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

Human induced pluripotent stem cells (iPSCs) are a renewable cell source that can be differentiated into neural progenitor cells (iNPCs) and transduced with glial cell line-derived neurotrophic factor (iNPC-GDNFs). The goal of the current study is to characterize iNPC-GDNFs and test their therapeutic potential and safety. Single-nuclei RNA-seq show iNPC-GDNFs express NPC markers. iNPC-GDNFs delivered into the subretinal space of the Royal College of Surgeons rodent model of retinal degeneration preserve photoreceptors and visual function. Additionally, iNPC-GDNF transplants in the spinal cord of SOD1G93A amyotrophic lateral sclerosis (ALS) rats preserve motor neurons. Finally, iNPC-GDNF transplants in the spinal cord of athymic nude rats survive and produce GDNF for 9 months, with no signs of tumor formation or continual cell proliferation. iNPC-GDNFs survive long-term, are safe, and provide neuroprotection in models of both retinal degeneration and ALS, indicating their potential as a combined cell and gene therapy for various neurodegenerative diseases. [Display omitted] •Human iNPC-GDNFs differentiate into astrocytes both in vitro and in vivo•iNPC-GDNFs can protect cells and function in the diseased rat retina and spinal cord•iNPC-GDNFs show long-term survival and GDNF production in the nude rat spinal cord•iNPC-GDNFs provide a safe and expandable combined cell and gene therapy Direct replacement of lost cells in neurodegenerative conditions remains challenging. Alternatively, diseased cells can be protected by delivering astrocytes and growth factors. Laperle et al. demonstrate that iPSC-derived neural progenitor cells can be engineered to stably produce GDNF (iNPC-GDNF), which survive in the central nervous system, are safe, can slow cell death in multiple disease models, and protect function.