Pre-clinical safety and efficacy of human induced pluripotent stem cell-derived products for autologous cell therapy in Parkinson's disease

Jeha Jeon¹, Young Cha¹, Yean Ju Hong¹, In-Hee Lee², Heejin Jang¹, Sanghyeok Ko¹, Serhiy Naumenko³, Minseon Kim¹, Hannah L Ryu¹, Zenith Shrestha¹, Nayeon Lee¹, Tae-Yoon Park¹, HoeWon Park⁴, Seo-Hyun Kim⁴, Ki-Jun Yoon⁵, Bin Song⁶, Jeffrey Schweitzer⁶, Todd M Herrington⁷, Sek Won Kong², Bob Carter⁸, Pierre Leblanc⁹, Kwang-Soo Kim¹⁰

Affiliations

¹ Molecular Neurobiology Laboratory, McLean Hospital and Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA; Program in Neuroscience, Harvard Medical School, Belmont, MA 02478, USA.
² Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
³ Department of Biostatistics, Harvard Chan School of Public Health, Boston, MA 02215, USA.
⁴ Molecular Neurobiology Laboratory, McLean Hospital and Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA; Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.
⁵ Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.
⁶ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁷ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁸ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: bcarter@mgh.harvard.edu.
⁹ Molecular Neurobiology Laboratory, McLean Hospital and Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA; Program in Neuroscience, Harvard Medical School, Belmont, MA 02478, USA. Electronic address: pleblanc@mclean.harvard.edu.
¹⁰ Molecular Neurobiology Laboratory, McLean Hospital and Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA; Program in Neuroscience, Harvard Medical School, Belmont, MA 02478, USA; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Harvard Stem Cell Institute, Harvard Medical School, Cambridge, MA 02138, USA. Electronic address: kskim@mclean.harvard.edu.

PMID: 39952239
PMCID: PMC11980241 (available on 2026-03-06)
DOI: 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 et al. Cell Stem Cell. 2025.

. 2025 Mar 6;32(3):343-360.e7.

doi: 10.1016/j.stem.2025.01.006. Epub 2025 Feb 13.

Authors

Affiliations

¹ Molecular Neurobiology Laboratory, McLean Hospital and Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA; Program in Neuroscience, Harvard Medical School, Belmont, MA 02478, USA.
² Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
³ Department of Biostatistics, Harvard Chan School of Public Health, Boston, MA 02215, USA.
⁴ Molecular Neurobiology Laboratory, McLean Hospital and Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA; Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.
⁵ Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.
⁶ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁷ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁸ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: bcarter@mgh.harvard.edu.
⁹ Molecular Neurobiology Laboratory, McLean Hospital and Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA; Program in Neuroscience, Harvard Medical School, Belmont, MA 02478, USA. Electronic address: pleblanc@mclean.harvard.edu.
¹⁰ Molecular Neurobiology Laboratory, McLean Hospital and Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA; Program in Neuroscience, Harvard Medical School, Belmont, MA 02478, USA; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Harvard Stem Cell Institute, Harvard Medical School, Cambridge, MA 02138, USA. Electronic address: kskim@mclean.harvard.edu.

PMID: 39952239
PMCID: PMC11980241 (available on 2026-03-06)
DOI: 10.1016/j.stem.2025.01.006

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.

Keywords: Parkinson's disease; autologous cell therapy; dopaminergic fiber density; genome integrity; human induced pluripotent stem cells; inter-individual variability; midbrain dopaminergic cells; phase 1 clinical trial; pre-clinical study; safety and efficacy.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests K.-S.K. reports grants, outside the submitted work. In addition, K.-S.K. has a patent “Methods for purifying midbrain dopaminergic neural progenitor cells” (US#9,750,768) with royalties paid from Cellular Dynamics (Fujifilm); a patent “Methods for suppressing teratoma formation via cell death of undifferentiated iPS cells” (US#9,657,273) issued; a patent “Synergistic genome-nonintegrating reprogramming by microRNAs and transcription factors” (US#11,898,169 B2) issued; a patent “Methods for manipulating cell fate” (US16/483,107) pending; and a patent “Novel methods for in vitro culture of human pluripotent stem cells” (US62/852,008) pending and concurrent with NIH and other reported funding sources disclosed by individual co-authors. One of the subjects reported in this manuscript provided philanthropic support to McLean Hospital and Massachusetts General Hospital, which is broadly designated for the development of cell therapy for PD and administered by the two co-senior authors of this report: B.C. and K.-S.K. Past and ongoing use of this support includes the following: development of iPSC reprogramming technology, pre-clinical testing, and cell product testing; ongoing multi-patient variability study of iPSC reprogramming; and ongoing phase 1 clinical trial design and implementation.

References

1. Bloem BR, Okun MS & Klein C Parkinson's disease. Lancet 397, 2284–2303 (2021). - PubMed
1. Kalia LV & Lang AE Parkinson's disease. Lancet 386, 896–912 (2015). - PubMed
1. Stoker TB & Barker RA Recent developments in the treatment of Parkinson's Disease. F1000Res 9 (2020). - PMC - PubMed
1. Meissner WG et al. Priorities in Parkinson's disease research. Nat Rev Drug Discov 10, 377–393 (2011). - PubMed
1. Obeso JA et al. Missing pieces in the Parkinson's disease puzzle. Nat Med 16, 653–661 (2010). - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Pre-clinical safety and efficacy of human induced pluripotent stem cell-derived products for autologous cell therapy in Parkinson's disease

Affiliations

Pre-clinical safety and efficacy of human induced pluripotent stem cell-derived products for autologous cell therapy in Parkinson's disease

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Medical