A combined cell and gene therapy approach for homotopic reconstruction of midbrain dopamine pathways using human pluripotent stem cells

Current Status and Future Perspectives on Stem Cell-Based Therapies for Parkinson’s Disease

“…169 Among them, a more recent study by Clare Parish and colleagues demonstrated that homotopic transplantation of hESC-derived mDANs recapitulates long-distance, anatomically precise innervation of appropriate targets throughout the host brain, including robust striatal innervation when combined with forebrain GDNF delivery, leading to the restoration of motor functions in a rodent model of PD. 137 Despite the fact that controlling the expression of viral vectors to deliver ectopic GDNF levels in vivo has been elusive, this 'proof-of-principle' study highlights the promising potential of combining cell and gene therapy to provide an optimal therapeutic intervention for the effective treatment of patients with inherited parkinsonism. Therefore, to realize this potential, a more comprehensive assessment of the long-term impact of this combined therapy is required to ensure its safety and efficacy as a prospective therapeutic candidate for PD.…”

“…Several preclinical studies have shown functional recovery in animal models of PD with transplanted mDANs using different conditions (Table 2). 47,65,70,71,90,92,103,125,[130][131][132][133][134][135][136][137] The lesson learned from various previous studies using dopamine neurons derived from human fetal tissues or PSCs is that even a single round of transplantation could be sufficient for longterm survival and functional outcomes. 138 Although there is no current consensus on the optimal number of cells for treating humans, based on the findings from human fetal cell transplantation studies, approximately 40,000-80,000 TH + mDANs with a unidirectional axonal architecture of ≥ 3-5 cm in length and dopamine release of ≥ 7 ng/mg of tissue may be required to achieve meaningful clinical improvements in PD patients.…”

Single-cell transcriptomics reveals correct developmental dynamics and high-quality midbrain cell types by improved hESC differentiation

“…Progress in understanding the molecular logic and mechanisms controlling mDA neuron development has led to important developments in different areas of stem cell biology, including PD modeling, drug screening, and personalized therapeutics ( Caiazza et al., 2020 ), as well as PD cell replacement therapy ( Adler et al., 2019 ; Arenas et al., 2015 ; Doi et al., 2020 ; Kikuchi et al., 2017 ; Kim et al., 2021 ; Kirkeby et al., 2017 ; Moriarty et al., 2022 ; Schweitzer et al., 2020 ; Tao et al., 2021 ). mDA neurons are currently thought to derive from radial glia-like progenitor cells at the caudal and ventral end of the midbrain floor plate ( Bonilla et al., 2008 ; Ono et al., 2007 ).…”

Single cell transcriptomics reveals correct developmental dynamics and high-quality midbrain cell types by improved hESC differentiation

“…Progress in understanding the molecular logic and mechanisms controlling mDA neuron development has led to important developments in different areas of stem cell biology, including PD modeling, drug screening and personalized therapeutics (Caiazza et al, 2020), as well as PD cell replacement therapy (Adler et al, 2019; Arenas et al, 2015; Doi et al, 2020; Kikuchi et al, 2017; Kim et al, 2021; Kirkeby et al, 2017; Moriarty et al, 2022; Schweitzer et al, 2020; Tao et al, 2021). mDA neurons are currently thought to derive from radial glia-like progenitor cells at the caudal and ventral end of the midbrain floorplate (Bonilla et al, 2008; Ono et al, 2007).…”