Establishing the Neuroprotective Potential of C9orf72 Hypermethylation in Repeat Expansion-Caused ALS
Abstract
ALS is a complex and devasting neurodegenerative disease, which origin has not been fully elucidated yet. Even in the case of ALS patients with known genetic causes, there is a lot of variability in both disease progression and symptom severity. This indicates that even if subjects carry genetic mutations that have been shown to cause ALS, there are other mechanisms that dictate how severely the disease will affect them. In addition to the genetic mutations, some patients, in which disease is significantly less severe, show a substantial increase in a type of epigenetic modifications that affect how the mutated gene manifests; this type of modification is called DNA methylation and the gene of interest in this proposal is C9orf72. Up to today, a large repeat expansion in this C9orf72 gene is the most common genetic cause for both ALS and frontotemporal dementia (FTD), known as C9ALS/FTD. A few years ago, the investigator leading this proposal generated multiple mouse models aiming to mimic what happens in human patients with this type of C9orf72 mutation. One of the transgenic animal models, which contains large human C9orf72 repeats, showed high resemblance to C9ALS/FTD. Interestingly, not all mice developed the same degree of deficits (cellular and behavioral) and, similarly to what has been documented in C9ALS/FTD patients, mice also displayed different levels of C9orf72 methylation. Importantly, the mice with higher methylation were the ones showing less prominent signs of the disease. These observations led us to propose that the increase in methylation can be the reason behind a milder C9ALS/FTD. Thus, this project aims to determine whether we can use editing tools to precisely change the level of C9orf72 methylation and test the corresponding effects using cellular and mouse models of ALS. If successful, the ultimate goal of this project is to design a therapeutic strategy that would increase the methylation of the C9orf72 in order to prevent severe ALS and FTD. Since currently there is no treatment that can prevent disease initiation and progression, such therapeutic strategy will definitely improve the quality of life of individuals with C9ALS/FTD as well as their families and caregivers. This proposal delineates the first several steps required to achieve this goal. Moreover, the influence of epigenetic factors (e.g., DNA methylation) in ALS etiology are far from being completely understood. It is therefore possible that besides C9ALS, other forms of ALS are also affected by changes in their methylation status. Thus, they could also benefit from the findings of this project as the tools being developed in this proposal can easily be applied to other ALS-relevant genes. In addition, this project will establish whether the opposite strategy, namely, decreasing methylation, leads to worsening of the studied outcomes; there is added value in this experiment as it can lead to the generation of better ALS models with robust phenotypes. Such models could be used to facilitate and promote drug screenings and development of new therapies, by us and other researchers in the field. Being an innovative project, it is difficult to foresee what risks will associate with such a therapeutic strategy. The experiments, to be performed in mice, will provide clues on its safety in addition to effectivity. Although this project is at a very early stage, we are using patient-derived cellular models, a humanized mouse model as well as tools that can easily be translated to accelerate its clinical development if successful. Also, the lead investigator has years of experience in therapeutic development and has already been involved in clinical trials for ALS in collaboration with biotech companies and clinicians, aiming to test his early work on other approaches like antisense oligonucleotide treatment. In conclusion, we are pursuing a completely new line of work in the design of therapies that can stop or even p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310196
Entities
People
- Qiang Zhu
Organizations
- United States Army
- Van Andel Institute