Transplantation of Human Neural Progenitor Cells (NPC) into Putamina of Parkinsonian Patients: A Case Series Study, Safety and Efficacy Four Years after Surgery

Abstract

Individuals with Parkinson’s disease (PD) suffer from motor and mental disturbances due to degeneration of dopaminergic and non-dopaminergic neuronal systems. Although they provide temporary symptom relief, current treatments fail to control motor and non-motor alterations or to arrest disease progression. Aiming to explore safety and possible motor and neuropsychological benefits of a novel strategy to improve the PD condition, a case series study was designed for brain grafting of human neural progenitor cells (NPCs) to a group of eight patients with moderate PD. A NPC line, expressing Oct-4 and Sox-2, was manufactured and characterized. Using stereotactic surgery, NPC suspensions were bilaterally injected into patients’ dorsal putamina. Cyclosporine A was given for 10 days prior to surgery and continued for 1 month thereafter. Neurological, neuropsychological, and brain imaging evaluations were performed pre-operatively, 1, 2, and 4 years post-surgery. Seven of eight patients have completed 4-year follow-up. The procedure proved to be safe, with no immune responses against the transplant, and no adverse effects. One year after cell grafting, all but one of the seven patients completing the study showed various degrees of motor improvement, and five of them showed better response to medication. PET imaging showed a trend toward enhanced midbrain dopaminergic activity. By their 4-year evaluation, improvements somewhat decreased but remained better than at baseline. Neuropsychological changes were minor, if at all. The intervention appears to be safe. At 4 years post-transplantation we report that undifferentiated NPCs can be delivered safely by stereotaxis to both putamina of patients with PD without causing adverse effects. In 6/7 patients in OFF condition improvement in UPDRS III was observed. PET functional scans suggest enhanced putaminal dopaminergic neurotransmission that could correlate with improved motor function, and better response to L-DOPA. Patients’ neuropsychological scores were unaffected by grafting. Trial Registration: Fetal derived stem cells for Parkinson’s disease https://doi.org/10.1186/ISRCTN39104513Reg#ISRCTN39104513

Dissecting the Effect of a 3D Microscaffold on the Transcriptome of Neural Stem Cells with Computational Approaches: A Focus on Mechanotransduction

“…One year after cell grafting, all but one of the seven patients completing the study showed various degrees of motor improvement, and five of them showed better response to medications. Moreover, none of the patients showed unwanted motor disturbances, tumor formation, or any immune responses to the grafted cells, demonstrating the safety and efficacy of this transplantation [36].…”

“…Moreover, the intravenous administration of NPCs in a preclinical animal model of traumatic SCI improved hind limb functional recovery, axons regenerations, and differentiation into cholinergic neuron cells [31,[33][34][35]. The safety and efficacy of NPCs as cell therapy was investigated not only in preclinical animal models but also in human patients [36]. In this context, Madrazo et al transplanted into the putamina of Parkinsonian patients human NPCs obtained from first trimester human fetal tissue.…”

Transplanted Human Neural Progenitor Cells Attenuate Motor Dysfunction and Lengthen Longevity in a Rat Model of Ataxia

“…In a recently completed Phase 1 trial, Celevie’s NPCs were implanted into the putamen of seven patients with mild-to-moderate Parkinson’s disease (PD). At the 4-yr follow-up study, six of the seven patients showed significant improvements in Unified Parkinson’s Disease Rating Scale part III (measuring motor function) compared to their previous baseline scores 21 . While a definitive conclusion on NPC efficacy will require larger controlled PD trials, these initial results suggest that transplanted NPCs have a positive and lasting effect on neurodegenerative disorders.…”

“…Human NPCs were obtained according to NIH Ethical Guidelines and have been fully described in previous studies 21 – 23 . Briefly, NPCs were grown for 13 doublings in ultra-low attachment culture flasks under feeder-free conditions in serum and xeno-free Eagle’s essential medium (Hyclone, Logan, UT, USA), supplemented with Gem21 (Gemini Bio-Products, Sacramento, CA, USA), epidermal growth factor (Peprotech, Rocky Hill, NJ, USA), basic fibroblast growth factor (Peprotech), transforming growth factor alpha (Peprotech), insulin-like growth factor I (Peprotech), leukemia inhibitory factor (Millipore, Temecula, CA, USA), calcium chloride (Fisher Scientific, Waltham MA, USA), Glutamax (Invitrogen, Carlsbad, CA, USA), non-essential amino acids (Hyclone), and an N2 supplement (Invitrogen), all of which were added at proprietary concentrations.…”

Is the Immunological Response a Bottleneck for Cell Therapy in Neurodegenerative Diseases?

“…More recently, results from the 4-years follow-up of the HSCfPD trial (NCT02780895, 2016) from Celavie Biosciences described an alternative method for monitoring immune responses. In this trial that used a cell-based product consisting of undifferentiated NPCs derived from human fetal brain tissue, named OK99, researchers showed a lack of an elicited immune response in one month CyA-immunosuppressed patient's blood samples analyzed by flow cytometry for both NPC-specific antibodies and antibody-dependent cell-mediated cytotoxicity, and after CyA treatment withdrawal at six months after grafting (Madrazo et al, 2019).…”