vision 1 year after gene therapy for leber's congenital amaurosis

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n engl j med 361;7 nejm.org august 13, 2009 725

ease. The most likely assumption seems to be that the patient died from a cocaine-induced arrhyth-mia. My question is whether the discussants agree, and whether the patient’s schistosomiasis could have potentiated this fatal arrhythmia.David L. Keller, M.D.Providence Healthcare West Torrance, CA

To the Editor: The discussion of donor assess-ment by Kotton et al. suggests that exclusion cri-teria from the Centers for Disease Control and Prevention (CDC) (Table 3 of the article) are used to reduce the likelihood of transmission of the human immunodeficiency virus (HIV). In fact, the CDC’s criteria do not have an exclusionary func-tion but define a group of donors considered to have a high risk for transmission of HIV. The policy of the United Network for Organ Sharing does stipulate that transplantation centers must disclose this organ-specific information to po-tential recipients at the time the organ is offered, presumably during a discussion of informed con-sent.1 The CDC’s criteria were devised in 19942 in an effort to exclude donors with an unacceptably high risk of transmitting HIV. Fifteen years later, rising waiting-list mortality, improved prospec-tive detection of infectious agents with nucleic acid testing, growing uncertainty regarding the effectiveness of the criteria, and the problem of promoting social bias against homosexual men have cast doubt on the importance of the criteria.3

Daniel S. Kamin, M.D. Sandra Burchett, M.D. Heung Bae Kim, M.D.Children’s Hospital Boston Boston, MA [email protected]

Acquired immune deficiency syndrome (AIDS), human pitu-1. itary derived growth hormone (HPDGH), and reporting of poten-tial recipient diseases or medical conditions, including malig-

nancies, of donor origin. Richmond, VA: United Network for Organ Sharing, 2009. (Accessed July 23, 2009, at http://unos.org/PoliciesandBylaws2/policies/pdfs/policy_16.pdf.)

Guidelines for preventing transmission of human immuno-2. deficiency virus through transplantation of human tissue and organs. MMWR Recomm Rep 1994;43(RR-8):1-17.

Halpern SD, Shaked A, Hasz RD, Caplan AL. Informing can-3. didates for solid-organ transplantation about donor risk factors. N Engl J Med 2008;358:2832-7.

The Discussants Reply: Kamin et al. are correct that the CDC criteria have been used to define donors at higher risk for transmission of HIV. The criteria are generally considered to be out-dated and less useful now than at the time they were developed, as the authors suggest.

Revision of these guidelines has been a work in progress for some time. Further guidance in this realm would help the clinicians involved with transplantation maximize the numbers of or-gans transplanted and minimize both the num-ber of transplant-related infections and the mor-tality among patients on the transplantation waiting list.

Hauptman and Keller express concern about the use of this donor’s heart. The cause of his ventricular fibrillation was presumed to be a co-caine overdose. Without further medical history, the surgeons involved in the case did not believe that placement of an implantable cardioverter–defibrillator for the recipient was indicated. Po-tentiation of this fatal arrhythmia by the donor’s schistosomiasis also seems extremely unlikely. Given his epidemiologic history, myocarditis due to Trypanosoma cruzi could have been a risk factor for this arrhythmia, although his serologic screen-ing for this disease was negative.Camille N. Kotton, M.D. Nahel Elias, M.D. Francis L. Delmonico, M.D.

Massachusetts General Hospital Boston, MA

Vision 1 Year after Gene Therapy for Leber’s Congenital Amaurosis

To the Editor: Leber’s congenital amaurosis, a common cause of blindness in infants and chil-dren,1 recently became the first human genetic retinal disease to show improved vision in re-sponse to treatment. Patients with mutations in

the gene encoding retinal pigment epithelium–specific 65-kD protein (RPE65) had gains in vision within weeks after subretinal injection of a vec-tor containing the gene in one eye.2-5 At 1-year follow-up after gene therapy, the three young

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adult patients in our trial4,5 remained without serious adverse events.

A noteworthy observation in one patient at 1 year after treatment prompted further studies. For the first time in her life, the patient reported that she could read the illuminated numerical clock display on the dashboard of the family vehicle while she was sitting in the front seat. The numerals subtended a visual angle equivalent to a visual acuity of 20/200, which is not differ-ent from her formally measured visual acuities at baseline or at 1 year after treatment. The sim-

plest explanation of this development would be increased visual sensitivity either at the fovea or in the treated region of the superotemporal retina. However, visual sensitivity (measured by means of microperimetry) was unchanged at this visit as compared with earlier post-treatment visits (Fig. 1A).

We sought to determine the basis of this devel-opment by quantifying fixation of the patient’s gaze to dim targets over a range of luminances straddling her perception. At baseline, the patient had foveal fixation in both eyes over a range of

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Figure 1. Slow Emergence of a Pseudo-Fovea within the Treated Retinal Region and Perception of Previously Unseen Stimuli.

Panel A shows the eye (upper image) and the patient’s retina (lower image). Overlaid contours of constant sensitivity (measured by means of microperimetry) show no change in visual sensitivity between 1 and 12 months after treat-ment. F denotes the fovea, and ST the superotemporal retina that received treatment. The circular pattern is a stan-dard grid centered on the fovea. Retinal distance calibration corresponding to 5 degrees of visual angle is shown. Panel B shows fixation clouds (scatter plots) in the study eye of the patient at baseline and the statistics of fixation dwell time (bar graphs) along the diagonal meridian as a function of the target luminance. All three luminances were perceived by the patient at all visits. At the 2.7- and 2.4-log10 luminances, fixation was within 3 degrees of the fovea more than 99% of the time at all visits except at the 12-month visit for 2.4-log10 luminance, when 68% of fixa-tion time dwelled in an ST retinal region 4 to 9 degrees from the fovea. At 2.1-log10 luminance, fixations showed in-creasingly greater excursions into the ST retina between 2 and 9 months after treatment. At 12 months, 89% of fixa-tion time dwelled in the ST region 4 to 9 degrees from the fovea. Thin vertical lines represent the foveal location. Red bars indicate significant (>3 degrees) excursions from the fovea. Panel C shows that a dimmer target (1.8 log10) was not perceived by the patient’s study eye during baseline though 9 months after treatment. At 12 months, this stimulus was perceived for the first time with a coincident shift of fixation into the ST retinal region.



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n engl j med 361;7 nejm.org august 13, 2009 727

target luminances from 2.1 to 2.7 log10 units higher than the normal foveal perceptual thresh-old (Fig. 1B), and the results were like those of other patients with Leber’s congenital amaurosis caused by RPE65 mutations and similar visual-acuity levels.5

Fixation dwell time, quantified along the di-agonal meridian with a range of target lumi-nances perceived by the patient, suggested a slow emergence of visual gain over many months caus-ing progressively greater fixational use of the treated superotemporal retina (Fig. 1B). This gain was particularly evident at lower luminances. By 12 months after treatment, the patient reported per-ception of the lowest luminance target (1.8 log10) for the first time. This target was not seen dur-ing any previous visit. New perception was ac-companied by a distinct shift in fixation into the treated superotemporal retina (Fig. 1C, and video in the Supplementary Appendix, available with the full text of this letter at NEJM.org). Cone sensi-tivities in the control and study eyes of the pa-tient were rendered as three-dimensional images on the view of the ocular fundus with a super-imposed circular grid (Fig. 1 in the Supplemen-tary Appendix). Foveal sensitivities in the two eyes were similar, but the superotemporal region of the treated eye, the “pseudo-fovea,” was remark-ably different from the cone blindness in the comparable region of the control eye.

The change in fixation by the patient was driven by the treatment-created extrafoveal cone vision with better sensitivity and greater expanse than the untreated foveal region (Fig. 1 in the Supplementary Appendix).4,5 The unexpected late emergence of visual gain in the patient to spa-tially coded and sustained stimuli and a coinci-dent change in preference for fixation from the fovea to the treated retinal region suggest a slow development of a pseudo-fovea and an underly-ing experience-dependent plasticity of the adult visual system. These results raise the possibility that this gene-based therapy may further improve visual function in an unexpected and useful way in previously untreatable congenital blindness.Artur V. Cideciyan, Ph.D.

University of Pennsylvania Philadelphia, PA [email protected]

William W. Hauswirth, Ph.D.

University of Florida Gainesville, FL

Tomas S. Aleman, M.D.University of Pennsylvania Philadelphia, PA

Shalesh Kaushal, M.D., Ph.D.University of Florida Gainesville, FL

Sharon B. Schwartz, M.S., C.G.C.University of Pennsylvania Philadelphia, PA

Sanford L. Boye, M.Sc.University of Florida Gainesville, FL

Elizabeth A.M. Windsor, B.Sc.University of Pennsylvania Philadelphia, PA

Thomas J. Conlon, Ph.D.University of Florida Gainesville, FL

Alexander Sumaroka, Ph.D. Alejandro J. Roman, M.Sc.University of Pennsylvania Philadelphia, PA

Barry J. Byrne, M.D., Ph.D.University of Florida Gainesville, FL

Samuel G. Jacobson, M.D., Ph.D.University of Pennsylvania Philadelphia, PA

Supported by a grant from the National Eye Institute of the National Institutes of Health, Department of Health and Human Services (U10 EY017280).

Drs. Byrne and Hauswirth report having a financial interest in the use of adeno-associated virus (AAV) therapies and owning equity in Applied Genetics Technologies, a company that might, in the future, commercialize some aspects of this work; Dr. Kaushal, serving as a principal investigator of a clinical trial of AAV-RPE65 to treat Leber’s congenital amaurosis sponsored by Applied Genetics Technologies; and Drs. Hauswirth and Jacob-son, being coinventors on a patent (20070077228) held by the University of Pennsylvania, the University of Florida, and Cornell University on “a method for treating or retarding the develop-ment of blindness” (Dr. Jacobson has waived all claims to any financial benefit as a coinventor on the patent). No other poten-tial conflict of interest relevant to this letter was reported.

den Hollander AI, Roepman R, Koenekoop RK, Cremers FP. 1. Leber congenital amaurosis: genes, proteins and disease mecha-nisms. Prog Retin Eye Res 2008;27:391-419.

Bainbridge JWB, Smith AJ, Barker SS, et al. Effect of gene 2. therapy on visual function in Leber’s congenital amaurosis. N Engl J Med 2008;358:2231-9.

Maguire AM, Simonelli F, Pierce EA, et al. Safety and effi-3. cacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 2008;358:2240-8.

Hauswirth WW, Aleman TS, Kaushal S, et al. Treatment of 4. Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther 2008;19:979-90.

Cideciyan AV, Aleman TS, Boye SL, et al. Human gene thera-5. py for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci U S A 2008; 105:15112-7.



vision 1 year after gene therapy for leber's congenital amaurosis

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