Search

We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson's disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson's disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson's disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the National Institutes of Health and others.).

The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson’s disease, which makes cell replacement a promising therapeutic approach1–4. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes5–8. Here we show that the surgical procedure itself (referred to here as ‘needle trauma’) triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells and brain cell death. When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation. By contrast, TH− grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson’s disease with 6-hydroxydopamine lesions. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH− grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons. Together, these data emphasize the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson’s disease.In mouse and rat models of Parkinson’s disease, co-transplanting regulatory T cells (Treg cells) improves the survival of grafted midbrain dopamine neurons in cell therapies by reducing the inflammatory response caused by surgical injury. [ABSTRACT FROM AUTHOR]

In the visual system, spatial attention enhances sensory responses to stimuli at attended locations relative to unattended locations. Which brain structures direct the locus of attention, and how is attentional modulation delivered to structures in the visual system? We trained monkeys on an attention-switch task designed to precisely measure the onset of attentional modulation during rapid shifts of spatial attention. Here we show that attentional modulation appears substantially earlier in the lateral intraparietal area (LIP) than in an anatomically connected lower visual area, the middle temporal area. This temporal sequence of attentional latencies demonstrates that endogenous changes of state can occur in higher visual areas before lower visual areas and satisfies a critical prediction of the hypothesis that LIP is a source of top-down attentional signals to early visual cortex. [ABSTRACT FROM AUTHOR]

We measured the behavioral time course of endogenously cued attentional shifts while recording from neurons in the middle temporal area (MT) and lateral intraparietal area (LIP) of two macaque monkeys. The monkeys were required to detect a subtle speed change of one of two continuously moving stimuli. The likely location of the speed change was cued throughout each trial but could switch at an unpredictable time. Attention was evident as an improvement in detection ability and reaction time at the cued location, and the focus of attention shifted over a 400 ms period in response to a switch of the cued stimulus. Attention modulated the ongoing neural response in both MT and LIP, and the sign of this modulation also rapidly shifted after a cue switch. Our data provide a framework for understanding the link between the neural and behavioral effects of attention. The responses of single neurons to the test stimulus in MT and LIP were correlated with stimulus detection and reaction time and, at the population level, a spike-rate threshold model was able to account for the effect of attention on detection rate and reaction time. In this view, the time course of the attentional shift can be understood as an interaction between the emerging attentional modulation and the neural response to the test stimulus in LIP. We also present evidence that the threshold model is not wholly explained by sensory (feed forward) information but may also be influenced by cognitive (feedback) processes at the time of stimulus detection. [ABSTRACT FROM AUTHOR]

It is widely reported that the activity of single neurons in visual cortex is correlated with the perceptual decision of the subject. The strength of this correlation has implications for the neuronal populations generating the percepts. Here we asked whether microsaccades, which are small, involuntary eye movements, contribute to the correlation between neural activity and behavior. We analyzed data from three different visual detection experiments, with neural recordings from the middle temporal (MT), lateral intraparietal (LIP), and ventral intraparietal (VIP) areas. All three experiments used random dot motion stimuli, with the animals required to detect a transient or sustained change in the speed or strength of motion. We found that microsaccades suppressed neural activity and inhibited detection of the motion stimulus, contributing to the correlation between neural activity and detection behavior. Microsaccades accounted for as much as 19% of the correlation for area MT, 21% for area LIP, and 17% for VIP. While microsaccades only explain part of the correlation between neural activity and behavior, their effect has implications when considering the neuronal populations underlying perceptual decisions. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cell (hiPSC)-derived midbrain dopaminergic cells (mDACs) represent a promising source for autologous cell therapy in Parkinson's disease (PD), but standardized regulatory criteria are essential for clinical translation. In this pre-clinical study, we generated multiple clinical-grade hiPSC lines from freshly biopsied fibroblasts of four sporadic PD patients using episomal reprogramming and differentiated them into mDACs using a refined 21-day protocol. Rigorous evaluations included whole-genome/exome sequencing, RNA sequencing, and in vivo studies, including a 39-week Good Laboratory Practice-compliant mouse safety study. While mDACs from all lines met safety criteria, mDACs from one patient failed to improve rodent behavioral outcomes, underscoring inter-individual variability. Importantly, in vitro assessments did not reliably predict in vivo efficacy, identifying dopaminergic fiber density as a key efficacy criterion. These findings support comprehensive quality control guidelines for autologous cell therapy and pave the way for a clinical trial with eight sporadic PD patients, scheduled to commence in 2025., Competing Interests: Declaration of interests K.-S.K. reports grants, outside the submitted work. In addition, K.-S.K. has a patent “Methods for purifying midbrain dopaminergic neural progenitor cells” (US#9,750,768) with royalties paid from Cellular Dynamics (Fujifilm); a patent “Methods for suppressing teratoma formation via cell death of undifferentiated iPS cells” (US#9,657,273) issued; a patent “Synergistic genome-nonintegrating reprogramming by microRNAs and transcription factors” (US#11,898,169 B2) issued; a patent “Methods for manipulating cell fate” (US16/483,107) pending; and a patent “Novel methods for in vitro culture of human pluripotent stem cells” (US62/852,008) pending and concurrent with NIH and other reported funding sources disclosed by individual co-authors. One of the subjects reported in this manuscript provided philanthropic support to McLean Hospital and Massachusetts General Hospital, which is broadly designated for the development of cell therapy for PD and administered by the two co-senior authors of this report: B.C. and K.-S.K. Past and ongoing use of this support includes the following: development of iPSC reprogramming technology, pre-clinical testing, and cell product testing; ongoing multi-patient variability study of iPSC reprogramming; and ongoing phase 1 clinical trial design and implementation., (Copyright © 2025 Elsevier Inc. All rights reserved.)