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Human iPSC-derived neural progenitor cells secreting GDNF provide protection in rodent models of ALS and retinal degeneration

ABSTRACT: Expanded populations of human fetal-derived neural progenitor cells transduced to produce GDNF (fNPC-GDNF) have now been shown to survive for over three years following injection into the human spinal cord and can provide neuroprotection in many animal models. However, low availability of starting material limits their widespread use. Human induced pluripotent stem cells (iPSCs) are an alternative, renewable cell source that can be differentiated into NPCs and transduced with GDNF (iNPC-GDNF). The goal of the current study was to characterize iNPC-GDNF cells and test their therapeutic potential and safety. Single nuclei RNA- seq showed that fNPC-GDNF and iNPC-GDNF had both overlapping and unique clusters of cells, suggesting that the two products were not identical. When transplanted into the subretinal space of a rodent model of retinal degeneration, iNPC-GDNF preserved photoreceptors and visual function. Transplantation of iNPC-GDNF into the lumbar spinal cord of a rodent model of ALS preserved motor neurons. Finally, to evaluate long-term safety and tolerability, iNPC-GDNF were transplanted into the spinal cord of athymic nude rats for 9 months. Surviving grafts secreting GDNF were found in all animals with no signs of tumor formation or cell proliferation. iNPC-GDNF survive long-term, are safe, and provide neuroprotection in models of both retinal degeneration and ALS, indicating their potential for clinical trials as a cell and gene therapy-based treatment for various neurodegenerative diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214210 | GEO | 2023/04/19

REPOSITORIES: GEO

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