Research ArticleRetinal Disease

A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration

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Science Translational Medicine  04 Apr 2018:
Vol. 10, Issue 435, eaao4097
DOI: 10.1126/scitranslmed.aao4097
  • Fig. 1 CPCB-RPE1 investigational implant.

    (A and B) Low-magnification (actual size 3.5 mm × 6.25 mm) (A) and high-magnification (B) color photographs of California Project to Cure Blindness–Retinal Pigment Epithelium 1 (CPCB-RPE1). Scale bar, 50 μm. (C) Schematic of the synthetic parylene substrate for human embryonic stem cell–derived RPE (hESC-RPE). The parylene membrane is 6 microns thick with submicrometer-thick circular regions and a smooth, nonporous anterior surface that promotes cell adherence and tightly spaced pattern of ultrathin circular regions that have molecular exclusion characteristics similar to Bruch’s membrane to facilitate nutrient and growth factor diffusion. Arrows show the bidirectional diffusion.

  • Fig. 2 Preoperative and postoperative color fundus photographs of the retina in two representative study subjects.

    (A and B) Preoperative fundus photographs of subject 204 (A) and subject 125 (B) showing large areas of RPE loss, consistent with geographic atrophy (GA). (C and D) Postoperative fundus photographs of subject 204 at 180 days (C) and subject 125 at 120 days (D). (E and F) Annotated version of (C) and (D) showing the location of GA (white dashed line) and CPCB-RPE1 (black dashed lines).

  • Fig. 3 Visual acuity assessment of subjects with CPCB-RPE1 implant.

    (A and B) Timeline of visual acuity data plotted as change in ETDRS letters from baseline for the study eye (A) and the nonstudy (fellow) eye (B). Each subject is plotted in a separate color, as defined in the key. The vertical, dashed gray line represents the day 120 time point, which is the latest time point available for the last subject enrolled. (C) Scatterplot of preoperative and postoperative visual acuity results for five subjects enrolled in the study at the last follow-up. The symbols that fall along the dashed diagonal line represent subjects with essentially no change in ETDRS letters. Symbols above the dashed line and below the dashed line represent subjects with visual improvement and worsening, respectively.

  • Fig. 4 Preoperative and postoperative fundus photographs and OCT images of CPCB-RPE1 in subject 128.

    (A) Preoperative color fundus photograph of GA. (B) High-magnification preoperative color fundus photograph of implanted region shows the absence of RPE. (C and D) High-magnification preoperative optical coherence tomography (OCT) image of implanted region shows the absence of RPE and ELM at GA border. (E and F) Preoperative infrared fundus images and two adjacent, corresponding OCT cross sections showing a region of GA without RPE or ELM within GA. The OCT cross sections correspond to the bold green arrow in the infrared image. Green lines indicate scans performed on this subject. The red bracketed lines denote an area of GA (without ELM at baseline) that is subsequently covered by the implant, as shown in the next several panels. (G) Postoperative color fundus photograph showing the subretinal location of CPCB-RPE1 implant relative to the area of GA. White dashed circle denotes GA. Black dashed line denotes CPCB-RPE1 implant. (H) High-magnification postoperative color fundus photograph of similar region as in (B) shows that the implant covers the area of GA. (I and J) High-magnification postoperative OCT image of implanted region shows ELM and RPE overlying the implant within the area of GA. (K and L) Postoperative infrared images and two corresponding OCT cross sections. Red bracketed lines indicate the same regions on infrared and OCT images, as identified by the coregistered and calibrated annotation tools available on the commercial OCT software. In these panels, hESC-RPE and ELM overlying the implant are continuous with, and essentially indistinguishable from, host RPE and ELM in terms of size, reflectivity, and subretinal location. An epiretinal membrane is also noted. The red brackets in (L) show a region that is within the area of GA [see red bracketed lines in (B) and (C)] and with reappearance of RPE and ELM overlying the implant. The OCT cross section corresponds to the bold green arrow in the infrared image. Red dots in (I) and (J) illustrate the location of the ELM. Two black dots in (A), (B), (E), (F), (G), (H), (K), and (L) identify the same vessel landmark for reference among panels.

  • Fig. 5 Preoperative and postoperative OCT images in subject 303.

    (A) Preoperative infrared fundus photograph. Red bracketed lines serve as anatomic landmarks that identify a focal region of GA that is separate from a much larger region of GA superior to it and is highlighted by a yellow circle. (B) Postoperative infrared fundus photograph at day 120 showing the implant location (green square) covering almost the entire region of GA including the focal region of GA within the yellow circle. (C and D) Low-magnification OCT cross sections through the bold green arrows shown in (A) and (B). Green lines indicate scans performed on this subject. The red brackets indicate the same region before implantation without ELM (C) and 120 days after implantation with ELM (D). This region was annotated using the OCT software tools that automatically coregister the OCT scan with the infrared fundus photograph above. (E and F) Higher magnification of OCT regions in dashed red boxes from (C) and (D). There is absence of the ELM (E) in the preoperative scan and reappearance of the ELM (F) in the postoperative scan in the same region. Blue arrows indicate the location of ELM band.

  • Fig. 6 Preoperative and postoperative fundus photographs and fixation testing in subject 303.

    (A and B) Preoperative color fundus photograph (A) and preoperative fixation testing (B). The red cross represents the location of fixation target. The fine blue dots visible in the magnification (top right) indicate the location of individual fixation attempts. (C) Preoperative distribution of fixation events within 2° and 4° circles. (D) Postoperative day 60 color fundus photograph demonstrating the location of CPCB-RPE1 (black dashed lines) in relation to GA (white dashed circle). (E and F) Postoperative day 60 fixation testing (E) and distribution of fixation events (F) located overlying the implant. (G) Postoperative day 120 color fundus photograph. (H and I) Postoperative day 120 fixation testing (H) and distribution of fixation events (I). Blue arrow indicates a vascular landmark that can be seen in all images for reference.

  • Fig. 7 Average preoperative and postoperative fixation data.

    Bar chart illustrating the average percentage of fixation events falling within a 2° and 4° retinal locus on fixation testing for preoperative and postoperative conditions. Error bars represent SEM. Fixation testing was performed in duplicate at each visit for each subject (n = 4 subjects). Statistical testing was performed using paired, Student’s t test. Note that subject 123 did not receive the implant, as described in the main text, but is included as part of intent-to-treat analysis.

  • Table 1 Baseline subject characteristics and postoperative testing results.

    Text in boldface indicates eyes implanted with CPCB-RPE1. L, left eye; R, right eye; F, female; M, male; ETDRS, Early Treatment of Diabetic Retinopathy Severity Score; LogMAR, logarithm of the minimum angle of resolution; Unstable, less than 75% of fixation events occurred within a 4° retinal locus; Stable, 75% or more of fixation events occurred within a 4° locus; ELM, external limiting membrane; ND, fixation testing was not carried out because the implant was not delivered in subject 123; +/−, the presence or absence of ELM band on OCT.

    ID-EyeAge, sexPreoperativePostoperative
    ETDRS
    (LogMar)
    ELMFixationDurationETDRS
    (LogMar)
    ELMFixation
    204L85, F21 (1.28)Unstable365 days23 (1.24)+Unstable
    204R50 (0.70)Unstable39 (0.92)Unstable
    123L85, M29 (1.12)Unstable365 days28 (1.14)ND
    123R24 (1.22)Unstable19 (1.32)ND
    125L84, F3 (1.64)Unstable270 days0 (3.00)+Stable
    125R67 (0.36)Stable69 (0.32)Stable
    303L84, M32 (1.06)Stable180 days28 (1.14)+Stable
    303R54 (0.62)Stable40 (0.90)Stable
    128L69, F7 (1.56)Unstable120 days24 (1.22)+Stable
    128R56 (0.58)Stable62 (0.46)Stable

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/10/435/eaao4097/DC2

    Fig. S1. Illustration of surgical insertion forceps used for the implant.

    Fig. S2. Preoperative and postoperative OCT images in subject 303.

    Fig. S3. Preoperative and postoperative fundus photographs and fixation testing in subject 128.

    Movie S1. Representative surgical video of CPCB-RPE1 implantation in subject 303.

    Appendix 1. Clinical study protocol.

  • Supplementary Material for:

    A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration

    Amir H. Kashani,* Jane S. Lebkowski, Firas M. Rahhal, Robert L. Avery, Hani Salehi-Had, Wei Dang, Chih-Min Lin, Debbie Mitra, Danhong Zhu, Biju B. Thomas, Sherry T. Hikita, Britney O. Pennington, Lincoln V. Johnson, Dennis O. Clegg, David R. Hinton, Mark S. Humayun*

    *Corresponding author. Email: humayun{at}usc.edu (M.S.H.); ahkashan{at}usc.edu (A.H.K.)

    Published 4 April 2018, Sci. Transl. Med. 10, eaao4097 (2018)
    DOI: 10.1126/scitranslmed.aao4097

    This PDF file includes:

    • Fig. S1. Illustration of surgical insertion forceps used for the implant.
    • Fig. S2. Preoperative and postoperative OCT images in subject 303.
    • Fig. S3. Preoperative and postoperative fundus photographs and fixation testing in subject 128.

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Movie S1 (.mp4 format). Representative surgical video of CPCB-RPE1 implantation in subject 303.
    • Appendix 1 (.pdf format). Clinical study protocol.

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