Lentivirus-modified hematopoietic stem cell gene therapy for advanced symptomatic juvenile metachromatic leukodystrophy: a long-term follow-up pilot study.

Zhao ZHANG; Hua JIANG; Li HUANG; Sixi LIU; Xiaoya ZHOU; Yun CAI; Ming LI; Fei GAO; Xiaoting LIANG; Kam-Sze TSANG; Guangfu CHEN; Chui-Yan MA; Yuet-Hung CHAI; Hongsheng LIU; Chen YANG; Mo YANG; Xiaoling ZHANG; Shuo HAN; Xin DU; Ling CHEN; Wuh-Liang HWU; Jiacai ZHUO; Qizhou LIAN

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Lentivirus-modified hematopoietic stem cell gene therapy for advanced symptomatic juvenile metachromatic leukodystrophy: a long-term follow-up pilot study.

Author: Zhao ZHANG ¹ ; Hua JIANG ² ; Li HUANG ¹ ; Sixi LIU ³ ; Xiaoya ZHOU ¹ ; Yun CAI ⁴ ; Ming LI ⁴ ; Fei GAO ⁵ ; Xiaoting LIANG ⁵ ; Kam-Sze TSANG ⁶ ; Guangfu CHEN ⁷ ; Chui-Yan MA ⁵ ; Yuet-Hung CHAI ⁵ ; Hongsheng LIU ⁸ ; Chen YANG ¹ ; Mo YANG ⁹ ; Xiaoling ZHANG ³ ; Shuo HAN ⁵ ; Xin DU ⁴ ; Ling CHEN ⁵ ; Wuh-Liang HWU ¹⁰ ; Jiacai ZHUO ⁴ ; Qizhou LIAN ¹
Author Information

1. Cord Blood Bank, Guangzhou Institute of Eugenics and Perinatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
2. Department of Haematology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
3. Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen 518026, China.
4. Department of Haematology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen University School of Medicine, Shenzhen University, Shenzhen 518060, China.
5. State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China.
6. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
7. Department of Paediatrics, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen University School of Medicine, Shenzhen University, Shenzhen 518060, China.
8. Department of Radiology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 518026, China.
9. Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China.
10. Department of Paediatrics and Medical Genetics, Taiwan University Hospital, Taipei 110024, China.
Publication Type:Journal Article
Keywords: HSCGT; advanced symptomatic; efficacy; juvenile; metachromatic leukodystrophy; patients; safety
MeSH: Humans; Leukodystrophy, Metachromatic/genetics*; Pilot Projects; Genetic Therapy/methods*; Hematopoietic Stem Cell Transplantation; Male; Follow-Up Studies; Female; Lentivirus/genetics*; Child; Child, Preschool; Hematopoietic Stem Cells/metabolism*; Cerebroside-Sulfatase/metabolism*; Adolescent
From: Protein & Cell 2025;16(1):16-27
CountryChina
Language:English
Abstract: Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over 9 years. The most common adverse events (AEs) within 2 months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.