Human cone photoreceptor transplantation stimulates remodeling and restores function in AIPL1 model of end-stage Leber congenital amaurosis

Christopher A. Procyk; Anna Melati; Joana Ribeiro; Jingshu Liu; Matthew J. Branch; Jamie D. Delicata; Menahil Tariq; Aikaterini A. Kalarygrou; Jessica Kapadia; Majid Moshtagh Khorsani; Emma L. West; Alexander J. Smith; Anai Gonzalez-Cordero; Robin R. Ali; Rachael A. Pearson

doi:10.1016/j.stemcr.2025.102470

Human cone photoreceptor transplantation stimulates remodeling and restores function in AIPL1 model of end-stage Leber congenital amaurosis

Christopher A. Procyk, Anna Melati, Joana Ribeiro, Jingshu Liu, Matthew J. Branch, Jamie D. Delicata, Menahil Tariq, Aikaterini A. Kalarygrou, Jessica Kapadia, Majid Moshtagh Khorsani, Emma L. West, Alexander J. Smith, Anai Gonzalez-Cordero, Robin R. Ali, Rachael A. Pearson^*

^*Corresponding author for this work

Gene Therapy and Regenerative Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Photoreceptor degeneration is a leading cause of untreatable sight loss. Previously, we showed that human pluripotent stem cell-derived cone photoreceptors (hCones) can rescue retinal function in the Rd1 mouse model of rod-cone dystrophy. However, retinal degenerations display markedly different severities and concomitant remodeling of the remaining retina; for photoreceptor replacement therapy to be broadly effective, it must work for a variety of disease phenotypes. Here, we sought to rescue the Aipl1^−/− model of Leber congenital amaurosis, a particularly fast, severe condition. After transplantation of hCones, host cone bipolar cells underwent extensive remodeling and formed nascent synaptic-like connections. Electrophysiological recordings showed robust rescue of light-evoked activity across visually relevant photopic intensities, and treated mice exhibited visually evoked optokinetic head-tracking behavior. Thus, human cone photoreceptor replacement therapy is feasible even in very severe cases of retinal dystrophy, offering promise as a disease-agnostic therapy in Leber congenital amaurosis (LCA) and in other advanced retinal degenerations.

Original language	English
Article number	102470
Journal	Stem cell reports
Volume	20
Issue number	4
Early online date	8 Apr 2025
DOIs	https://doi.org/10.1016/j.stemcr.2025.102470
Publication status	E-pub ahead of print - 8 Apr 2025

Keywords

blindness
degeneration
function
macular
organoid
photoreceptor
rescue
synapse
therapy
transplant

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10.1016/j.stemcr.2025.102470

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Procyk, C. A., Melati, A., Ribeiro, J., Liu, J., Branch, M. J., Delicata, J. D., Tariq, M., Kalarygrou, A. A., Kapadia, J., Khorsani, M. M., West, E. L., Smith, A. J., Gonzalez-Cordero, A., Ali, R. R., & Pearson, R. A. (2025). Human cone photoreceptor transplantation stimulates remodeling and restores function in AIPL1 model of end-stage Leber congenital amaurosis. Stem cell reports, 20(4), Article 102470. Advance online publication. https://doi.org/10.1016/j.stemcr.2025.102470

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title = "Human cone photoreceptor transplantation stimulates remodeling and restores function in AIPL1 model of end-stage Leber congenital amaurosis",

abstract = "Photoreceptor degeneration is a leading cause of untreatable sight loss. Previously, we showed that human pluripotent stem cell-derived cone photoreceptors (hCones) can rescue retinal function in the Rd1 mouse model of rod-cone dystrophy. However, retinal degenerations display markedly different severities and concomitant remodeling of the remaining retina; for photoreceptor replacement therapy to be broadly effective, it must work for a variety of disease phenotypes. Here, we sought to rescue the Aipl1−/− model of Leber congenital amaurosis, a particularly fast, severe condition. After transplantation of hCones, host cone bipolar cells underwent extensive remodeling and formed nascent synaptic-like connections. Electrophysiological recordings showed robust rescue of light-evoked activity across visually relevant photopic intensities, and treated mice exhibited visually evoked optokinetic head-tracking behavior. Thus, human cone photoreceptor replacement therapy is feasible even in very severe cases of retinal dystrophy, offering promise as a disease-agnostic therapy in Leber congenital amaurosis (LCA) and in other advanced retinal degenerations.",

keywords = "blindness, degeneration, function, macular, organoid, photoreceptor, rescue, synapse, therapy, transplant",

author = "Procyk, {Christopher A.} and Anna Melati and Joana Ribeiro and Jingshu Liu and Branch, {Matthew J.} and Delicata, {Jamie D.} and Menahil Tariq and Kalarygrou, {Aikaterini A.} and Jessica Kapadia and Khorsani, {Majid Moshtagh} and West, {Emma L.} and Smith, {Alexander J.} and Anai Gonzalez-Cordero and Ali, {Robin R.} and Pearson, {Rachael A.}",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = apr,

day = "8",

doi = "10.1016/j.stemcr.2025.102470",

language = "English",

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Procyk, CA, Melati, A, Ribeiro, J, Liu, J, Branch, MJ, Delicata, JD, Tariq, M, Kalarygrou, AA, Kapadia, J, Khorsani, MM, West, EL, Smith, AJ, Gonzalez-Cordero, A, Ali, RR & Pearson, RA 2025, 'Human cone photoreceptor transplantation stimulates remodeling and restores function in AIPL1 model of end-stage Leber congenital amaurosis', Stem cell reports, vol. 20, no. 4, 102470. https://doi.org/10.1016/j.stemcr.2025.102470

TY - JOUR

T1 - Human cone photoreceptor transplantation stimulates remodeling and restores function in AIPL1 model of end-stage Leber congenital amaurosis

AU - Procyk, Christopher A.

AU - Melati, Anna

AU - Ribeiro, Joana

AU - Liu, Jingshu

AU - Branch, Matthew J.

AU - Delicata, Jamie D.

AU - Tariq, Menahil

AU - Kalarygrou, Aikaterini A.

AU - Kapadia, Jessica

AU - Khorsani, Majid Moshtagh

AU - West, Emma L.

AU - Smith, Alexander J.

AU - Gonzalez-Cordero, Anai

AU - Ali, Robin R.

AU - Pearson, Rachael A.

PY - 2025/4/8

Y1 - 2025/4/8

N2 - Photoreceptor degeneration is a leading cause of untreatable sight loss. Previously, we showed that human pluripotent stem cell-derived cone photoreceptors (hCones) can rescue retinal function in the Rd1 mouse model of rod-cone dystrophy. However, retinal degenerations display markedly different severities and concomitant remodeling of the remaining retina; for photoreceptor replacement therapy to be broadly effective, it must work for a variety of disease phenotypes. Here, we sought to rescue the Aipl1−/− model of Leber congenital amaurosis, a particularly fast, severe condition. After transplantation of hCones, host cone bipolar cells underwent extensive remodeling and formed nascent synaptic-like connections. Electrophysiological recordings showed robust rescue of light-evoked activity across visually relevant photopic intensities, and treated mice exhibited visually evoked optokinetic head-tracking behavior. Thus, human cone photoreceptor replacement therapy is feasible even in very severe cases of retinal dystrophy, offering promise as a disease-agnostic therapy in Leber congenital amaurosis (LCA) and in other advanced retinal degenerations.

AB - Photoreceptor degeneration is a leading cause of untreatable sight loss. Previously, we showed that human pluripotent stem cell-derived cone photoreceptors (hCones) can rescue retinal function in the Rd1 mouse model of rod-cone dystrophy. However, retinal degenerations display markedly different severities and concomitant remodeling of the remaining retina; for photoreceptor replacement therapy to be broadly effective, it must work for a variety of disease phenotypes. Here, we sought to rescue the Aipl1−/− model of Leber congenital amaurosis, a particularly fast, severe condition. After transplantation of hCones, host cone bipolar cells underwent extensive remodeling and formed nascent synaptic-like connections. Electrophysiological recordings showed robust rescue of light-evoked activity across visually relevant photopic intensities, and treated mice exhibited visually evoked optokinetic head-tracking behavior. Thus, human cone photoreceptor replacement therapy is feasible even in very severe cases of retinal dystrophy, offering promise as a disease-agnostic therapy in Leber congenital amaurosis (LCA) and in other advanced retinal degenerations.

KW - blindness

KW - degeneration

KW - function

KW - macular

KW - organoid

KW - photoreceptor

KW - rescue

KW - synapse

KW - therapy

KW - transplant

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DO - 10.1016/j.stemcr.2025.102470

M3 - Article

C2 - 40154478

AN - SCOPUS:105001343309

SN - 2213-6711

VL - 20

JO - Stem cell reports

JF - Stem cell reports

IS - 4

M1 - 102470

ER -

Human cone photoreceptor transplantation stimulates remodeling and restores function in AIPL1 model of end-stage Leber congenital amaurosis

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