July 25, 2024

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Gene-Engineered Stem Cells Show Promise in Improved Parkinson’s Disease Treatment

Gene-Engineered Stem Cells Show Promise in Improved Parkinson’s Disease Treatment



Gene-Engineered Stem Cells Show Promise in Improved Parkinson’s Disease Treatment

Parkinson’s Disease (PD), a complex neurodegenerative disorder and the second most common neurodegenerative disease worldwide after Alzheimer’s Disease (AD), affects approximately 1%-2% of individuals aged 65 and above.

With global aging populations, the prevalence of Parkinson’s disease is expected to significantly increase.

Currently, over 6 million people worldwide suffer from Parkinson’s disease, with approximately 60,000 new diagnoses each year. The loss of dopamine-producing neurons in the brain leads to motor and cognitive impairments, resulting in symptoms such as tremors, muscle stiffness, blurred consciousness, and dementia.

In recent years, research on using stem cells to treat Parkinson’s disease has made significant strides. Now, a groundbreaking study has yielded powerful results in terms of effectiveness without side effects for long-term treatment.

On December 5, 2023, researchers from Aarhus University in Denmark published a paper titled “Enhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells” in the journal Nature Communications.

The study utilized gene editing to knock out transcription factors GBX2 and CDX1/2/4 in pluripotent stem cells, creating lineage-restricted undifferentiated stem cells (LR-USCs) with enhanced capability to generate specific neurons—dopamine-producing neurons. In a rat model of Parkinson’s disease, this approach resulted in a more potent and sustained therapeutic effect.

Gene-Engineered Stem Cells Show Promise in Improved Parkinson's Disease Treatment

Stem cells, differentiating into specific neurons, provide a promising new avenue for treating Parkinson’s disease. However, current differentiation methods from human pluripotent stem cells (hPSC) into midbrain dopamine-producing (mesDA) neurons yield low purity when transplanted in vivo. This low purity poses a significant challenge in liver cell therapy for Parkinson’s disease, emphasizing the importance of achieving high-purity differentiation for effectively restoring the motor abilities of Parkinson’s patients.

In this study, the research team used gene knockout methods to restrict cell fate and prevent differentiation into non-midbrain dopamine-producing (mesDA) neurons, enhancing differentiation into mesDA neurons.

Specifically, they focused on the early developmental stage, identifying transcription factors—GBX2 and CDX1/2/4—that are crucial for these lineages when major lineage choices are made but are not necessary for mesDA fate.

Through inducing functional loss mutations in lineage-determining genes expressed in non-dopamine lineages, they generated stem cells that could be expanded in an undifferentiated pluripotent state and limited in their potential during differentiation, naming them lineage-restricted undifferentiated stem cells (LR-USCs).

Importantly, LR-USCs generated significantly more mesDA neurons under midbrain and hindbrain conditions in vitro and in vivo.

The team genetically engineered pluripotent stem cells by knocking out GBX2 and CDX1/2/4 to prevent them from differentiating into the wrong types of neurons. The newly modified stem cells exhibited a stronger ability to generate specific neurons—dopamine-producing neurons.

Moreover, the study further demonstrated that these gene-engineered stem cells improved motor recovery in a rat model of Parkinson’s disease. Experiments on rat models revealed that the quantity and purity of cultured stem cells are crucial for the treatment’s effectiveness and duration. This breakthrough in treating Parkinson’s disease opens up a potential new approach for patients.

Gene-Engineered Stem Cells Show Promise in Improved Parkinson's Disease Treatment

Professor Mark Denham, the lead author of the paper, stated that using our gene-engineered cells produced higher-purity midbrain dopamine-producing (mesDA) neurons. For patients, this could reduce the recovery time and decrease the risk of relapse and drug usage.

Our goal is to help patients move away from dependence on drug therapy, which requires high-purity dopamine-producing neurons. Building on this research, the next step is to advance our method into clinical trials.

Link to the Paper

Gene-Engineered Stem Cells Show Promise in Improved Parkinson’s Disease Treatment

(sourceinternet, reference only)


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