Inducible Expression of GDNF in Transplanted iPSC-Derived Neural Progenitor Cells

Abstract

SummaryTrophic factor delivery to the brain using stem cell-derived neural progenitors is a powerful way to bypass the blood-brain barrier. Protection of diseased neurons using this technology is a promising therapy for neurodegenerative diseases. Glial cell line-derived neurotrophic factor (GDNF) has provided benefits to Parkinsonian patients and is being used in a clinical trial for amyotrophic lateral sclerosis. However, chronic trophic factor delivery prohibits dose adjustment or cessation if side effects develop. To address this, we engineered a doxycycline-regulated vector, allowing inducible and reversible expression of a therapeutic molecule. Human induced pluripotent stem cell (iPSC)-derived neural progenitors were stably transfected with the vector and transplanted into the adult mouse brain. Doxycycline can penetrate the graft, with addition and withdrawal providing inducible and reversible GDNF expression in vivo, over multiple cycles. Our findings provide proof of concept for combining gene and stem cell therapy for effective modulation of ectopic protein expression in transplanted cells.

Viral Delivery of GDNF Promotes Functional Integration of Human Stem Cell Grafts in Parkinson’s Disease

“…The dual effects of early and late GDNF on grafted DA neurons suggest that the desired therapeutic approach may involve phasic exposure to GDNF -such that acute GDNF delivery at the time of implantation can promote survival, with a subsequent exposure within the target tissue at a defined period (potentially weeks to months) after cell transplantation. With the recent demonstration of inducible expression vectors, for the temporal control of GDNF in the intact brain 56 , this presents a feasible consideration for the future.…”

Glial Cell Line-derived Neurotrophic Factor-overexpressing Human Neural Stem/Progenitor Cells Enhance Therapeutic Efficiency in Rat with Traumatic Spinal Cord Injury

“…Human fetal cortex-derived primary NSPCs genetically modified to stably express GDNF using a lentivirus survive, migrate, secrete GDNF, and protect degenerating neurons [55,56]. These cells are safe and non-tumorigenic, and are currently being used in a phase 1/2a clinical trial incorporating cell and gene therapy to protect motor neurons in patients with amyotrophic lateral sclerosis [57]. Therefore, in this study, we evaluated the regenerative ability of human fetal brain-derived NSPCs engineered to secrete GDNF via infection of an adenovirus in rats with SCI and compared their therapeutic efficiency with that of Mock-hNSPCs for a future clinical trial.…”

Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders

“…For instance, astrocytes modified to secrete high amounts of L-3,4-dihydroxyphenylalanine (DOPA) were shown to ameliorate the phenotype of a rat model of PD [97]. Further-more, several papers described the in vivo transplantation of precursors engineered to overexpress the glial cell line-derived neurotrophic factor (GDNF) and their efficacy in ameliorating the pathological phenotype of rodent models of ALS [98][99][100] and PD [101,102]. Based on this, a phase I/IIa clinical trial assessing the safety of GDNF-overexpressing human stem cells committed to astrocyte transplantation in the lumbar spinal cord of ALS patients was later activated (NCT02943850).…”