Validation of Novel CSF1R Inhibitors for the Treatment of C9ORF72 FTD
Abstract
Frontotemporal degeneration (FTD) is a fatal neurodegenerative disease with no effective treatment, and it is an FY21 PRMRP Topic Area. The goal of our proposed project is to identify a candidate drug to advance toward clinical trials for the most common form of FTD called C9ORF72 FTD (5%-10% of cases) since it is caused by a mutation in a gene called C9ORF72. If successful, the short-term outcome of our project would be the selection of a candidate drug to move into clinical trials for C9ORF72 FTD or perform preclinical safety testing before evaluating in clinical trials. The long-term outcome of the study would be testing the drug’s efficacy in C9ORF72 FTD patients and possibly slowing or stopping disease progression. Developing a therapeutic for FTD directly aligns with an Area of Encouragement. Recent genetic studies and laboratory experiments have found that the immune cells of the brain play a surprisingly large role in FTD and related dementias. These brain-resident immune cells, or microglia, seem to be able to affect FTD disease progression to a large degree, but they seem to take on different forms that can either accelerate or slow neurodegeneration. These forms are not yet well-defined, nor is it clear which forms of microglia were protective or toxic to nerve cells. Thus, there is a pressing need to understand how microglia modulate neurodegeneration and leverage this knowledge for therapeutic benefit. To better understand the forms of microglia and their impact on nerve cells in C9ORF72 FTD, we derived C9ORF72 FTD patient nerve cells and microglia in the laboratory and studied them. We found that there were two populations of C9ORF72 FTD, one neurotoxic and the other neuroprotective. Furthermore, we found that blocking a specific microglial protein with a drug called a CSF1R inhibitor could shift the neurotoxic microglia to the neuroprotective state and stop neurodegeneration in the patient-derived nerve cells and mice with the C9ORF72 mutation. Unfortunately, the CSF1R inhibitor drug we used is not suitable for use in FTD patients since they would require long-term treatment and the drug causes liver toxicity if administered over long periods since it unintentionally blocks proteins other than CSF1R. There are other existing CSF1R inhibitors that have been shown to be safe in humans and are available for licensing from the pharma companies that made them. Since these are already known to be safe in humans, they could be directly and rapidly moved into a clinical trial to test efficacy and safety in C9ORF72 FTD. In addition, we have generated new CSF1R inhibitors with increased specificity for CSF1R, which should provide even better safety. The critical question we will address in the proposed study is to determine which of the existing or new CSF1R inhibitors is most efficacious in our laboratory and mouse models of C9ORF72 FTD. Once we determine this in our study, we will advance the most promising CSF1R inhibitor toward clinical testing for C9ORF72 FTD. To aid in this endeavor, the proposed study will also focus on developing methods for determining the correct dose of the drug in patients. If successful, our study will evaluate the efficacy of several existing and novel CSF1R inhibitors in laboratory models of C9ORF72 FTD, and we will disseminate these results to inform others who may be interested in this therapeutic approach. Ideally, we will identify a CSF1R inhibitor that shows strong efficacy in the laboratory experiments, and we will advance this into clinical trials for C9ORF72 FTD and perform additional preclinical safety testing first if necessary. If successful, in the long term we anticipate that our CSF1R inhibitor program could become the first disease-modifying treatment for FTD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210246
Entities
People
- Justin K Ichida
Organizations
- United States Army
- University of Southern California