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Cell Stem Cell, February 13, 2025 | https://doi.org/10.1016/j.stem.2025.01.006
Pre-clinical safety and efficacy of human induced pluripotent stem cell-derived products for autologous cell therapy in Parkinson’s disease
Jeha Jeon,1,2,10 Young Cha,1,2,10 Yean Ju Hong,1,2 In-Hee Lee,3,4 Heejin Jang,1,2 Sanghyeok Ko,1,2 Serhiy Naumenko,5 Minseon Kim,1,2 Hannah L. Ryu,1,2 Zenith Shrestha,1,2 Nayeon Lee,1,2 Tae-Yoon Park,1,2 HoeWon Park,1,6 Seo-Hyun Kim,1,6 Ki-Jun Yoon,6 Bin Song,7 Jeffrey Schweitzer,7 Todd M. Herrington,8 Sek Won Kong,3,4 Bob Carter,7,* Pierre Leblanc,1,2,* and Kwang-Soo Kim 1,2,7,9,11,*
1Molecular Neurobiology Laboratory, McLean Hospital and Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA
2Program in Neuroscience, Harvard Medical School, Belmont, MA 02478, USA
3Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
4Computational Health Informatics Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
5Department of Biostatistics, Harvard Chan School of Public Health, Boston, MA 02215, USA
6Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
7Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
8Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
9Harvard Stem Cell Institute, Harvard Medical School, Cambridge, MA 02138, USA
10These authors contributed equally
11Lead contact
2Program in Neuroscience, Harvard Medical School, Belmont, MA 02478, USA
3Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
4Computational Health Informatics Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
5Department of Biostatistics, Harvard Chan School of Public Health, Boston, MA 02215, USA
6Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
7Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
8Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
9Harvard Stem Cell Institute, Harvard Medical School, Cambridge, MA 02138, USA
10These authors contributed equally
11Lead contact
*Corresponding authors: correspondence to Bob Carter, Pierre Leblanc or Kwang-Soo Kim
Abstract
Human induced pluripotent stem cell (hiPSC)-derived midbrain dopaminergic cells (mDACs) represent a promising source for autologous cell therapy in Parkinson’s disease (PD), but standardized regulatory criteria are essential for clinical translation. In this pre-clinical study, we generated multiple clinical-grade hiPSC lines from freshly biopsied fibroblasts of four sporadic PD patients using episomal reprogramming and differentiated them into mDACs using a refined 21-day protocol. Rigorous evaluations included whole-genome/exome sequencing, RNA sequencing, and in vivo studies, including a 39-week Good Laboratory Practice-compliant mouse safety study. While mDACs from all lines met safety criteria, mDACs from one patient failed to improve rodent behavioral outcomes, underscoring inter-individual variability. Importantly, in vitro assessments did not reliably predict in vivo efficacy, identifying dopaminergic fiber density as a key efficacy criterion. These findings support comprehensive quality control guidelines for autologous cell therapy and pave the way for a clinical trial with eight sporadic PD patients, scheduled to commence in 2025.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-17)
- 국외 연구진
- 생명과학 > 세포생물학
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