The RNA-Binding Protein Zfp106 as a Therapeutic Target for Suppression of Amyotrophic Lateral Sclerosis
Abstract
Amyotrophic lateral sclerosis (ALS) comprises a deadly and debilitating group of neurodegenerative disorders and affects approximately 30,000 people in the United States. There are approximately 5,000 new ALS cases diagnosed each year in the U.S., and 90% of patients die within 5 years of diagnosis. ALS is a highly variable disease, but all forms share the loss of motor neurons, the nerves that connect to muscles, as a common feature. Many of the most common forms of ALS are caused by abnormal processing and handling of ribonucleic acid (RNA) molecules inside motor neurons. Unfortunately, there are no effective therapies currently available for treating ALS caused by dysregulated RNA metabolism. A recently described protein, Zfp106, exhibits the remarkable ability to suppress the neurotoxicity, cellular death, and neurodegeneration characteristic of ALS caused by mishandling of RNA inside motor neurons in cell and animal models of ALS. Thus, Zfp106 appears to function as a natural suppressor of RNA-mediated neurodegeneration. Therefore, the overall objective of this proposal is to develop strategies to leverage the natural ability of Zfp06 to suppress ALS and to create molecular therapeutics based on this remarkable ability. As a first step to developing Zfp106 into a therapeutic molecule, it is essential to identify the regions of Zfp106 that confer its anti-neurodegenerative properties. The goal of this part of the research is to identify a small fragment of Zfp106 that is sufficient to suppress neurodegeneration and that is small enough to fit into a viral delivery vehicle such that it can be introduced into motor neurons for the purpose of expressing high enough levels of Zfp106 to suppress neurodegeneration. A second goal of this research proposal is to determine how the human Zfp106 gene is normally produced in motor neurons using preclinical mouse models to inform the regulation of the human gene. The ultimate goal of this part of the research is to use an advanced molecular approach, referred to as CRISPR activation, to increase the expression of the endogenous human Zfp106 gene in motor neurons in patients to suppress ALS. This work has the potential to help a wide range of ALS patients, including all of those who have ALS resulting from dysregulated RNA processing and metabolism utilizing a natural repressor of ALS. Although delivery of these advanced therapies will still be several years away, the studies in this research proposal will establish the proof-of-concept that Zfp106 can be used as a therapeutic and will develop the tools and strategies necessary to advance this work to the preclinical stage. If successful, the specific strategy of increasing expression of Zfp106 would be groundbreaking and could have a major impact as a new therapeutic target; more generally, the strategy of delivering or increasing expression of natural suppressors of neurodegeneration using viral delivery vectors will be revolutionary and could have broad application for treating many forms of ALS caused by dysregulation of RNA processing and metabolism.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210591
Entities
People
- Brian L Black
Organizations
- United States Army
- University of California, San Francisco