Periodic Reporting for period 1 - MANTIS (Understanding the impact of DNA demethylation in Motor Neuron Disorders)
Periodo di rendicontazione: 2020-07-01 al 2022-06-30
The primary focus of this research is on motor neuron disorders (MND), including spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). These disorders are severe, with a major symptom being the degeneration of motor neurons. Motor neurons are essential for the central nervous system, responsible for transmitting signals from the brain to muscles throughout the body. When these neurons degenerate or die, it leads to muscle weakness, paralysis, and eventually can be life-threatening. A significant aspect of this MANTIS project is the investigation of DNA methylation, a biological process where a methyl group (a specific chemical structure) is added to DNA. This process significantly affects gene expression without changing the actual DNA sequence. In the context of MND, alterations in DNA methylation patterns have been observed, but the exact role and mechanisms of these changes are not well understood. Understanding these epigenetic changes (changes in gene expression caused by factors other than changes in the DNA sequence) is crucial because they could be key drivers in the progression of these diseases or potential targets for treatment.
The importance of this research for society cannot be understated. SMA and ALS, as part of MNDs, pose significant challenges not only to the individuals directly affected but also to their families, healthcare systems, and society at large. These diseases often lead to a rapid decline in the quality of life, as patients lose their ability to perform everyday tasks and become increasingly dependent on others. This results also in substantial economic burdens due to medical costs and loss of productivity.
Moreover, these diseases currently have limited treatment options. In the case of SMA, the currently approved treatment achieves survival milestone but complete muscle function restoration remains limited. Understanding the underlying mechanisms, especially the role of DNA methylation in these diseases, could pave the way for the development of new, more effective treatments.
The project has several ambitious but crucial objectives centered on understanding and potentially manipulating the process of DNA methylation to treat or prevent MNDs.
Firstly, the project aims to define precisely how DNA methylation and demethylation regulate gene expression in SMA. This involves mapping the specific changes in DNA methylation patterns and understanding how these changes affect the functioning of genes involved in motor neuron health and survival. By identifying these patterns, researchers hope to pinpoint specific genes or pathways that could be targeted in treatments.
Secondly, the research focuses on the role of TET enzymes, which are involved in converting methylated cytosines (5mC) in DNA to hydroxymethylated cytosines (5hmC), a change that can influence gene expression. The interaction of these enzymes with motor neuron pathology, specifically in relation to the Survival of Motor Neuron (SMN1) protein, is of particular interest. SMN1 is crucial in SMA, as its deficiency leads to motor neuron death. Understanding how TET enzymes interact with SMN1 could reveal new therapeutic targets or strategies.
Finally, the project seeks to establish the potential of using targeted demethylation as a therapeutic strategy. This involves using advanced technologies like CRISPR/Cas9 to specifically alter DNA methylation at targeted genomic locations. The goal is to reverse or correct the disease-related epigenetic profiles, potentially restoring normal gene function and rescuing motor neuron health.
The importance of this research for society cannot be understated. SMA and ALS, as part of MNDs, pose significant challenges not only to the individuals directly affected but also to their families, healthcare systems, and society at large. These diseases often lead to a rapid decline in the quality of life, as patients lose their ability to perform everyday tasks and become increasingly dependent on others. This results also in substantial economic burdens due to medical costs and loss of productivity.
Moreover, these diseases currently have limited treatment options. In the case of SMA, the currently approved treatment achieves survival milestone but complete muscle function restoration remains limited. Understanding the underlying mechanisms, especially the role of DNA methylation in these diseases, could pave the way for the development of new, more effective treatments.
The project has several ambitious but crucial objectives centered on understanding and potentially manipulating the process of DNA methylation to treat or prevent MNDs.
Firstly, the project aims to define precisely how DNA methylation and demethylation regulate gene expression in SMA. This involves mapping the specific changes in DNA methylation patterns and understanding how these changes affect the functioning of genes involved in motor neuron health and survival. By identifying these patterns, researchers hope to pinpoint specific genes or pathways that could be targeted in treatments.
Secondly, the research focuses on the role of TET enzymes, which are involved in converting methylated cytosines (5mC) in DNA to hydroxymethylated cytosines (5hmC), a change that can influence gene expression. The interaction of these enzymes with motor neuron pathology, specifically in relation to the Survival of Motor Neuron (SMN1) protein, is of particular interest. SMN1 is crucial in SMA, as its deficiency leads to motor neuron death. Understanding how TET enzymes interact with SMN1 could reveal new therapeutic targets or strategies.
Finally, the project seeks to establish the potential of using targeted demethylation as a therapeutic strategy. This involves using advanced technologies like CRISPR/Cas9 to specifically alter DNA methylation at targeted genomic locations. The goal is to reverse or correct the disease-related epigenetic profiles, potentially restoring normal gene function and rescuing motor neuron health.
This project aims to unravel the unknown pathophysiological mechanism of Spinal Muscular Atrophy (SMA), with a particular focus on the roles of DNA methylation and its impact on the disease. Our primary objective has been to unravel the roles of two crucial DNA modifications, 5mC and 5hmC, in SMA's development. To achieve this, we utilized a recent method capable of distinguishing between different types of DNA methylation. In a significant advancement, our research in a mouse model of SMA revealed a marked change in 5mC and 5hmC level and distribution, indicating a disruption in the typical pattern of DNA demethylation. This discovery is critical as it connects these DNA modifications to vital biological processes, such as calcium signaling and lipid metabolism, implicating potential pathways that contribute to SMA's pathology.
Parallel to this exploration, we have further analyzed the potential therapeutic interventions. Our innovative approach, employing modified CRISPR/Cas9 technology, is designed to precisely target DNA demethylation to specific genes. Early experiments in cell cultures have been promising, suggesting that this technique might enhance motor neuron survival. We are now poised to extend this therapy to mouse models of SMA, with the hope of opening new therapeutic avenues.
Our project has significantly advanced the understanding of SMA, especially in terms of epigenetic regulation. The insights we have gained, coupled with our ongoing development of novel therapeutic strategies, provide new avenue to improve treatments. This project offers fresh hope in boosting treatment efficacy for MND, potentially transforming the lives of those affected.
Parallel to this exploration, we have further analyzed the potential therapeutic interventions. Our innovative approach, employing modified CRISPR/Cas9 technology, is designed to precisely target DNA demethylation to specific genes. Early experiments in cell cultures have been promising, suggesting that this technique might enhance motor neuron survival. We are now poised to extend this therapy to mouse models of SMA, with the hope of opening new therapeutic avenues.
Our project has significantly advanced the understanding of SMA, especially in terms of epigenetic regulation. The insights we have gained, coupled with our ongoing development of novel therapeutic strategies, provide new avenue to improve treatments. This project offers fresh hope in boosting treatment efficacy for MND, potentially transforming the lives of those affected.
This project represents a significant leap in our understanding of Spinal Muscular Atrophy (SMA). Our studies have confirmed the pivotal role of DNA methylation in the disease's development and progression. A major effort has been our development to refine a method to distinguish between different types of DNA methylation (5mC and 5hmC). This modified technique is not only crucial for deeper analysis into SMA's epigenetic mechanisms, particularly hydroxymethylation, but also has broad applications in studying other motor neuron diseases. Furthermore, we have associated changes in DNA methylation patterns to disruptions in key biological processes like calcium signaling and lipid metabolism, offering new insights into SMA's pathogenesis. Additionally, our exploration of the relationship between SMN protein deficiency and TET enzyme activity in DNA demethylation provides a novel perspective on the molecular aspects of the disease.
Moving forward, we aim to further validate the potential of targeted DNA demethylation as a therapeutic strategy. Utilizing modified CRISPR/Cas9 technology for site-specific demethylation, we hope to open new avenues for treatment. Our ultimate goal is a comprehensive understanding of epigenetic regulation in SMA and validating the effectiveness of targeted DNA demethylation in animal models.
The socio-economic impact of our project is promising. Enhancing our understanding of SMA and developing novel therapeutic strategies could lead to considerable improvements in patient care and reductions in healthcare costs. Moreover, our findings have wider societal implications, extending to other neurodegenerative and genetic diseases. The techniques and insights we have uncovered could be pivotal in studying various conditions where epigenetics play a role, potentially revolutionizing our approach to these debilitating motor neuron diseases.
Moving forward, we aim to further validate the potential of targeted DNA demethylation as a therapeutic strategy. Utilizing modified CRISPR/Cas9 technology for site-specific demethylation, we hope to open new avenues for treatment. Our ultimate goal is a comprehensive understanding of epigenetic regulation in SMA and validating the effectiveness of targeted DNA demethylation in animal models.
The socio-economic impact of our project is promising. Enhancing our understanding of SMA and developing novel therapeutic strategies could lead to considerable improvements in patient care and reductions in healthcare costs. Moreover, our findings have wider societal implications, extending to other neurodegenerative and genetic diseases. The techniques and insights we have uncovered could be pivotal in studying various conditions where epigenetics play a role, potentially revolutionizing our approach to these debilitating motor neuron diseases.