AAV-based gene therapy with modified HEXB confers lasting therapeutic benefits in GM2 gangliosidosis models.

Overview

Authors: Keisuke Kitakaze¹, Yukiya Ohnishi², Daisuke Tsuji^2,3, Ryosuke Watanabe², Nijiho Kamori³, Yuko Katakai⁴, Hiroaki Shibata⁴, Sota Yoshizawa⁵, Mika Ito⁶, Naomi Takino⁶, Shin-ichi Muramatsu^5,6, Kohji Itoh^2,3,7

ORCID iDs: Keisuke Kitakaze, Kohji Itoh

Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
Department of Medicinal Biotechnology, Graduate School of Pharmaceutical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
Department of Medicinal Biotechnology, Faculty of Pharmaceutical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
The Corporation for Production and Research of Laboratory Primates, 1-16-2 Sakura, Tsukuba, Ibaraki 305-0003, Japan
ONODERA GT Pharma, Inc., 3-25-22 Tonomachi, Kawasaki, Kanagawa 210-0821, Japan
Division of Neurological Gene Therapy, Center for Open Innovation, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
Division of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan

Institutions: Kawasaki Medical School (Japan); Tokushima University (Japan); Corporation for Production and Research of Laboratory Primates (Japan); Jichi Medical University (Japan)

Journal: Cell reports. Medicine, volume 7, issue 5, article 102762

Dates: received 26 September 2025; accepted 23 March 2026; published online 22 April 2026; in print May 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1016/j.xcrm.2026.102762 · PMID 42025166 · PMCID PMC13198282 · OpenAlex W4414641260

Open access: gold, a free copy (OpenAlex)

Preprint: doi:10.2139/ssrn.5546058

Status: code on request

Categories: human (organism), mouse (organism), rat (organism)

Methods: Statistics, Evoked potentials

Keywords: lysosomal storage disorders, GM2 gangliosidosis, Tay-Sachs disease, Sandhoff disease, neurodegenerative disease, gene therapy, adeno-associated virus, intrathecal administration, translational study, GT0005X

MeSH: beta-Hexosaminidase beta Chain*, Dependovirus*, Gangliosidoses, GM2*, Genetic Therapy*, Animals, Brain, Disease Models, Animal, G(M2) Ganglioside, Gene Therapy Agents, Genetic Vectors, Humans, Male, Mice, Rats (* major topic)

Topic: Toxin Mechanisms and Immunotoxins (Immunology, Immunology and Microbiology), according to OpenAlex

Funding: Osaka University; Okayama University Hospital; Tokushima University; Jichi Medical University; Japan Agency for Medical Research and Development (17im0210605h0002, 17lm0203037h0001, 19lm0203094h0001, 21im0210116h0003)

Citations: not cited yet (Europe PMC); 70 references in the paper

Research resources: anti-NeuN antibody RRID:AB_10807945, Anti-rabbit IgG, HRP-linked Antibody RRID:AB_2099233, anti-GAPDH antibody (6C5) RRID:AB_2107448, Anti-GFP antibody (JL-8) RRID:AB_2313808, Anti-CD68 antibody (FA-11) RRID:AB_2572857, anti-HexB antibody RRID:AB_3065101, Anti-mouse IgG, HRP-linked Antibody RRID:AB_330924, RRID:AB_955209, SH-SY5Y RRID:CVCL_0019, Crl:CD(SD) rat RRID:RGD_734476, Prism ver. 8.42 RRID:SCR_002798, ImageJ ver. 1.52 RRID:SCR_003070, SAS System ver. 9.4 RRID:SCR_008567

Abstract

GM2 gangliosidoses, including Tay-Sachs (TSD) and Sandhoff (SD) diseases, are lysosomal storage disorders with neurological manifestations caused by the excessive accumulation of GM2 ganglioside due to the deficiency of the β-hexosaminidase A (HexA). Although gene therapy approaches are underway, concerns regarding efficacy and safety remain. Here, we evaluate a tyrosine-mutant adeno-associated virus serotype 9 (AAV9/3) vector encoding modified HEXB (modHEXB) wherein nine amino acid residues are substituted from HEXA. The intracerebroventricular administration of AAV9/3-modHEXB in SD mice results in modHexB expression in the brain, reduces GM2 accumulation, and attenuates neuroinflammation. Furthermore, AAV9/3-modHEXB rescues motor function, and longer lifespan in SD mice. In addition, intrathecal administration in non-human primates and rats demonstrates broad biodistribution and an overall favorable safety profile. These findings support the translational potential of AAV9/3-modHEXB as a gene therapy approach for TSD and SD.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 10 keywords, 14 MeSH terms, 5 funders, 69 references, 13 RRIDs.

Cite

This paper

Kitakaze, K., Ohnishi, Y., Tsuji, D., Watanabe, R., Kamori, N., Katakai, Y., Shibata, H., Yoshizawa, S., Ito, M., Takino, N., Muramatsu, S.-i., & Itoh, K. (2026). AAV-based gene therapy with modified HEXB confers lasting therapeutic benefits in GM2 gangliosidosis models. Cell reports. Medicine, 7(5), 102762. https://doi.org/10.1016/j.xcrm.2026.102762

BibTeX

@article{kitakaze2026aav, author = {Kitakaze, Keisuke and Ohnishi, Yukiya and Tsuji, Daisuke and Watanabe, Ryosuke and Kamori, Nijiho and Katakai, Yuko and Shibata, Hiroaki and Yoshizawa, Sota and Ito, Mika and Takino, Naomi and Muramatsu, Shin-ichi and Itoh, Kohji}, title = {{AAV-based gene therapy with modified HEXB confers lasting therapeutic benefits in GM2 gangliosidosis models}}, journal = {Cell reports. Medicine}, year = {2026}, month = apr, volume = {7}, number = {5}, pages = {102762}, publisher = {Elsevier}, issn = {2666-3791}, doi = {10.1016/j.xcrm.2026.102762}, url = {https://doi.org/10.1016/j.xcrm.2026.102762}, pmid = {42025166}, pmcid = {PMC13198282} }

RIS

TY - JOUR AU - Kitakaze, Keisuke AU - Ohnishi, Yukiya AU - Tsuji, Daisuke AU - Watanabe, Ryosuke AU - Kamori, Nijiho AU - Katakai, Yuko AU - Shibata, Hiroaki AU - Yoshizawa, Sota AU - Ito, Mika AU - Takino, Naomi AU - Muramatsu, Shin-ichi AU - Itoh, Kohji TI - AAV-based gene therapy with modified HEXB confers lasting therapeutic benefits in GM2 gangliosidosis models T2 - Cell reports. Medicine J2 - Cell Rep Med PY - 2026 DA - 2026/04/22 VL - 7 IS - 5 SP - 102762 SN - 2666-3791 PB - Elsevier DO - 10.1016/j.xcrm.2026.102762 UR - https://doi.org/10.1016/j.xcrm.2026.102762 LA - en ER -

CSL-JSON

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