Restoring AIBP expression in the retina provides neuroprotection in glaucoma

Won-Kyu Ju¹, Keun-Young Kim², Tonking Bastola³, Ziyao Shen³, Seunghwan Choi³, Guy A Perkins², Sinwoo Hwang³, Jungsu Kim⁴, Jin-Woo Kwon⁵, Muna Poudel³, Sébastien Phan², Fan Xia⁶, Shuizhen Shi⁶, Hyunkyung Cho⁷, Hua Liu⁶, Wenbo Zhang⁶, Robert N Weinreb³, Mark H Ellisman², Yury I Miller⁸, Soo-Ho Choi⁹

Affiliations

¹ Hamilton Glaucoma Center, and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, La Jolla, CA 92039, USA. Electronic address: wju@health.ucsd.edu.
² National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92039, USA.
³ Hamilton Glaucoma Center, and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, La Jolla, CA 92039, USA.
⁴ Department of Medicine, University of California, San Diego, La Jolla, CA 92039, USA.
⁵ Hamilton Glaucoma Center, and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, La Jolla, CA 92039, USA; Department of Ophthalmology and Visual Science, St. Vincent's Hospital, The Catholic University of Korea, Jungbu-daero 93, Paldal-gu, Suwon, Gyeonggi-do 16247, Republic of Korea.
⁶ Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX 77555-0144, USA.
⁷ Hamilton Glaucoma Center, and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, La Jolla, CA 92039, USA; Department of Ophthalmology, Gyeongsang National University Changwon Hospital, Gyeongsang National University, School of Medicine, Changwon, Gyeongsangnam-do 51472, Republic of Korea.
⁸ Department of Medicine, University of California, San Diego, La Jolla, CA 92039, USA; Raft Pharmaceuticals LLC, San Diego, CA 92121, USA.
⁹ Department of Medicine, University of California, San Diego, La Jolla, CA 92039, USA. Electronic address: soc002@health.ucsd.edu.

PMID: 40349106
PMCID: PMC12461634 (available on 2026-08-06)
DOI: 10.1016/j.ymthe.2025.05.009

Restoring AIBP expression in the retina provides neuroprotection in glaucoma

Won-Kyu Ju et al. Mol Ther. 2025.

. 2025 Aug 6;33(8):3841-3862.

doi: 10.1016/j.ymthe.2025.05.009. Epub 2025 May 9.

Authors

Affiliations

¹ Hamilton Glaucoma Center, and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, La Jolla, CA 92039, USA. Electronic address: wju@health.ucsd.edu.
² National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92039, USA.
³ Hamilton Glaucoma Center, and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, La Jolla, CA 92039, USA.
⁴ Department of Medicine, University of California, San Diego, La Jolla, CA 92039, USA.
⁵ Hamilton Glaucoma Center, and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, La Jolla, CA 92039, USA; Department of Ophthalmology and Visual Science, St. Vincent's Hospital, The Catholic University of Korea, Jungbu-daero 93, Paldal-gu, Suwon, Gyeonggi-do 16247, Republic of Korea.
⁶ Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX 77555-0144, USA.
⁷ Hamilton Glaucoma Center, and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, La Jolla, CA 92039, USA; Department of Ophthalmology, Gyeongsang National University Changwon Hospital, Gyeongsang National University, School of Medicine, Changwon, Gyeongsangnam-do 51472, Republic of Korea.
⁸ Department of Medicine, University of California, San Diego, La Jolla, CA 92039, USA; Raft Pharmaceuticals LLC, San Diego, CA 92121, USA.
⁹ Department of Medicine, University of California, San Diego, La Jolla, CA 92039, USA. Electronic address: soc002@health.ucsd.edu.

PMID: 40349106
PMCID: PMC12461634 (available on 2026-08-06)
DOI: 10.1016/j.ymthe.2025.05.009

Abstract

Glaucoma is a neurodegenerative disease manifested by retinal ganglion cell (RGC) death and irreversible blindness. We have identified apolipoprotein A-I binding protein (AIBP) that controls excessive cholesterol accumulation and neuroinflammation in the retina by upregulating the cholesterol transporter ABCA1 and reducing TLR4 signaling and mitochondrial dysfunction. Here, we demonstrated that AIBP and ABCA1 expression were decreased, whereas Toll-like receptor 4 (TLR4), interleukin-1β (IL-1β), and the cholesterol content increased in the retina of patients with glaucoma and mouse models of glaucoma. Restoring AIBP deficiency by a single intravitreal injection of adeno-associated virus (AAV) protected RGCs and ameliorated visual dysfunction in experimental glaucoma. Conversely, AAV-mediated RGC-specific AIBP knockdown exacerbated RGC loss and visual dysfunction in a mouse model of glaucoma. Mechanistically, AAV-AIBP attenuated TLR4 and IL-1β expression and localization of TLR4 to lipid rafts, reduced cholesterol accumulation, and ameliorated visual dysfunction. Additionally, AAV-AIBP promoted mitochondrial complexity and function in Müller glia in vivo. Recombinant AIBP protein inhibited TLR4 and IL-1β activation and alleviated mitochondrial dysfunction in Müller glia in response to elevated pressure in vitro. These studies indicate that restoring AIBP expression in the glaucomatous retina reduces neuroinflammation and protects RGCs and Müller glia, suggesting the therapeutic potential of AAV-AIBP in human glaucoma.

Keywords: AAV; AIBP; Müller glia; RGC; TLR4; cholesterol; glaucoma; mitochondria; neuroinflammation; neuroprotection.

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Conflict of interest statement

Declaration of interests W.K.J., S.H.C., and Y.I.M. are co-inventors named on patents and patent applications by the University of California, San Diego. Y.I.M. is a scientific co-founder of Raft Pharmaceuticals LLC. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. Other authors declare no competing interests.

Update of

Restoring AIBP expression in the retina provides neuroprotection in glaucoma.
Ju WK, Ha Y, Choi S, Kim KY, Bastola T, Kim J, Weinreb RN, Zhang W, Miller YI, Choi SH. Ju WK, et al. bioRxiv [Preprint]. 2023 Dec 29:2023.10.16.562633. doi: 10.1101/2023.10.16.562633. bioRxiv. 2023. Update in: Mol Ther. 2025 Aug 6;33(8):3841-3862. doi: 10.1016/j.ymthe.2025.05.009. PMID: 37905114 Free PMC article. Updated. Preprint.

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Restoring AIBP expression in the retina provides neuroprotection in glaucoma

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Restoring AIBP expression in the retina provides neuroprotection in glaucoma

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