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Mol. Ther., May 24 2024, S1525-0016(24)00329-0 | https://doi.org/10.1016/j.ymthe.2024.05.027 In vivo adenine base editing rescues adrenoleukodystrophy in a humanized mouse model

Ramu Gopalappa ^1,#, MinYoung Lee ^1,2,#, Globinna Kim ^3,4*, Eul Sik Jung^1,5, Hanahrae Lee ^1,2, Hye-Yeon Hwang ⁶, Jong Geol Lee ³, Su Jung Kim³, Hyun Ju Yoo ³, Young Hoon Sung ^3,4, Daesik Kim ⁶, In-Jeoung Baek ^3,4*, Hyongbum Henry Kim ^1,2,7,8,9*

¹Department of Pharmacology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea

²Brain Korea 21 Plus Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea

³ConveRgence mEDIcine research cenTer (CREDIT), ASAN Institute for Life Sciences, ASAN Medical Center, Seoul 05505, Republic of Korea

⁴Department of Cell and Genetic Engineering, ASAN Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea

⁵JES Clinic, Incheon 21550, Republic of Korea

⁶Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon 16419, Republic of Korea

⁷Center for Nanomedicine, Institute for Basic Science, Seoul 03722, Republic of Korea

⁸Graduate Program of Nano Biomedical Engineering, Advanced Science Institute, Yonsei University, Seoul 03722, Republic of Korea

⁹Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea

^#These authors contributed equally.

*Corresponding authors: Globinna Kim, In-Jeoung Baek, Hyongbum Henry Kim

Abstract

X-linked adrenoleukodystrophy (ALD), an inherited neurometabolic disorder caused by mutations in ABCD1, which encodes the peroxisomal ABC transporter, mainly affects the brain, spinal cord, adrenal glands, and testes. In ALD patients, very long-chain fatty acids (VLCFAs) fail to enter the peroxisome and undergo subsequent β-oxidation, resulting in their accumulation in the body. It has not been tested whether in vivo base editing or prime editing can be harnessed to ameliorate ALD. We developed a humanized mouse model of ALD by inserting a human cDNA containing the pathogenic variant into the mouse Abcd1 locus. The humanized ALD model showed increased levels of VLCFAs. To correct the mutation, we tested both base editing and prime editing and found that base editing using ABE8e(V106W) could correct the mutation in patient-derived fibroblasts at an efficiency of 7.4%. Adeno-associated virus (AAV)-mediated systemic delivery of NG-ABE8e(V106W) enabled robust correction of the pathogenic variant in the mouse brain (correction efficiency: ∼5.5%), spinal cord (∼5.1%), and adrenal gland (∼2%), leading to a significant reduction in the plasma levels of C26:0/C22:0. This established humanized mouse model and the successful correction of the pathogenic variant using a base editor serve as a significant step towards treating human ALD disease.

논문정보

형식Research article
게재일2024년 05월 (BRIC 등록일 2024-05-27)
연구진국내 연구진
분야 의약학 > 유전 및 유전체의학

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