Dopamine producing organoids for therapy of Parkinson’s Disease

Researchers at the University Medical Center in Göttingen, Germany, have developed a method to produce special brain organoids called "dopamine-producing neuronal organoids" (d-NOs). These organoids have been shown to release dopamine at levels that are effective for biological processes. This method is ideal for the production of an advanced therapy medicinal tissue-engineered product (ATMP-TEP) for clinical use in Parkinson's disease. Furthermore, the invention provides a method for producing d-NOs for use in disease modelling, drug screening and drug development.

Challenge

Patients with Parkinson's disease suffer from a progressive decline in dopamine production. The main pathological feature is the degeneration of dopaminergic neurons in the substantia nigra of the midbrain, leading to a dopamine deficiency in the human brain. The current state of therapy is the stimulation of dopamine receptors by natural ligands (dopamine) or receptor agonists (e.g. pramipexole, rotigotine). However, these pharmacological treatments only control symptoms for about 10 years and are associated with numerous side effects such as dyskinesia, psychotic phases, orthostatic disturbances, arrhythmias, sleep disturbances, impulse control disorders.
The introduction of human pluripotent stem cells (e.g. embryonic stem cells (ESC) and induced pluripotent stem cells (iPS)) and their differentiation into neurons, including dopaminergic neurons, has opened the door to their use as a scalable cell therapy. However, low maturation and dopaminergic activity, as well as limited retention after injection into the brain, remain unresolved issues with ESC and iPS cell approaches.

Our Solution

Dopamine-producing neuronal organoids (d-NOs) are prepared from an undifferentiated, homogeneous population of human iPSC. The invention describes a robust and versatile method for producing an Advanced Therapy Medicinal Product-Tissue Engineered Product (ATMP-TEP) for clinical use. For example, d-NOs can be injected into specific brain regions using clinical stereotactic injection techniques with a 1.6-2 mm biopsy needle. D-NOs can be generated from hypoimmune iPSCs to reduce or even eliminate the need for immunosuppression. In addition, d-NOs are also suitable for disease modeling (e.g. alpha synuclein-related dopaminergic neuron loss), drug screening and drug development, particularly when PSCs are derived from patients with PD-causing mutations or engineered to carry known or suspected PD mutations or disease modifiers.

Fig. 1 shows bright field images of a d-NO over 30 days of development (Bar = 1 mm). After suspension in a defined collagen hydrogel, the cells are subjected to stage-specific differentiation stimuli. This process can be seamlessly automated and scaled up to produce the desired number of organoids for in vivo dopamine release. Source: DE102025111075.1.

Advantages

• robust and versatile method for making brain organoids that produce dopamine (d-NOs),
• made from human pluripotent stem cells using cutting-edge tissue engineering,
• process can be easily automated and scaled up,
• d-NOs may integrate better after implantation due to complex regulation of dopaminergic neurons by related excitatory and inhibitory neurons,
• d-NOs can be maintained in culture for extended periods,
• d-NOs can be shipped to the point-of-care at room temperature without loss of dopamine release,
• superior model for drug development and screening (functional neuronal network).

Fig. 2: Schematic of a d-NO plated in a well of a multi-electrode array (MEA) plate. D-NOs consist of functionally interconnected GABAergic, glutamatergic and cholinergic neurons and glial cells. Thus, d-NOs show a complex regulation of dopaminergic neurons by related excitatory and inhibitory neurons, suggesting control mechanisms for effective dopamine production. Source: DE102025111075.1.

Fig. 3: Immunofluorescence analysis of a day 60 d-NO (initial casting volume: 12.5 µl). As demonstrated, the d-NO axons (Neurofilament, NF, green), floor plate cells (FOXA2, red) and dopaminergic neurons (Thyrosine hydrolase, TH, white) have been formed. Source: DE102025111075.1.

Applications

• new tissue-based therapy for Parkinson's disease,
• dopamine-producing neuronal organoids for disease modelling, drug screening and drug development.

Development Status

The new method has been successfully established in a laboratory setting, resulting in brain organoids that possess fully functional neuronal networks. The method has been streamlined for the efficient production of dopamine.

Fig. 4: Dopamine ELISA on day 62 d-NOs compared with a control brain organoid (BENO, not optimized for dopamine production). Organoids were analyzed by dopamine ELISA (Abnova). Statistical analysis by unpaired t-test or Mann-Whitney test depending on normality *p<0.05. Dopamine content in pmol/organoid (left) and in ng/ml (right) in a sample consisting of 3 organoids. Source: DE102025111075.1.

Patent Status

We have filed a priority patent application (Applicant: Georg-August-Universität Göttingen public law foundation, University Medicine (UMG)).

Contact

Dr. Stefan Uhle
Patent & Innovation Manager Biotechnology
E-Mail: This email address is being protected from spambots. You need JavaScript enabled to view it.
Tel: +49 551 30724 154
Reference: BioC-2569-UMG

Tags: Surgery, Implants, Research tools, Therapy, Life science