Revolutionising Neurodegenerative Disease Treatment: Immunotherapy and Advanced Stem Cell Techniques
What drives the progression of neurodegenerative diseases like ALS, Alzheimer’s, and MS?
Unraveling the mechanisms of neuroinflammation is at the heart of Prof. Bob Harris’s research at the Karolinska Institutet. His team is pioneering new therapeutic approaches by targeting microglial activity and harnessing advanced stem cell techniques. Their goal is to transform treatment strategies for these debilitating conditions.
Neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease (AD), and chronic Multiple Sclerosis (MS) are marked by a common culprit: neuroinflammation. This inflammation is driven by the chronic activation of microglia, the brain’s resident immune cells, and begins as a protective mechanism. However, when prolonged, it is a cause of destructive cytotoxicity and neurodegeneration. We spoke with Prof. Bob Harris, the leader of the research group Applied Immunology and Immunotherapy at the Centre for Molecular Medicine, Karolinska Institutet. He and his research group are focused on understanding the underlying mechanisms of chronic neurodegenerative diseases and translating this knowledge into practical treatment solutions. Given that no effective treatments currently exist for neurodegenerative diseases, their objective is to develop novel therapeutic platforms to address this significant unmet medical need.
A brain on fire
Normally, microglia play a role in maintaining brain health. They release factors that promote neuronal survival and restoration of neuronal function after injury. But perpetual activation prevents them from executing their physiological and beneficial functions. Chronically activated microglia release harmful cytokines, oxygen radicals, and other molecules that impair neuronal function and threaten cell survival. Additionally, the essential phagocytic function of microglia- their ability to clear out cellular waste and misfolded proteins— is compromised in neurodegenerative diseases. This failure results in the buildup of toxic aggregates in the central nervous system (CNS), which in turn triggers further microglial activation, creating a vicious cycle of inflammation and damage. For example, in ALS, overactive microglia gather around dying motor neurons. Their numbers directly correlate with the extent of neuron damage.
Similarly, in MS, activated microglia are found at sites of demyelination, interacting with T and B cells through factors released behind a closed blood-brain barrier (BBB). Scientific evidence shows that activated microglia and monocytes can have both beneficial and detrimental effects at different disease stages. This means that approaches that modulate microglial activity can potentially be used in the treatment of a wide range of neurodegenerative diseases. “Strategies that modulate microglial activity and clearance function are thus promising for treatment of a range of neurodegenerative diseases” explains Prof. Harris.
Putting the
Fire Out Before Rebuilding
Immunotherapy, which involves modulating immune cells to reduce or stop inflammatory disease processes, has revolutionized the treatment of certain cancers and autoimmune diseases.
However, currently, there is no effective immunotherapy for neurodegenerative diseases. According to Prof. Harris, before a tissue can be healed, the inflammatory process driving the disease must be halted.
“It is impossible to rebuild a house that is still burning, so first the fire must be put out – only then will rebuilding be efficient. The same principle applies to immunotherapy – but in a perfect world the therapeutic intervention would not only reduce the neuroinflammation but also activate the regenerative processes,” he explains.
Unruly cells can be trained to behave
“If we think about how macrophages and microglia can be activated, it is like a Yin-Yang, with one activation state, represented by white, being helpful, while the other, represented by black, is harmful. In disease situations there is a dominance of the harmful cells over the helpful cells,” explains Bob Harris. His research team has developed a microglia microglia/ macrophage cell therapy protocol. A large number of beneficial cells have been specifically activated by exposure to a specific combination of cytokines. This activation successfully induced an immunosuppressive M2 phenotype. By transferring M2 microglia and macrophages into mouse models with Type 1 diabetes and Multiple Sclerosis, they prevented or significantly reduced disease severity. In
their MS model, known as experimental autoimmune encephalomyelitis (EAE), the team transferred M2 microglia intranasally into mice. This resulted in a significant reduction in inflammatory responses and less demyelination in the central nervous system (CNS). Similarly, the team conducted a cell transfer of M2 macrophages into a mouse model for Type 1 diabetes. Remarkably, a single transfer protected over 80% of treated mice from
Folding DNA to create novel parcels for delivery
Though DNA origami nanobiologics are a relatively new technology, they have become a prime focus in biomedical research due to their capability to deliver pharmaceuticals with precision, coupled with the natural biocompatibility of DNA. Additionally, the ability to engineer these structures into complex, combinational biomolecular formations enhances their appeal. The DNA
“Strategies that modulate microglial activity and clearance function are thus promising for treatment of a range of neurodegenerative diseases.”
developing diabetes for at least three months. This was achieved even when the transfer was conducted just before the clinical onset of the disease. The team found that harmful cells recovered from the blood of patients with multiple sclerosis can be retrained using their activation protocol. Once retrained, these cells were able to modulate the function of other harmful cells in cell essays. “Our activation protocol (IL-10/ IL- 4/TGFb) has been successfully used by other researchers in other disease settings and to reduce rejection of transplants, clearly demonstrating its widespread applicability,” says Bob Harris.
origami technique involves using hundreds of short DNA strands to create a single-stranded DNA scaffold, which is then intricately folded into specific three-dimensional nanoscale shapes, akin to the art of folding paper into delicate origami shapes. The development of scaffold DNA routing algorithms now allows for the precise control of nanoscale structures through an automated design process. Modern DNA origami designs, which use open wireframe structures, offer the most flexibility. This technology can incorporate existing FDA-approved drugs, repurposing them for conditions like ALS. Prof. Harris and his collaborators developed a DNA origami construct in which DNA was made into
cylindrical rods, in which a repurposed cancer drug (Topetecan) was loaded. The surface of the construct was modified to express a carbohydrate molecule that would specifically bind to receptors on microglia. “It’s like packing a present in a parcel box, wrapping it in paper, and adding an address and postage. We are able to specifically deliver immunomodulatory drugs to the harmful microglia, forcing them to be less harmful” says Bob Harris. The MS symptoms were significantly improved through a single treatment. In their research, they demonstrated that topoisomerase 1 (TOP1) inhibitors, like topotecan, reduce inflammatory responses in microglia and reduce neuroinflammation in vivo providing a promising therapeutic strategy for neuroinflammatory diseases. Their lab continues to develop a range of DNA origami constructs, each loaded with different therapeutic cargoes aimed at modulating specific functions of microglia and macrophages.
Harnessing a mother’s protective instincts
Amniotic epithelial cells (AECs) are a type of stem cell derived from human placenta that exhibit strong immunomodulatory properties, contributing to the safe development of the baby. They have the ability to differentiate into a variety of cell types, which makes them very versatile. The clinical use of human amniotic membranes has been recognized for over a century, with the first application in treating burned and ulcerated skin reported in 1910. Instead of using the entire amniotic membrane, more long-term and enhanced effects have been achieved by using isolated AECs. At Karolinska Institutet, a protocol has been developed to recover AECs from the innermost layer of the amniotic sac in discarded placental tissue, and these cells display potent immunomodulatory and immunosuppressive properties. After AEC transplantation, there is no host rejection in either mice or humans. These cells have shown disease-modifying properties in various conditions, including ischemia, bronchopulmonary dysplasia, and liver
diseases, primarily by reducing inflammatory damage. AECs are currently undergoing testing in several clinical trials. In a mouse model of Alzheimer’s disease, intrathecal administration of AECs significantly reduced amyloid plaque burden in the brain, possibly through enhanced microglial phagocytosis.
The Harris lab is currently testing protocols for the adoptive transfer of immunomodulatory AECs in different experimental models of neurodegeneration to stimulate anti-inflammatory and restorative responses in the degenerating CNS. Their unpublished results indicate that a single injection of cells could significantly reduce the severity of an experimental model of multiple sclerosis. ”AECs are a special type of stem cell with particular properties that make them excellent candidates for cell therapy in a wide range of neurodegenerative diseases,” says Bob Harris.
Why 3 is better than 1
As neurodegenerative diseases involve a multitude of cell types including both immune cells and CNS cells, multiple immunotherapeutic approaches will likely be necessary to target these different cell types. There is also significant variability in the disease progression among patients with the same neurodegenerative condition. “Having developed these three separate therapeutic principles, we are now testing them in different combinations in our experimental neurodegenerative disease models. There will likely be an optimal combination that allows different targeting of microglia at different phases of the disease process”, explains Bob Harris.
The Harris lab has a clear vision to Make A Difference, not only by increasing scientific knowledge within the field of neurodegenerative diseases but also by improving the life quality of patients with these incurable diseases. “Meeting neurodegenerative disease patients, their carers, and families is a humbling experience, but it gives us such energy to conduct our research,” he concludes.
NOvel ImmUNOTHeRAPIeS FOR NeURODegeNeRATIve DISeASeS
Project Objectives
There are currently no effective treatments for any neurodegenerative disease, and this remains a major unmet medical need. The origin and progression of many neurodegenerative diseases are still not clearly understood, and basic research is required to provide a platform for the development of novel and effective therapies. The objective of our research programme is to address this unmet need by developing multiple therapeutic platforms.
Project Funding
This project is funded by the Swedish Medical Research Council, Alltid Litt Sterkere, Neurofonden, Ulla-Carin Lindquist Stiftelse for ALS Research, Karolinska Institutet Doctoral funding.
Project Collaborators
• Prof Björn Högberg, Karolinska Institutet
• Assoc Prof Roberto Gramignoli, Karolinska Institutet
Contact Details
Professor Bob Harris
CMM L8:04, Karolinska University Hospital Visionsgatan 18, S-171 76 Stockholm, Sweden
e: robert.harris@ki.se
W: https://ki.se/en/research/groups/ immunotherapy-robert-harris-research-group W: https://www.cmm.ki.se/research-groupsteams/robert-harris-group-2/
Bob Harris is Professor of Immunotherapy in Neurological Diseases and leads the research group Applied Immunology and Immunotherapy at the Centre for Molecular Medicine, a designated translational medicine center at Karolinska Institutet. They conduct a strongly interconnected research program aimed at using knowledge gained from projects in basic science to applications in a clinical setting, with a focus on understanding why chronic neurodegenerative diseases of the nervous system occur, and then devise ways to prevent or treat them.
