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Human Gene Therapy for RPE65 Isomerase Deficiency Activates the Retinoid Cycle of Vision but with Slow Rod Kinetics

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Human Gene Therapy for RPE65 Isomerase Deficiency Activates the Retinoid Cycle of Vision but with Slow Rod Kinetics Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics Artur V. Cideciyan*†, Tomas S. Aleman*, Sanford L. Boye‡, Sharon B. Schwartz*, Shalesh Kaushal‡, Alejandro J. Roman*, Ji-jing Pang‡, Alexander Sumaroka*, Elizabeth A. M. Windsor*, James M. Wilson§, Terence R. Flotte¶, Gerald A. Fishmanʈ, Elise Heon**, Edwin M. Stone††, Barry J. Byrne‡, Samuel G. Jacobson*, and William W. Hauswirth‡ *Scheie Eye Institute, Department of Ophthalmology and §Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104; ‡Department of Ophthalmology, University of Florida, Gainesville, FL 32610; ¶University of Massachusetts Medical School, Worcester, MA 01655; ʈDepartment of Ophthalmology and Visual Sciences, University of Illinois, Chicago, IL 60612; **Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada M5G 1X8; and ††Department of Ophthalmology, University of Iowa Carver College of Medicine, Iowa City, IA 52242 Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD, and approved August 6, 2008 (received for review July 21, 2008) The RPE65 gene encodes the isomerase of the retinoid cycle, the (trials NCT00481546, NCT00643747, NCT00516477, and enzymatic pathway that underlies mammalian vision. Mutations in NCT00422721, www.clinicaltrials.gov). Early reports from hu- RPE65 disrupt the retinoid cycle and cause a congenital human man retinal gene replacement trials suggest there are no short- blindness known as Leber congenital amaurosis (LCA). We used term safety concerns and that modest increases in visual function adeno-associated virus-2-based RPE65 gene replacement therapy to can be found in some of the subjects (15–17). treat three young adults with RPE65-LCA and measured their vision Key scientific questions were not answered in these recent human before and up to 90 days after the intervention. All three patients studies. It remains unclear whether rod or cone vision, or both, were showed a statistically significant increase in visual sensitivity at 30 restored. It is also unknown whether any vision improvement was days after treatment localized to retinal areas that had received the complete and fully explained by the level of potentially rescuable vector. There were no changes in the effect between 30 and 90 days. photoreceptors remaining in the treatment area. To determine if Both cone- and rod-photoreceptor-based vision could be demon- the genetically flawed retinoid cycle could be restored, we used strated in treated areas. For cones, there were increases of up to 1.7 AAV-based RPE65 gene replacement in three young adult subjects log units (i.e., 50 fold); and for rods, there were gains of up to 4.8 log with severe visual loss caused by recessive RPE65 mutations. Rod units (i.e., 63,000 fold). To assess what fraction of full vision potential and cone visual parameters were studied before and after inter- was restored by gene therapy, we related the degree of light sensi- vention. Rod photoreceptor-based vision was present in all patients tivity to the level of remaining photoreceptors within the treatment after treatment. Unexpectedly, rod kinetics of dark adaptation, a area. We found that the intervention could overcome nearly all of the surrogate for retinoid cycle activity (18), were remarkably slow. loss of light sensitivity resulting from the biochemical blockade. Increased cone photoreceptor-based vision was demonstrated in However, this reconstituted retinoid cycle was not completely nor- two of the patients. Comparison of photoreceptor nuclear layer mal. Resensitization kinetics of the newly treated rods were remark- structure and co-localized visual function indicated that the inter- ably slow and required8hormore for the attainment of full vention had ameliorated the severe retinoid cycle blockade com- sensitivity, compared with <1 h in normal eyes. Cone-sensitivity ponent of this complex disease and converted it to a simpler recovery time was rapid. These results demonstrate dramatic, albeit photoreceptor degeneration. imperfect, recovery of rod- and cone-photoreceptor-based vision after RPE65 gene therapy. Results Human Gene Therapy Surmounts Biochemical Blockade in RPE65-LCA. ͉ ͉ ͉ dark adaptation photoreceptor retinal degeneration retinoid cycle The retinoid cycle enzymatic pathway allows continuous vision by regeneration of 11-cis- from all-trans-retinal (Fig. 1 A and B). he enzymatic pathway in the human eye that regenerates AAV2-based RPE65 gene replacement was delivered by injection Tlight-altered vitamin A molecules is known as the retinoid (5.96 ϫ 1010 vg in 150 ␮l) between the RPE cell layer and the cycle of vision. Molecular defects in retinoid cycle genes can lead photoreceptor layer (Fig. 1C) into one eye (i.e., study eye) of three to inherited retinal diseases in man (1). The severity of visual RPE65-LCA subjects. Subjects’ ages were 24 years (patient 1), 23 disturbance in these diseases is thought to be related to how the mutation alters the biochemical activity and whether there is redundancy at the multiple biochemical steps of the cycle. A Author contributions: A.V.C., T.S.A., S.K., T.R.F., B.J.B., S.G.J., and W.W.H. designed re- severe form of incurable childhood blindness, Leber congenital search; A.V.C., T.S.A., S.L.B., S.B.S., S.K., A.J.R., J.-j.P., E.A.M.W., G.A.F., E.H., E.M.S., B.J.B., S.G.J., and W.W.H. performed research; A.V.C., S.L.B., J.M.W., S.G.J., and W.W.H. contrib- amaurosis (LCA), is caused by mutations in RPE65 (retinal uted new reagents/analytic tools; A.V.C., T.S.A., S.L.B., S.B.S., A.J.R., A.S., S.G.J., and W.W.H. pigment epithelium-specific protein, 65 kDa), the gene in the analyzed data; and A.V.C., S.G.J., and W.W.H. wrote the paper. retinal pigment epithelium (RPE) that encodes the isomerase. Conflict of interest statement: B.J.B., W.W.H., and the University of Florida have a financial This is the only known enzyme that catalyzes isomerization of interest in the use of AAV therapies and own equity in a company (AGTC Inc.) that might, all-trans-retinyl esters to 11-cis-vitamin A. In RPE65 deficiency, in the future, commercialize some aspects of this work. J.M.W. is an inventor on patents related to gene therapy that have been licensed to a number of biopharmaceutical photoreceptor cells do not regenerate their visual pigment and companies. University of Pennsylvania, University of Florida, and Cornell University hold a vision is not sustained. Retinal anatomy also degenerates, but patent on the described gene therapy technology (United States Patent 20070077228, not entirely (2, 3). ‘‘Method for Treating or Retarding the Development of Blindness’’). RPE65-deficient animals have been characterized, and proof- This article is a PNAS Direct Submission. of-principle studies using recombinant adeno-associated virus †To whom correspondence should be addressed. Email: [email protected]. (AAV) vector delivery of RPE65 to RPE cells have described This article contains supporting information online at www.pnas.org/cgi/content/full/ restoration of vision (2, 4–14). These studies provided the 0807027105/DCSupplemental. impetus for human safety studies of RPE65 gene replacement © 2008 by The National Academy of Sciences of the USA 15112–15117 ͉ PNAS ͉ September 30, 2008 ͉ vol. 105 ͉ no. 39 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0807027105 Downloaded by guest on September 29, 2021 Fig. 2. Biological activity resulting from localized gene therapy in three patients with inherited blindness. (A) Clinical kinetic visual field maps (repre- sented as left retina for clarity and comparability) in control (blue) and study Fig. 1. Schematic of the retina, retinoid cycle, and localized delivery of gene eyes at 1 month after treatment (red) are shown. Light sensitivity measures in therapy in three patients with inherited blindness. (A) Light enters the eye and study eyes along vertical (patients 1 and 2) and horizontal (patient 3) merid- is absorbed by visual pigments (rhodopsin) in photoreceptors of the retina ians at 1, 2, and 3 months after treatment compared with before treatment are (red), the complex brain-like neural layer. (B) The retinoid cycle and its also shown. The increased superior (patient 1), inferior (patient 2), and tem- isomerase, RPE65, converts all-trans-to11-cis-retinal to regenerate the visual poral (patient 3) retinal extent of vision boundary on visual field maps of study pigment. (C) Series of retinal cross-sections from patient 2 rendered in three eyes corresponds to the region of vector injection. These regions show in- dimensions and overlaid onto the ocular fundus view illustrate the superior creases in light sensitivity after treatment compared with before treatment. retinal site of subretinal vector injection. Fovea and optic nerve head locations (B) Retinal loci demonstrating significant change (stars) in light sensitivity at are shown. (D) Photoreceptor cell layer (i.e., ONL) thickness topography 1, 2, and 3 months after treatment compared with before treatment. All (pseudocolor scale) in a normal subject and pretreatment in study eyes of significant changes were increases in sensitivity (ranging from 1 to 3 log units) patients 1, 2, and 3 (P1, P2, and P3). Site of injection (syringe tip) and the and correspond to regions of study eyes that received gene therapy; control estimate of the bleb formed by the injection (dashed circle) are shown. Data eyes of the three patients did not show significant changes. Test-retest vari- in C and D are shown in equivalent left retina representation for clarity. ability estimated from five additional patients with RPE65-LCA along the vertical meridian was smaller than the magnitude of sensitivity changes observed in study eyes.
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