Survival of an HLA-mismatched, bioengineered RPE implant in dry age-related macular degeneration

Amir H Kashani; Jane S Lebkowski; David R Hinton; Danhong Zhu; Mohamed A Faynus; Sanford Chen; Firas M Rahhal; Robert L Avery; Hani Salehi-Had; Clement Chan; Neal Palejwala; April Ingram; Wei Dang; Chih-Min Lin; Debbie Mitra; Juan Carlos Martinez-Camarillo; Jeff Bailey; Cassidy Arnold; Britney O Pennington; Narsing Rao; Lincoln V Johnson; Dennis O Clegg; Mark S Humayun

doi:10.1016/j.stemcr.2022.01.001

Survival of an HLA-mismatched, bioengineered RPE implant in dry age-related macular degeneration

Stem Cell Reports. 2022 Mar 8;17(3):448-458. doi: 10.1016/j.stemcr.2022.01.001. Epub 2022 Feb 3.

Authors

Amir H Kashani¹, Jane S Lebkowski², David R Hinton³, Danhong Zhu⁴, Mohamed A Faynus⁵, Sanford Chen⁶, Firas M Rahhal⁷, Robert L Avery⁸, Hani Salehi-Had⁹, Clement Chan¹⁰, Neal Palejwala¹¹, April Ingram², Wei Dang¹², Chih-Min Lin¹², Debbie Mitra¹³, Juan Carlos Martinez-Camarillo¹, Jeff Bailey⁵, Cassidy Arnold⁵, Britney O Pennington⁵, Narsing Rao¹³, Lincoln V Johnson², Dennis O Clegg¹⁴, Mark S Humayun¹⁵

Affiliations

¹ Wilmer Eye Institute, Johns Hopkins University, 600 N. Wolfe Street, Baltimore, MD 21087 USA.
² Regenerative Patch Technologies, 150 Gabarda Way, Portola Valley, CA 94028, USA.
³ Department of Pathology, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, 7503, Los Angeles, CA 90033, USA; USC Roski Eye Institute, USC Ginsburg Institute for Biomedical Therapeutics and Department of Ophthalmology, Keck School of Medicine, University of Southern California, 1450 San Pablo, Los Angeles, CA 90033, USA.
⁴ Department of Pathology, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, 7503, Los Angeles, CA 90033, USA.
⁵ Regenerative Patch Technologies, 150 Gabarda Way, Portola Valley, CA 94028, USA; Center for Stem Cell Biology and Engineering, Neuroscience Research Institute, Mail Code 5060, University of California, Santa Barbara, CA 93016, USA.
⁶ Orange County Retina Medical Group, 1200 N. Tustin Avenue, Suite 140, Santa Ana, CA 92705, USA.
⁷ Retina-Vitreous Associates Medical Group, 9001 Wilshire Boulevard, Suite 301, Beverly Hills, CA 90211, USA.
⁸ California Retina Consultants, 525 E. Micheltorena Street, Santa Barbara, CA 93103, USA.
⁹ Retina Associates of Southern California, 7777 Edinger Avenue, Suite 234, Huntington Beach, CA 92647, USA.
¹⁰ Southern California Desert Retina Consultants, University Park, 36-949 Cook Street, Suite 101, Palm Desert, CA 92211, USA.
¹¹ Retinal Consultants of Arizona, 15401 North 29th Avenue, Phoenix, AZ 85053, USA.
¹² Center for Biomedicine and Genetics, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
¹³ USC Roski Eye Institute, USC Ginsburg Institute for Biomedical Therapeutics and Department of Ophthalmology, Keck School of Medicine, University of Southern California, 1450 San Pablo, Los Angeles, CA 90033, USA.
¹⁴ Center for Stem Cell Biology and Engineering, Neuroscience Research Institute, Mail Code 5060, University of California, Santa Barbara, CA 93016, USA.
¹⁵ USC Roski Eye Institute, USC Ginsburg Institute for Biomedical Therapeutics and Department of Ophthalmology, Keck School of Medicine, University of Southern California, 1450 San Pablo, Los Angeles, CA 90033, USA; Department of Biomedical Engineering, Denney Research Center (DRB) 140, University of Southern California, 1042 Downey Way, Los Angeles, CA 90089, USA. Electronic address: humayun@usc.edu.

Abstract

Cell-based therapies face challenges, including poor cell survival, immune rejection, and integration into pathologic tissue. We conducted an open-label phase 1/2a clinical trial to assess the safety and preliminary efficacy of a subretinal implant consisting of a polarized monolayer of allogeneic human embryonic stem cell-derived retinal pigmented epithelium (RPE) cells in subjects with geographic atrophy (GA) secondary to dry age-related macular degeneration. Postmortem histology from one subject with very advanced disease shows the presence of donor RPE cells 2 years after implantation by immunoreactivity for RPE65 and donor-specific human leukocyte antigen (HLA) class I molecules. Markers of RPE cell polarity and phagocytosis suggest donor RPE function. Further histologic examination demonstrated CD34⁺ structures beneath the implant and CD4⁺, CD68⁺, and FoxP3⁺ cells in the tissue. Despite significant donor-host HLA mismatch, no clinical signs of retinitis, vitreitis, vasculitis, choroiditis, or serologic immune response were detected in the deceased subject or any other subject in the study. Subretinally implanted, HLA-mismatched donor RPE cells survive, express functional markers, and do not elicit clinically detectable intraocular inflammation or serologic immune responses even without long-term immunosuppression.

Keywords: allogeneic; clinical trial; geographic atrophy; histology; implant; macular degeneration; parylene; polarized; retinal pigmented epithelium; stem cells.

Publication types

Clinical Trial, Phase I
Clinical Trial, Phase II
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Geographic Atrophy* / therapy
Human Embryonic Stem Cells / pathology
Humans
Macular Degeneration* / pathology
Macular Degeneration* / therapy
Prostheses and Implants* / adverse effects
Retinal Pigment Epithelium / pathology