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modeling the protein aggregation and toxicity characteristic application, including batch-to-batch variability, limited
of late-onset PD. They identified a small molecule, BAG956, scalability, and high-throughput screening constraints
capable of mitigating α-synuclein aggregation-induced due to heterogeneity in organoid size and structure. 73,74
toxicity in hiPSC-derived midbrain DA neurons and hMOs. Additionally, organoids often exhibit developmental
OASIS offers a promising platform to investigate disease immaturity, lacking key aging-related features necessary for
pathology and therapeutic interventions in a controlled modeling late-onset diseases such as PD and AD. The absence
and physiologically relevant context. 68 of a functional microenvironment, including vasculature,
Zhu et al. developed an innovative drug screening immune cells, and the blood-brain barrier, further limits
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platform utilizing electrochemical cytometry with nano-tip their ability to predict drug penetration, metabolism, and
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microelectrodes to analyze vesicular storage in hMOs. This toxicity accurately. Furthermore, the dense 3D structure of
platform allows for precise measurement of neurotransmitter organoids can hinder drug diffusion, leading to inconsistent
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storage in a high-throughput manner, providing valuable exposure across models. High costs, technical expertise
insights into the underlying cellular mechanisms of PD. requirements, and a lack of standardized protocols also
Their study revealed a significant reduction in vesicular pose significant barriers to their integration into preclinical
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storage of neurotransmitters in young-onset PD iPSC- drug development. Despite these limitations, advances in
derived hMOs, which correlated with the upregulation bioprinting, microfluidic platforms, artificial intelligence-
of α-synuclein. Importantly, treatment with amantadine, driven analysis, and clustered regularly interspaced short
a clinically used drug for PD, was found to alleviate this palindromic repeats-based disease modeling continue to
vesicular storage defect, demonstrating the potential of enhance organoid technology, making them increasingly
this model for assessing therapeutic efficacy. Additionally, valuable for precision medicine and next-generation drug
phorbol 12-myristate 13-acetate, a promising candidate discovery.
for PD treatment, also showed potential in restoring 4. Organoid transplantation: A promising
vesicular function, further validating this electrochemical
cytometry-based platform as an effective tool for screening approach for PD treatment
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PD drugs. These findings highlight the capability of this Organoids show the ability to replicate key aspects of tissue
innovative platform to replicate key features of PD and its architecture, cell-type composition, and organ functionality
utility in identifying novel therapeutic candidates with the while retaining the benefits of simplified and accessible
potential to target early disease mechanisms. cell culture models. As a result, organoid technology
Several studies, not originally designed for high- holds significant potential as a promising alternative to
throughput drug screening, have utilized hMOs PD traditional cell and tissue transplantation. Moreover, recent
models and identified promising therapeutic compounds. studies have demonstrated that these in vitro cultured
For instance, in patient-derived brain organoids, organoids can be successfully transplanted into multiple
2-hydroxypropyl-β-cyclodextrin was found to not only animal models, including dogs, mice, and others. 78-80 In
enhance the proportion of DA neurons but also boost PD studies, several research groups have also reported
neuronal autophagy and mitophagy capacity. Similarly, preliminary findings using hMOs in mouse models.
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in LRRK2 G2019S mutant hMOs, reduced expression of To evaluate the feasibility of transplanting hMOs for PD
nuclear receptor-related 1 protein (Nurr1) led to lower treatment, Zheng et al. generated organoids from hiPSCs
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Nurr1 and TH mRNA levels compared to isogenic controls. and transplanted them into the striatum of 6-OHDA-
However, treatment with a newly designed Nurr1 agonist lesioned immunodeficient mice to assess the safety and
effectively restored these expression levels, underscoring efficacy of the graft. Twelve weeks post-transplantation,
the therapeutic potential of Nurr1 activation in PD. they observed that hMOs survived and matured into
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Additionally, one study utilizing an α-synuclein aggregation midbrain DA neurons in the striatum of PD mice. This
assay identified four candidates—entacapone, tolcapone, transplantation resulted in a reversal of motor function and
phenazopyridine hydrochloride, and zalcitabine—that the establishment of bidirectional connections with native
inhibited α-synuclein seeding activity in real-time brain target regions, with no signs of tumor formation or
quaking-induced conversion assays. These findings were graft overgrowth. Moreover, another study using a similar
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further validated in SNCA triplication organoids, where the approach also demonstrated that the transplanted cell
compounds significantly reduced α-synuclein aggregation survived, differentiated efficiently into DA neurons, and
and alleviated mitochondrial dysfunction. 72 integrated into the neural network of the PD mice. The
Organoid models hold great promise for drug discovery, differentiated human DA neurons were capable of releasing
offering human-derived, physiologically relevant platforms dopamine, and 4 weeks post-transplantation, the motor
for studying disease mechanisms and therapeutic responses. function of the mice showed significant improvement.
However, several challenges hinder their widespread These findings suggest that cell therapy using iPSC-derived

Volume 1 Issue 2 (2025) 7 doi: 10.36922/OR025040006