Effectiveness and Safety of Intravenous Administration of Mesenchymal Stem Cells Overexpressing Arylsulfatase A for the Treatment of Metachromatic Leukodystrophy in a Pig Model
https://doi.org/10.52667/2712-9179-2025-5-4-69-76
Abstract
This study evaluated intravenous administration of allogeneic mesenchymal stem cells (MSCs) transduced with AAV9-ARSA to pigs. The MSCs were modified to overexpress human arylsulfatase A (ARSA). Thirty-five days after treatment, ARSA activity significantly increased in CNS tissues. No hepatotoxicity or systemic inflammation was observed. The results confirm the safety and efficacy of this MSC-based gene therapy for metachromatic leukodystrophy (MLD).
About the Authors
Aisilu A. Ayupova
Institute of Fundamental Medicine and Biology, Kazan Federal University
Russian Federation
Russian Federation
Kazan, 420008
Alisa A. Fattakhova
Institute of Fundamental Medicine and Biology, Kazan Federal University
Russian Federation
Russian Federation
Kazan, 420008
Valeria V. Solovyeva
Institute of Fundamental Medicine and Biology, Kazan Federal University
Russian Federation
Russian Federation
Kazan, 420008
Yana O. Mukhamedshina
Institute of Fundamental Medicine and Biology, Kazan Federal University; Division of Medical and Biological Sciences, Tatarstan Academy of Sciences; Department of Histology, Cytology, and Embryology, Kazan State Medical University
Russian Federation
Russian Federation
Kazan, 420008; Kazan, 420111; 420012 Kazan
Albert A. Rizvanov
Institute of Fundamental Medicine and Biology, Kazan Federal University; Division of Medical and Biological Sciences, Tatarstan Academy of Sciences
Russian Federation
Russian Federation
Kazan, 420008; Kazan, 420111
References
1. Shaimardanova, A.A.; Chulpanova, D.S.; Solovyeva, V.V.; Mullagulova, A.I.; Kitaeva, K.V.; Allegrucci, C.; Rizvanov, A.A. Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches. Front Med (Lausanne). 2020; 7:576221, https://doi.org/10.3389/fmed.2020.576221.
2. Shaimardanova, A.A.; Chulpanova, D.S.; Solovyeva,; Mullagulova, A.I.; Kitaeva, K.V.; Rizvanov, A.A. New therapeutic strategies for the treatment of metachromatic leukodystrophy. Genes & Cells. 2020; 15:41-50.
3. Piguet, F.; Sondhi, D.; Piraud, M.; Fouquet, F.; Hackett, N.R.; Ahouansou, O.; Vanier, M.T.; Bieche, I.; Aubourg, P.; Crystal, R.G.; et al. Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice. Hum Gene Ther. 2012; 23:903-914, https://doi.org/10.1089/hum.2012.015.
4. Mullagulova, A.I.; Timechko, E.E.; Solovyeva, V.V.; Yakimov, A.M.; Ibrahim, A.; Dmitrenko, D.D.; Sufianov, A.A.; Sufianova, G.Z.; Rizvanov, A.A. Adeno-Associated Viral Vectors in the Treatment of Epilepsy. Int J Mol Sci. 2024; 25, https://doi.org/10.3390/ijms252212081.
5. Issa, S.S.; Shaimardanova, A.A.; Solovyeva, V.V.; Rizvanov, A.A. Various AAV Serotypes and Their Applications in Gene Therapy: An Overview. Cells. 2023; 12, https://doi.org/10.3390/cells12050785.
6. Xu, L.; Yao, S.; Ding, Y.E.; Xie, M.; Feng, D.; Sha, P.; Tan, L.; Bei, F.; Yao, Y. Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside. J Transl Med. 2024; 22:866, https://doi.org/10.1186/s12967-024-05661-2.
7. Miyake, N.; Miyake, K.; Asakawa, N.; Yamamoto, M.; Shimada, T. Long-term correction of biochemical and neurological abnormalities in MLD mice model by neonatal systemic injection of an AAV serotype 9 vector. Gene Ther. 2014; 21:427-433, https://doi.org/10.1038/gt.2014.17.
8. Mullagulova, A.; Shaimardanova, A.; Solovyeva, V.; Mukhamedshina, Y.; Chulpanova, D.; Kostennikov, A.; Issa, S.; Rizvanov, A. Safety and Efficacy of Intravenous and Intrathecal Delivery of AAV9-Mediated ARSA in Minipigs. Int J Mol Sci. 2023, 24, https://doi.org/10.3390/ijms24119204.
9. Moldavskii, D.; Gilazieva, Z.; Fattakhova, A.; Solovyeva, V.; Issa, S.; Sufianov, A.; Sufianova, G.; Rizvanov, A. AAV-Based Gene Therapy: Opportunities, Risks, and Scale-Up Strategies. Int J Mol Sci. 2025, 26, https://doi.org/10.3390/ijms26178282.
10. Issa, S.S.; Shaimardanova, A.A.; Valiullin, V.V.; Rizvanov, A.A.; Solovyeva, V.V. Mesenchymal Stem Cell-Based Therapy for Lysosomal Storage Diseases and Other Neurodegenerative Disorders. Front Pharmacol. 2022; 13:859516, https://doi.org/10.3389/fphar.2022.859516.
11. Han, X.; Liao, R.; Li, X.; Zhang, C.; Huo, S.; Qin, L.; Xiong, Y.; He, T.; Xiao, G.; Zhang, T. Mesenchymal stem cells in treating human diseases: molecular mechanisms and clinical studies. Signal Transduct Target Ther. 2025; 10:262, https://doi.org/10.1038/s41392-025-02313-9.
12. Bu, Z.; Lou, J.; Xu, W.; Zhang, L.; Tang, Y. Human umbilical cord mesenchymal stem cell-based gene therapy for hemophilia B using scAAV-DJ/8-LP1-hFIXco transduction. Stem Cell Res Ther. 2024; 15:210, https://doi.org/10.1186/s13287-024-03824-y.
13. Zakirova, E.; Aimaletdinov, A.; Tambovsky, M.; Rizvanov, A. Comparative characteristics of mesenchymal stem cell lines of different animal species. Cytolog. 2021; 63:139-146.
14. Voitenko, N.; Makarova, M. Variability of blood biochemical parameters and establishment of reference intervals in preclinical studies. Report 3: minipigs. Laboratory animals for scientific research. 2020; 7-15.
15. Cavazza, A.; Moiani, A.; Mavilio, F. Mechanisms of retroviral integration and mutagenesis. Hum Gene Ther. 2013; 24:119-131, https://doi.org/10.1089/hum.2012.203.
16. Meuleman, N.; Vanhaelen, G.; Tondreau, T.; Lewalle, P.; Kwan, J.; Bennani, J.; Martiat, P.; Lagneaux, L.; Bron, D. Reduced intensity conditioning haematopoietic stem cell transplantation with mesenchymal stromal cells infusion for the treatment of metachromatic leukodystrophy: a case report. Haematologica. 2008; 93:e11-13, https://doi.org/10.3324/haematol.11802.
17. Tashima, T. Mesenchymal Stem Cell (MSC)-Based Drug Delivery into the Brain across the Blood-Brain Barrier. Pharmaceutics. 2024; 16, https://doi.org/10.3390/pharmaceutics16020289.
18. Huang, Y.; Wu, Q.; Tam, P.K.H. Immunomodulatory Mechanisms of Mesenchymal Stem Cells and Their Potential Clinical Applications. Int J Mol Sci. 2022; 23, https://doi.org/10.3390/ijms231710023.
Review
For citations:
Ayupova A.A., Fattakhova A.A., Solovyeva V.V., Mukhamedshina Ya.O., Rizvanov A.A. Effectiveness and Safety of Intravenous Administration of Mesenchymal Stem Cells Overexpressing Arylsulfatase A for the Treatment of Metachromatic Leukodystrophy in a Pig Model. Personalized Psychiatry and Neurology. 2025;5(4):69-76. https://doi.org/10.52667/2712-9179-2025-5-4-69-76
Views:
38
Email this article 