Periodic Reporting for period 4 - NSC-Reconstruct (Novel Strategies for Cell-based Neural Reconstruction)
Reporting period: 2024-01-01 to 2024-12-31
Debilitating and incurable age-associated neurodegenerative diseases are on the rise worldwide as a result of our continuously increasing life expectancy. The focus of the project was on cell-based repair and neural circuit reconstruction for the treatment of neurodegenerative diseases such as Parkinson’s disease (PD), Huntington’s Disease (HD) and cortical injuries. We developed strategies to repair complex cellular networks and therefore we expect this work will have implications for an even wider number of brain conditions, such as stroke and trauma. In summary, NSC-Reconstruct (NSCR) aimed at four overarching goals:
(i) develop cellular products, reprogramming methods and research tools with broad potential for brain repair;
(ii) develop novel strategies for cell-based repair to pave the way for the treatment of major neurodegenerative and traumatic diseases;
(iii) achieve integration and reconstruction of neural circuit using transplants of diverse subtypes of stem cell-derived neurons;
(iv) translate and commercialize new cell and gene products, research tools and therapies for clinical trials and market approval.
(i) develop cellular products, reprogramming methods and research tools with broad potential for brain repair;
(ii) develop novel strategies for cell-based repair to pave the way for the treatment of major neurodegenerative and traumatic diseases;
(iii) achieve integration and reconstruction of neural circuit using transplants of diverse subtypes of stem cell-derived neurons;
(iv) translate and commercialize new cell and gene products, research tools and therapies for clinical trials and market approval.
NSCR activities led to the following results within the four overarching goals:
(i) We have created new tools to modify genes and viral delivery methods to develop improved cell types for future medical treatments. Our team has focused on enhancing the potential of stem cell-derived dopamine neurons for PD, refining their growth, transplantation, and interaction with their surroundings for better treatment outcomes. We also established a method to produce another type of brain cell, cholinergic neurons, which were successfully tested in animal models. New imaging technologies now allow us to study transplanted neurons in 3D, improving our understanding of how they develop and function. A cutting-edge sequencing method was introduced to precisely classify different dopamine neuron types. Additionally, we advanced techniques to directly reprogram brain cells, which could help restore key brain circuits in diseases like HD.
(ii) To develop novel strategies for cell-based repair, we have worked on improving how stem cell-derived neurons grow, function, and integrate into diseased brains. Our research explored how these cells interact with their environment and how targeted genetic tools can help control their activity. We also studied how the immune system responds to these cells to find ways to reduce rejection. By combining transplantation experiments, single-cell genetic analysis, and advanced viral vector screening tools, we gained valuable knowledge on maximizing the therapeutic benefits of these neurons and improving their long-term survival.
(iii) Our goal is to repair brain damage by replacing lost neurons and restoring neuronal circuits. We showed that transplanted human stem cells can develop into different types of brain cells like neurons and astrocytes. Depending on the combination of cell types in the transplant, they can form specific types of dopamine neurons. We also demonstrated that stem cells taken from blood can integrate into damaged brain tissue and form new synapses. Further studies confirmed that transplanted cortical neurons mature properly, and optogenetic tests showed they actively participate in brain functions, reinforcing their potential for treating brain injuries and diseases.
(iv) During this project, several new innovations were developed, leading to multiple patents and commercial products. Of the 15 innovations with commercial potential, some are still being developed, while others have already reached the market. These include a quality control tool for dopamine-producing cells and a new platform for advanced microscope imaging. Additionally, a newly identified marker for isolating dopamine-producing cells was sold to the industry, and a respective patent has been filed.
(i) We have created new tools to modify genes and viral delivery methods to develop improved cell types for future medical treatments. Our team has focused on enhancing the potential of stem cell-derived dopamine neurons for PD, refining their growth, transplantation, and interaction with their surroundings for better treatment outcomes. We also established a method to produce another type of brain cell, cholinergic neurons, which were successfully tested in animal models. New imaging technologies now allow us to study transplanted neurons in 3D, improving our understanding of how they develop and function. A cutting-edge sequencing method was introduced to precisely classify different dopamine neuron types. Additionally, we advanced techniques to directly reprogram brain cells, which could help restore key brain circuits in diseases like HD.
(ii) To develop novel strategies for cell-based repair, we have worked on improving how stem cell-derived neurons grow, function, and integrate into diseased brains. Our research explored how these cells interact with their environment and how targeted genetic tools can help control their activity. We also studied how the immune system responds to these cells to find ways to reduce rejection. By combining transplantation experiments, single-cell genetic analysis, and advanced viral vector screening tools, we gained valuable knowledge on maximizing the therapeutic benefits of these neurons and improving their long-term survival.
(iii) Our goal is to repair brain damage by replacing lost neurons and restoring neuronal circuits. We showed that transplanted human stem cells can develop into different types of brain cells like neurons and astrocytes. Depending on the combination of cell types in the transplant, they can form specific types of dopamine neurons. We also demonstrated that stem cells taken from blood can integrate into damaged brain tissue and form new synapses. Further studies confirmed that transplanted cortical neurons mature properly, and optogenetic tests showed they actively participate in brain functions, reinforcing their potential for treating brain injuries and diseases.
(iv) During this project, several new innovations were developed, leading to multiple patents and commercial products. Of the 15 innovations with commercial potential, some are still being developed, while others have already reached the market. These include a quality control tool for dopamine-producing cells and a new platform for advanced microscope imaging. Additionally, a newly identified marker for isolating dopamine-producing cells was sold to the industry, and a respective patent has been filed.
After many years of preclinical work, stem cell-based cell replacement therapies for neurological disorders have progressed beyond the lab bench and are now entering clinical trials in several countries. These first-generation stem cell therapies consist of single-cell-type products aimed to either replace or provide trophic support to a dying population of endogenous neurons. Our ambition was to move beyond the current state-of-the-art and work towards goal-oriented, improved second-generation cell therapy products with more advanced properties, clinical relevance and commercial potential. NSCR made significant progress towards impacting health care systems, strengthen the European (bio)medical industry and boost European competitiveness in the field by offering innovative, efficient and cost-effective regenerative stem cell-based therapies for chronic and debilitating diseases where, today, there is very little to offer in terms of effective treatments. In fact, our restorative strategies have the potential to result in an entirely new approach to treatment of a broader range of chronic and debilitating brain injury caused by neurodegeneration or trauma that promises to increase the quality of life for a large number of affected individuals, with obvious economic benefits to our societies. Cell therapies could lead ultimately to allow the patients to live a fuller life and potentially make all current anti-PD therapies redundant.