Gustav Ceder, 29 October 2024
Photo: Jan Greune
In recent years, CRISPR technology has opened new horizons in genetics, biology, and medicine. One of the prominent researchers advancing this field is Professor Stefan Stricker, a Group Leader at the German Research Center for Environmental Health and a professor at Ludwig Maximilian University’s Biomedical Centre in Munich. He is part of the Regenerar Project, a consortium that aims to address some of the most pressing neurological diseases, such as stroke and Alzheimer’s, funded by the European Commission under the Horizon Europe research and innovation program.
It is anticipated that successful cell reprogramming in stroke survivors could lead to significant cost savings, with estimates suggesting up to 2 billion euros in annual savings across the EU. These savings reflect the reduced need for long-term care and rehabilitation as patients regain lost functions, underscoring the far-reaching societal benefits of regenerative brain therapies.Through this project, Stricker seeks to enhance our understanding of brain repair and cell reprogramming using CRISPR while employing spatial transcriptomics to deepen insight into the molecular changes at work.
CRISPR’s Expanding Possibilities: Beyond Gene Editing
When CRISPR technology first gained prominence, much of the attention focused on its ability to edit genes with high precision and efficiency. However, Stricker believes that CRISPR’s true potential extends far beyond merely altering DNA.
While genome editing is powerful, Stricker argues, “The real excitement lies in harnessing CRISPR for non-genetic modifications—using it not to introduce mutations, but to precisely control gene expression without altering the underlying DNA sequence.” Epigenetic engineering allows scientists to control which genes are turned on or off without making irreversible changes to the DNA sequence. This precision is particularly valuable when addressing diseases linked to complex processes like aging, environmental stress, and epigenetic memory. By manipulating gene expression, CRISPR can offer therapeutic benefits without the long-term risks associated with permanent genetic alterations.
Regenerar: Reprogramming the Brain with CRISPR
At the core of the Regenerar is an ambitious approach called neuronal reprogramming, which aims to convert non-neuronal cells, such as glial cells, into functioning neurons. Given the brain’s limited ability to regenerate lost neurons, this approach could unlock new treatments for neurodegenerative diseases.
“Early experiments from a number of pioneering labs have already shown that this neuronalreprogramming is possible, and we are optimistic that refining these methods could provide a powerful means to regenerate neurons in the patient lost to injury or disease,” says Stricker.
This concept of reprogramming is groundbreaking because it offers a way to regenerate neurons within the brain itself, eliminating the need for external cell transplants or stem cells.
However, there are major obstacles. One of the most significant challenges in applying CRISPR to the brain is overcoming the blood-brain barrier—a protective shield that prevents many treatments from reaching brain tissue. Regenerar addresses this by developing innovative delivery methods that can bypass the blood-brain barrier and allow CRISPR to target specific cells within the brain. This level of precision and control is made possible by a technique known as spatial transcriptomics.
The Critical Role of Spatial Transcriptomics
Spatial transcriptomics is one of the vital tools in the Regenerar project. Unlike traditional gene expression analysis, which provides an average of gene activity across many cells, spatial transcriptomics allows scientists to pinpoint gene expression at the level of individual cells and tissue regions. This is essential for understanding the fine-scale effects of CRISPR interventions on brain architecture.
“Spatial transcriptomics will be essential for us to accurately characterize the effects of our CRISPR treatments, particularly given the nature of non-genetic CRISPR approaches. Unlike permanent genetic modifications, these non-genetic CRISPR interventions are temporary, which means we need a reliable and comprehensive way to assess their impact within the brain over time. Spatial transcriptomics provides an ideal solution for this, as it allows us to not only measure gene expression but also map these changes within the precise anatomical context of the brain.”
By mapping gene activity spatially, the Regenerar team can gain a detailed picture of how CRISPR-induced changes play out in specific brain regions.
Single Technologies, a Swedish biotechnology company with roots at the KTH Royal Institute of Technology, and a key member of the Regenerar consortium, plays an important role in providing the spatial transcriptomics platform. Their 3D sequencing technology enables the Regenerar team to monitor CRISPR’s effects on cell identity, neuronal function, and tissue recovery with precision.
“This technology will be crucial in determining whether our CRISPR-based strategies for neuronal reprogramming and gene regulation are achieving the desired outcomes, both in terms of cell identity changes and functional recovery. As we develop these innovative tools, having a clear and detailed readout of their effects will be critical for refining our approaches and ensuring they can be safely and effectively applied in therapeutic settings, ”Stricker emphasizes.
Toward a New Era of Brain Therapies
The Regenerar Project represents an important step forward in the treatment of neurological diseases. By combining CRISPR’s reprogramming capabilities with technologies such as spatial transcriptomics, the project is laying the groundwork for therapies that could regenerate neurons and restore brain function in patients suffering from neurodegenerative conditions. This approach has potential not only to improve individual patient outcomes but also the healthcare systems as a whole.