Genetically engineered stem cell‐derived neurons can be rendered resistant to alpha‐synuclein aggregate pathology

Brundin, Patrik; Coetzee, Gerhard A.

doi:10.1111/ejn.14333

Cited by 2 publications

(1 citation statement)

References 38 publications

(45 reference statements)

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“…Other examples are drugs or antibodies that prevent Lewy body formation and/or prevent the potential spread of ␣Syn from host to graft that are under development and could be used in combination with autologous grafting in both sporadic and familial patient groups [53,54]. Future studies could also investigate the effect of engineering ␣Syn null cells for transplantation, as it has been suggested that cells lacking ␣Syn may be resistant to synuclein pathology [26,55]. These developments could allow for autologous cell therapy and the associated benefits, while minimizing potential pathological effects on the grafted cells and ensuring their long-term function.…”

Section: Discussionmentioning

confidence: 99%

Grafts Derived from an α-Synuclein Triplication Patient Mediate Functional Recovery but Develop Disease-Associated Pathology in the 6-OHDA Model of Parkinson’s Disease

Shrigley

Nilsson

Mattsson

et al. 2021

JPD

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Background: Human induced pluripotent stem cells (hiPSCs) have been proposed as an alternative source for cell replacement therapy for Parkinson’s disease (PD) and they provide the option of using the patient’s own cells. A few studies have investigated transplantation of patient-derived dopaminergic (DA) neurons in preclinical models; however, little is known about the long-term integrity and function of grafts derived from patients with PD. Objective: To assess the viability and function of DA neuron grafts derived from a patient hiPSC line with an α-synuclein gene triplication (AST18), using a clinical grade human embryonic stem cell (hESC) line (RC17) as a reference control. Methods: Cells were differentiated into ventral mesencephalic (VM)-patterned DA progenitors using an established GMP protocol. The progenitors were then either terminally differentiated to mature DA neurons in vitro or transplanted into 6-hydroxydopamine (6-OHDA) lesioned rats and their survival, maturation, function, and propensity to develop α-synuclein related pathology, were assessed in vivo. Results: Both cell lines generated functional neurons with DA properties in vitro. AST18-derived VM progenitor cells survived transplantation and matured into neuron-rich grafts similar to the RC17 cells. After 24 weeks, both cell lines produced DA-rich grafts that mediated full functional recovery; however, pathological changes were only observed in grafts derived from the α-synuclein triplication patient line. Conclusion: This data shows proof-of-principle for survival and functional recovery with familial PD patient-derived cells in the 6-OHDA model of PD. However, signs of slowly developing pathology warrants further investigation before use of autologous grafts in patients.

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