Figure 1 and Video 1). The vitreous gel was relatively degenerate; a posterior vitreous detachment was present in Patient 2 and was readily induced in Patients 1 and 3 by active aspiration at the optic disk with the use of the vitreous cutter. To deliver the vector to the relatively well-preserved retina at the posterior pole, we performed a retinotomy superior to the proximal part of the superotemporal vascular arcade. To minimize injection of the vector into the vitreous or choroid, we first induced a small detachment of the neurosensory retina, using Hartmann's solution before injecting up to 1 ml of recombinant adeno-associated virus vector (thus creating a "bleb") through the same single retinotomy. In Patient 2, the bleb of the vector extended spontaneously across the macula. We actively manipulated the bleb in Patients 1 and 3 — to involve the macula — by injecting air into the vitreous cavity. We caused no iatrogenic retinal tears, and we left the vector in situ under fluid without retinopexy or intraocular tamponade. On clinical examination 24 hours after surgery, the induced retinal detachment had almost fully resolved in each patient (Figure 1A). Optical coherence tomography showed minimal persistent subretinal fluid at the macula that resolved 2 to 3 days after surgery (Figure 1B). On clinical examination, the appearance of the retinas was unchanged for the duration of the follow-up period (up to 12 months).

View larger version (58K): [in this window] [in a new window]   Figure 1. Images of the Fundus and Maculae before and after Experimental Treatment. In Panel A, fundus photographs show the appearance of the retina in each patient before administration of the vector (before surgery), immediately after subretinal injection of the vector (during surgery), and at 1 day and 4 months after surgery. The site of injection of the vector is indicated by white arrows (see Video 1). Panel B shows cross-sectional images of the retina obtained by optical coherence tomography with the use of six 6-mm radial-line scans and a standardized mapping protocol to show the structure of the retinal layers in each patient. The presence of residual subretinal vector 1 day after surgery is shown (arrows) in Patients 1 and 3 by an area of low signal (black). Images in Patient 2 were unrecordable 1 day after surgery because of high-amplitude nystagmus.

 
We detected no dissemination of the vector, as assessed by means of polymerase-chain-reaction amplification of DNA isolated from samples of tears, serum, and saliva collected 1 day and 30 days after administration of the vector and from semen collected at 30 days (data not shown). We observed mild, self-limiting postoperative intraocular inflammation, which typically follows vitrectomy. There were no other adverse events. We found no evidence of cystoid macular edema clinically or on optical coherence tomography. We detected no specific cellular or humoral immune responses to adeno-associated virus capsid (Fig. 2 of the Supplementary Appendix) or specific humoral responses to the transgene product (Fig. 2 and Table 2 of the Supplementary Appendix). We detected a small increase in nonspecific activation of T cells in two patients, which is consistent with a rebound in the numbers of some lymphocyte subgroups after the withdrawal of corticosteroids (Fig. 2A of the Supplementary Appendix).

Visual acuity decreased predictably in association with the temporary retinal detachment induced by administration of the vector and returned to preoperative levels by 6 months (Table 1). We observed no clinically significant improvement in visual acuity in any of the three patients (Table 1) or any change in peripheral visual fields on Goldmann perimetry testing. We detected no change in retinal responses to flash or pattern electroretinography. Before surgery, Patient 2 had high-amplitude nystagmus, which did not change after treatment.

View this table: [in this window] [in a new window]   Table 1. Visual Acuities and Contrast Sensitivities at Baseline and in the Postoperative Period.

 
Microperimetry showed no change in retinal function in Patients 1 and 2 but improved retinal function in Patient 3 (Figure 2A). The baseline data for Patient 3 were obtained from the average of two measurements taken 1 week apart. Measurements were performed on the same retinal loci by registering the fundus image with the baseline image. In an area extending from the outer macula to a point beyond the major vascular arcade, the retinal sensitivity improved progressively in the right (study) eye by as much as 14 dB (a factor of 25). Thus, the patient could see small spots of light that were 1/25th as bright as those that could be seen before treatment. There was no improvement in the left (control) eye.

View larger version (44K): [in this window] [in a new window]   Figure 2. Assessment of Visual Function by Microperimetry and Dark-Adapted Perimetry. The upper portion of each panel shows the microperimetry results for each patient. The size of the circular symbols indicates retinal sensitivity on a scale of 0 to 14 dB. The change in sensitivity in Patient 3 at each tested location from baseline to 6 months' follow-up was evaluated with pointwise linear regression. Of the 55 locations that were tested, 12 (indicated by asterisks) had significant positive slopes (P<0.05), ranging from 12 to 28 dB per year. We would expect no more than three points to pass this test by chance alone. A major change in sensitivity of 9 dB or more (an increase in sensitivity by a factor of 8) is indicated by a plus sign. The lower portion of each panel shows the dark-adapted perimetry results for each patient. The analysis provides significance levels for change over time at each individual test location. We made a series of eight measurements during the 6-month follow-up period. Each measurement is depicted by a bar; the lengths of the bars represent sensitivity, with the long bars showing loss of sensitivity and the short bars showing normal sensitivity. Yellow indicates a decline in sensitivity that is not significant, red indicates a decline that is significant (P<0.05), and green indicates an improvement that is significant (P<0.01). One example, at the X/Y coordinate –9, +3 of the right eye of Patient 3, is magnified to show the sensitivity measurements going from baseline on the left sequentially through the follow-up assessments on the right. In this example, the long gray bars on the left indicate that the patient was unable to see the light stimulus at maximum intensity. The shorter bars on the right indicate progressive improvement in sensitivity (P<0.01).

 
Dark-adapted perimetry showed no change in retinal function in Patients 1 and 2 but showed improved retinal function in Patient 3 (Figure 2). In Patients 1 and 2, there was no single location that showed significant improvement or deterioration (P<0.05). In Patient 3, some locations in the left (control) eye had yellow bars representing nonsignificant decreases and red bars representing significant decreases in sensitivity. In the right (study) eye, 37 locations showed significant improvements in sensitivity (P<0.01). The mean sensitivity at nine locations in the inferonasal region improved from 4 dB at baseline to 26 dB after treatment, and nine locations in the inferotemporal quadrant improved from 7 dB to 28 dB. This finding is equivalent to an improvement in sensitivity of more than 20 dB for these 18 locations, or 100 times the sensitivity threshold observed at baseline.

Visual mobility in low light was unchanged in Patients 1 and 2 but improved in Patient 3 (Figure 3 and Video 2). In bright conditions, the visually guided mobility in Patient 3 was within normal limits at baseline and follow-up. Under low illumination at baseline, the visual performance of Patient 3 was very poor with the study eye as compared with the control eye (with which he made no errors). At follow-up, we observed a small change for the control eye. We attribute this change to a general learning effect; a similar improvement in travel time to complete the course under dim illumination was also observed in Patient 1. However, after administration of the vector, the travel time for Patient 3 improved from 77 seconds to 14 seconds for the study eye, and mobility errors decreased from 8 to 0. Similar results were obtained in a second follow-up test 4 weeks later.

View larger version (37K): [in this window] [in a new window]   Figure 3. Assessment of Visual Mobility. Visually guided mobility was assessed at the Pedestrian Accessibility and Movement Environment Laboratory at University College London (see Fig. 1 and the videos of the Supplementary Appendix). Panels A, B, and C show data for Patients 1, 2, and 3, respectively, at ambient illumination levels of 4 lux and 240 lux. Average travel times for completing the course (±1 SD) for five control subjects are indicated.

 
Discussion

Recombinant adeno-associated virus 2/2 vector efficiently transduces retinal pigment epithelial cells after subretinal delivery in animal models.²⁴ We investigated the feasibility of subretinal vector injection in patients with advanced retinal degeneration and found that we could achieve this outcome predictably and without immediate adverse events, using a transvitreal, transretinal approach after pars plana vitrectomy. A relatively degenerate vitreous facilitated detachment and removal of the posterior vitreous cortex, which otherwise might have resisted passage of the fine cannula. We found that we could deliver through a single retinotomy up to 1 ml of vector subretinally without causing tears in thinned, degenerate retina. To investigate the effect of RPE65 gene therapy on macular function, we included the macula in the area of vector administration by injection of air into the vitreous cavity when necessary. An important concern was that detachment of the neurosensory retina as a result of subretinal injection could adversely affect vision in the long term, particularly if the detachment involved the macula. We found that the induced retinal detachment resolved spontaneously and fully within a few days after injection, with subsequent recovery of vision to preexisting levels. We did not identify any clinically significant adverse effect of subretinal vector delivery, and the absence of systemic dissemination suggests that any extraocular leakage of vector from the subretinal space was minimal.

To minimize the possibility of intraocular inflammation elicited by vector capsid proteins, we used perioperative systemic immunosuppressive agents. Because of concerns about the possibility of immune responses to the transgene product, we used a tissue-specific promoter and excluded patients with null mutations. We observed no clinically significant intraocular inflammation and detected no immune responses to either adeno-associated virus capsid or RPE65.

We found consistent evidence, on the basis of both microperimetry and dark-adapted perimetry, of improved vision in one patient (Patient 3). The improvement in his visual mobility in low light was also substantially greater than that which would be due to a modest learning effect and was consistent with the improvement in visual function established by means of perimetry. It is not clear whether the improvement in visual responses in the peripheral macula is rod-mediated or cone-mediated. Neither can we be sure that the improvement in visual function is entirely due to enhanced levels of RPE65 in the retina. Evidence for this could be obtained only by biopsy of retinal material, which would be unsafe and unethical. Central macula function and visual acuity did not improve, despite exposure of this region to the vector; this may be due either to amblyopia (i.e., the study eye was amblyopic) or to a requirement for higher levels of RPE65 at the fovea. Visual function improved in only one patient (Patient 3); he had better baseline visual acuity in both the study (amblyopic) eye and the control eye than either of the other patients. He was not the youngest patient, but he probably had less advanced retinal disease at baseline, which may explain why the improvement in this patient was not observed in the other patients. Whether further retinal degeneration is delayed in any of the patients will become apparent only after several years.

The results of this study suggest that subretinal administration of recombinant adeno-associated virus vector is not associated with immediate adverse events in patients with severe retinal dystrophy and that adeno-associated virus–mediated RPE65 gene therapy can lead to modest improvements in visual function, even in patients with advanced degeneration. Our findings provide support for the development of further clinical studies in children with RPE65 deficiency; these children are more likely to benefit than adults.

Supported by grants from the U.K. Department of Health, the British Retinitis Pigmentosa Society, and the Special Trustees of Moorfields Eye Hospital, and by the Sir Jules Thorn Charitable Trust, the Wellcome Trust, the European Union (EVI-Genoret and Clinigene programs), the Medical Research Council, Foundation Fighting Blindness, Fight for Sight, the Ulverscroft Foundation, Fighting Blindness (Ireland), Moorfields Eye Hospital, and Institute of Ophthalmology Biomedical Research Centre for Ophthalmology, University College London.

Drs. Bainbridge and Ali report being the inventors associated with a U.S. patent application assigned to University College London and Targeted Genomics Corporation entitled, "Devices and methods for delivering polynucleotides into retinal cells of the macula and fovea"; Drs. Fitzke and Viswanathan report being two of the inventors of Progressor software, the intellectual property rights for which are owned by University College London and Moorfields Eye Hospital and licensed to Medisoft; Dr. Carter reports being an employee of Targeted Genetics and receiving consulting fees from Sangamo Biosciences. No other potential conflict of interest relevant to this article was reported.

We thank Andrew Dick and the U.K. RPE65 Gene Therapy Data and Safety Monitoring Committee; Alan Bird and the Moorfields Eye Hospital RPE65 Gene Therapy Advisory Committee; Vivien Perry and Moorfields Pharmaceuticals; Graeme Black, for help with genotyping; David Wong, for advice on surgical techniques; and the patients and their families for their effort and commitment.

Source Information

From the Institute of Ophthalmology, University College London (J.W.B.B., A.J.S., S.S. Barker, S.R., R.H., K.B., A.V., G.E.H., A.S., S.S. Bhattacharya, F.W.F., G.S.R., A.T.M., R.R.A.); Moorfields Eye Hospital (J.W.B.B., A.V., G.E.H., A.T.M.); the National Institute of Health Research Biomedical Research Centre for Ophthalmology, University College London and Moorfields Eye Hospital (J.W.B.B., G.S.R., A.T.M., R.R.A.); the Department of Civil and Environmental Engineering, University College London (N.T.); and the Institute of Child Health, University College London (A.J.T., R.R.A.) — all in London; Michigan State University, East Lansing (S.P.-J.); and Targeted Genetics Corporation, Seattle (B.J.C.).

Drs. Bainbridge and Smith contributed equally to this article.

This article (10.1056/NEJMoa0802268) was published at www.nejm.org on April 27, 2008. It will appear in the May 22 issue of the Journal.

Address reprint requests to Dr. Ali at the Institute of Ophthalmology, University College London, Bath St., London EC1V 9EL, United Kingdom, or at r.ali{at}ucl.ac.uk.

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The following investigators, who are members of the Moorfields Eye Hospital and University College London Eye Gene Therapy Study Group, participated in this trial: G.W. Aylward, D. Boampong, C. Broderick, P. Buch, C. Childs, Y. Duran, D. Ehlich, S. Falk, M. Feely, T. Fujiyama, F. Ikeji, V. Luong, A. Milliken, R. Maclaren, P. Moradi, F. Mowat, M. Richardson, C. Ripamonti, A.G. Robson, H. Rostron, I. Russell-Eggitt, P. Schlottmann, M. Tschernutter, and N. Wasseem.

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