Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects the motor neurons, leading to progressive muscle weakness and eventual paralysis. One of the critical steps in developing effective therapies for ALS is identifying novel drug targets. These targets are essential because they serve as the foundation for new treatments that could potentially halt or reverse the progression of the disease.
Target ALS is dedicated to funding research to uncover these novel targets. In this blog, we cover exciting progress presented at our Annual Meeting by global researchers focused on identifying drug targets, both by utilizing innovative techniques or exploring uncharted avenues of study.
The Nervous System: Deepening our Understanding
Understanding the biology of the central nervous system, which includes the brain and spinal cord, is essential in ALS research. Scientists continue to experiment with innovative techniques to deepen our understanding of how ALS affects the nervous system and identify potential drug targets.
Big Data Unlocks Novel Targets
A collaborative effort between prestigious institutions, including the University of Pennsylvania and the Weizmann Institute of Science, is leveraging big data to uncover genetic changes in specific cell types affected by ALS. The group is utilizing high-throughput screens, a technique that allows the researchers to rapidly test thousands of samples, to narrow down potential drug targets with precision. Two promising targets have emerged from this work. The first is a protein found only in astrocytes, the supportive cells in the brain and spinal cord. Increasing the activity of this protein has been shown to protect motor neurons in ALS. The second target is specific to motor neurons; reducing its levels in cell cultures has demonstrated protective effects. These findings are significant as they highlight the potential of targeting specific cell types within the nervous system to develop effective therapies.
Masking a Drug Target
Innovative approaches are also being explored to protect synapses, the connections between neurons that are critical for signals to be transmitted throughout the body, from elimination. Researchers from the Swiss Federal Institute of Technology and Ludwig-Maximilians University have discovered a drug target on synapses that sends an “eat me” signal to immune cells. By developing a protein to mask this target, they can prevent immune cells from eliminating the synapses. This method has shown promising results in mouse models, protecting the spinal cord and improving motor function.
The Immune System: Exploring the Role of T Cells in ALS
The immune system’s role in ALS is gaining attention, especially the function of T cells. Researchers are exploring different aspects of T cell involvement in ALS, inspired by breakthroughs in cancer treatment.
Reactivating Exhausted T Cells
Dr. Jenna Gregory of the University of Aberdeen is investigating methods to reactivate exhausted T cells in ALS patients. T cell exhaustion occurs when the increased T cell response leads to suppression of their activity. Dr. Gregory’s research focuses on a protein that suppresses T cell activation, elevated in ALS models and human tissue. By developing an antibody to block this protein, she aims to restore normal T cell function. Additionally, she is exploring the protein’s potential as a biomarker for ALS, which could aid in early detection and treatment.
Balancing T Cell Subtypes
Dr. Caroline Ingre from the Karolinska Institute is studying the balance of T cell subtypes in ALS. She discovered that patients with slow-progressing ALS have higher levels of regulatory T cells and lower levels of effector T cells compared to fast-progressing patients. This finding led to a clinical trial aimed at restoring the balance of these T cell populations using an antibody. The trial’s results, expected within a year, will provide valuable insights into the therapeutic potential of this approach.
An ALS “Organ Chip” to Model Disease
Dr. Mai Yamakawa of UCLA is creating an ALS “organ chip” to model the disease more accurately than traditional mouse models. This innovative tool uses stem cells and peripheral blood mononuclear cells from ALS patients to recreate a microcosm of their nervous systems and immune responses. The organ chip allows researchers to test candidate therapeutics and biomarkers reliably, bridging the gap between preclinical research and clinical trials.
The Digestive System: Exploring the Microbiome and Lipids
Target ALS encourages scientists from various fields to engage in ALS research, both expanding the breadth of experts focused on ALS and exploring uncharted areas of study for potential breakthroughs. Recent studies suggest that other systems in the body, such as the digestive system, may also play a role in ALS.
The Role of Gut Health in ALS
Dr. Aaron Burberry of Case Western Reserve University is investigating the gut microbiome’s impact on ALS. Dr. Burberry’s research indicates that gut microbiota differences between ALS patients and healthy individuals could influence disease progression. By breeding mice without the C9orf72 gene, he replicated an ALS population and observed significant health differences based on their environment. Mice bred at a Harvard University laboratory were unhealthy and died early, while those bred at a germ-free facility at the Broad Institute were healthy and lived longer. This disparity was linked to differences in their gut microbes. Dr. Burberry is now identifying probiotics that could potentially become part of ALS treatment regimens, aiming to leverage “good” microbes to prevent disease development.
Lipids and ALS
Another promising area of research focuses on lipids. A consortium of scientists from Ulm University, Université de Strasbourg, and the University of Alberta is studying the role of lipids in ALS. They found a correlation between a specific lipid and the size of the hypothalamus, the brain region controlling appetite, which is smaller in ALS patients. Building on a German clinical study that demonstrated improved survival with a high-caloric, fat-rich diet, the consortium plans to launch a larger study to further explore the benefits of such a diet and the role of lipids as potential biomarkers or therapeutic targets.
A Collaborative Effort Towards Hope
The quest to identify novel drug targets for ALS is a complex and collaborative effort involving researchers from diverse scientific backgrounds. By exploring various systems in the body and employing cutting-edge techniques, scientists are uncovering new targets that hold promise for future therapies. Target ALS’s commitment to funding and supporting this research is driving significant progress in the fight against ALS.
As we continue to expand our understanding of ALS and identify new drug targets, the hope for effective treatments becomes more tangible. The efforts of the scientific community bring us closer to transforming ALS from a terminal diagnosis to a manageable condition.
