Testing Mitochondrial-Targeted Drugs in iPSC-RPE from Patients with Age-Related Macular Degeneration

Mara C. Ebeling; Zhaohui Geng; Madilyn R. Stahl; Rebecca J. Kapphahn; Heidi Roehrich; Sandra R. Montezuma; Deborah A. Ferrington; James R. Dutton

doi:10.3390/ph15010062

Testing Mitochondrial-Targeted Drugs in iPSC-RPE from Patients with Age-Related Macular Degeneration

Mara C. Ebeling, Zhaohui Geng, Madilyn R. Stahl, Rebecca J. Kapphahn, Heidi Roehrich, Sandra R. Montezuma, Deborah A. Ferrington, James R. Dutton

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

13 Scopus citations

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. No universally effective treatments exist for atrophic or “dry” AMD, which results from loss of the retinal pigment epithelium (RPE) and photoreceptors and accounts for ≈80% of all AMD patients. Prior studies provide evidence for the involvement of mitochondrial dysfunction in AMD pathology. This study used induced pluripotent stem cell (iPSC) RPE derived from five AMD patients to test the efficacy of three drugs (AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide), Metformin, trehalose) that target key processes in maintaining optimal mitochondrial function. The patient iPSC-RPE lines were used in a proof-of-concept drug screen, utilizing an analysis of RPE mitochondrial function following acute and extended drug exposure. Results show considerable variability in drug response across patient cell lines, supporting the need for a personalized medicine approach for treating AMD. Furthermore, our results demonstrate the feasibility of using iPSC-RPE from AMD patients to develop a personalized drug treatment regime and provide a roadmap for the future clinical management of AMD.

Original language	English (US)
Article number	62
Journal	Pharmaceuticals
Volume	15
Issue number	1
DOIs	https://doi.org/10.3390/ph15010062
State	Published - Jan 2022

Bibliographical note

Funding Information:
Funding: This research was funded by the National Institutes of Health/National Eye Institute (grant number R01EY028554 to D.A.F. and J.R.D., P30EY11374 to H.R.), Regenerative Medicine Minnesota (grant number 091718 TR009), an anonymous benefactor for Age-related Macular Degeneration Research, the Lindsay Family Foundation, and the Elaine and Robert Larson Endowed Research Chair (D.A.F.).

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Age-related macular degeneration
Human-induced pluripotent stem cells
Personalized drug testing
Retinal pigment epithelium

PubMed: MeSH publication types

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Testing Mitochondrial-Targeted Drugs in iPSC-RPE from Patients with Age-Related Macular Degeneration",

abstract = "Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. No universally effective treatments exist for atrophic or “dry” AMD, which results from loss of the retinal pigment epithelium (RPE) and photoreceptors and accounts for ≈80% of all AMD patients. Prior studies provide evidence for the involvement of mitochondrial dysfunction in AMD pathology. This study used induced pluripotent stem cell (iPSC) RPE derived from five AMD patients to test the efficacy of three drugs (AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide), Metformin, trehalose) that target key processes in maintaining optimal mitochondrial function. The patient iPSC-RPE lines were used in a proof-of-concept drug screen, utilizing an analysis of RPE mitochondrial function following acute and extended drug exposure. Results show considerable variability in drug response across patient cell lines, supporting the need for a personalized medicine approach for treating AMD. Furthermore, our results demonstrate the feasibility of using iPSC-RPE from AMD patients to develop a personalized drug treatment regime and provide a roadmap for the future clinical management of AMD.",

keywords = "Age-related macular degeneration, Human-induced pluripotent stem cells, Personalized drug testing, Retinal pigment epithelium",

author = "Ebeling, {Mara C.} and Zhaohui Geng and Stahl, {Madilyn R.} and Kapphahn, {Rebecca J.} and Heidi Roehrich and Montezuma, {Sandra R.} and Ferrington, {Deborah A.} and Dutton, {James R.}",

note = "Funding Information: Funding: This research was funded by the National Institutes of Health/National Eye Institute (grant number R01EY028554 to D.A.F. and J.R.D., P30EY11374 to H.R.), Regenerative Medicine Minnesota (grant number 091718 TR009), an anonymous benefactor for Age-related Macular Degeneration Research, the Lindsay Family Foundation, and the Elaine and Robert Larson Endowed Research Chair (D.A.F.). Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

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AU - Ebeling, Mara C.

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AU - Kapphahn, Rebecca J.

AU - Roehrich, Heidi

AU - Montezuma, Sandra R.

AU - Ferrington, Deborah A.

AU - Dutton, James R.

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PY - 2022/1

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N2 - Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. No universally effective treatments exist for atrophic or “dry” AMD, which results from loss of the retinal pigment epithelium (RPE) and photoreceptors and accounts for ≈80% of all AMD patients. Prior studies provide evidence for the involvement of mitochondrial dysfunction in AMD pathology. This study used induced pluripotent stem cell (iPSC) RPE derived from five AMD patients to test the efficacy of three drugs (AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide), Metformin, trehalose) that target key processes in maintaining optimal mitochondrial function. The patient iPSC-RPE lines were used in a proof-of-concept drug screen, utilizing an analysis of RPE mitochondrial function following acute and extended drug exposure. Results show considerable variability in drug response across patient cell lines, supporting the need for a personalized medicine approach for treating AMD. Furthermore, our results demonstrate the feasibility of using iPSC-RPE from AMD patients to develop a personalized drug treatment regime and provide a roadmap for the future clinical management of AMD.

AB - Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. No universally effective treatments exist for atrophic or “dry” AMD, which results from loss of the retinal pigment epithelium (RPE) and photoreceptors and accounts for ≈80% of all AMD patients. Prior studies provide evidence for the involvement of mitochondrial dysfunction in AMD pathology. This study used induced pluripotent stem cell (iPSC) RPE derived from five AMD patients to test the efficacy of three drugs (AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide), Metformin, trehalose) that target key processes in maintaining optimal mitochondrial function. The patient iPSC-RPE lines were used in a proof-of-concept drug screen, utilizing an analysis of RPE mitochondrial function following acute and extended drug exposure. Results show considerable variability in drug response across patient cell lines, supporting the need for a personalized medicine approach for treating AMD. Furthermore, our results demonstrate the feasibility of using iPSC-RPE from AMD patients to develop a personalized drug treatment regime and provide a roadmap for the future clinical management of AMD.

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KW - Human-induced pluripotent stem cells

KW - Personalized drug testing

KW - Retinal pigment epithelium

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Testing Mitochondrial-Targeted Drugs in iPSC-RPE from Patients with Age-Related Macular Degeneration

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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