Clinical-Grade Human Induced Pluripotent Stem Cell-Derived Neural Precursor Cells Restore Motor Function and Preserve Striatal Integrity in a Quinolinic Acid-Lesioned Rat Model of Huntington's Disease

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disease characterised by progressive degeneration of GABAergic medium spiny neurons (MSNs) in the striatum. Neural precursor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) have been considered as a promising and scalable source for neuronal replacement and circuit restoration. In this study, we investigated the therapeutic effects of a clinical-grade, human leukocyte antigen (HLA)-homozygous iPSC line (YZWJ-s513) differentiated into NPCs (s513-NPCs) in a quinolinic acid (QA)-lesioned rat model of HD. Following intrastriatal transplantation, s513-NPCs not only survived for 12 weeks but also differentiated into neurons, astrocytes, and oligodendrocytes, while generating new DARPP32⁺ GABAergic MSNs. Specifically, graft-derived neurons projected to the host globus pallidus, indicating structural integration into the striato-pallidal pathways. Additionally, NPC-transplanted rats exhibited significant motor recovery across multiple tasks for up to 12 weeks, accompanied by reduced striatal atrophy and ventricular enlargement. Histological findings also revealed attenuated astrogliosis and microgliosis, along with a shift toward an anti-inflammatory milieu. Collectively, these results demonstrate that transplantation of clinical-grade, HLA-homozygous iPSC-derived NPCs can provide both neuronal replacement and modulation of the diseased microenvironment, supporting their potential as a regenerative therapy for HD. Key quality attributes and release criteria supporting the clinical-grade characterisation of the cell product used in vivo are summarised in Table S1.

Keywords

HLA-homozygous / Huntington's disease / induced pluripotent stem cells / medium spiny neurons / neural precursor cells / neuroinflammation / quinolinic acid (QA)

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