Systemic immunosuppression promotes survival and integration of subretinally implanted human ESC-derived photoreceptor precursors in dogs

Ana Ripolles-Garcia; Natalia Dolgova; M Joseph Phillips; Svetlana Savina; Allison L Ludwig; Sara A Stuedemann; Uchenna Nlebedum; John H Wolfe; Oliver A Garden; Arvydas Maminishkis; Juan Amaral; Kapil Bharti; David M Gamm; Gustavo D Aguirre; William A Beltran

doi:10.1016/j.stemcr.2022.06.009

Systemic immunosuppression promotes survival and integration of subretinally implanted human ESC-derived photoreceptor precursors in dogs

Stem Cell Reports. 2022 Aug 9;17(8):1824-1841. doi: 10.1016/j.stemcr.2022.06.009. Epub 2022 Jul 28.

Authors

Affiliations

¹ Division of Experimental Retinal Therapies, Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
² Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA.
³ Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁴ Walter Flato Goodman Center for Comparative Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁵ Section on Epithelial and Retinal Physiology and Disease, National Eye Institute, NIH, Bethesda, MD 20892, USA.
⁶ Office of Scientific Director, National Eye Institute, NIH, Bethesda, MD 20892, USA.
⁷ Unit on Ocular and Stem Cell Translational Research, National Eye Institute, NIH, Bethesda, MD 20892, USA.
⁸ Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁹ Division of Experimental Retinal Therapies, Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: wbeltran@vet.upenn.edu.

Abstract

Regenerative therapies aimed at replacing photoreceptors are a promising approach for the treatment of otherwise incurable causes of blindness. However, such therapies still face significant hurdles, including the need to improve subretinal delivery and long-term survival rate of transplanted cells, and promote sufficient integration into the host retina. Here, we successfully delivered in vitro-derived human photoreceptor precursor cells (PRPCs; also known as immature photoreceptors) to the subretinal space of seven normal and three rcd1/PDE6B mutant dogs with advanced inherited retinal degeneration. Notably, while these xenografts were rejected in dogs that were not immunosuppressed, transplants in most dogs receiving systemic immunosuppression survived up to 3-5 months postinjection. Moreover, differentiation of donor PRPCs into photoreceptors with synaptic pedicle-like structures that established contact with second-order neurons was enhanced in rcd1/PDE6B mutant dogs. Together, our findings set the stage for evaluating functional vision restoration following photoreceptor replacement in canine models of inherited retinal degeneration.

Keywords: canine models; fluorescence live imaging; hESC-PRPCs; immunosuppression; photoreceptor precursor; retinal degeneration; retinal organoid.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Dogs
Humans
Immunosuppression Therapy
Photoreceptor Cells / transplantation
Photoreceptor Cells, Vertebrate
Retina
Retinal Degeneration* / therapy

Abstract

Publication types

MeSH terms

Grants and funding