microRNA Replacement Therapy for ALS Treatment
Abstract
Genetic studies have identified a number of mutations associated with ALS, but it remains unclear if motor neuron diseases arise from a spectrum of different disorders or whether the disease pathways converge on the same molecular targets. If a treatment can be identified that targets a common feature of ALS shared by different forms of the disease this would provide the most benefit to the widest group of patients. In addition to having multiple genetic underpinnings, a further aspect of ALS that remains unclear is why mutations in genes that are expressed in many tissues cause relatively selective motor neuron degeneration. It has been speculated that defects in RNA biogenesis and microRNA function may be linked to ALS, and that this could be a feature that is shared by different forms of the disease. We recently discovered a lower motor neuron-specific microRNA called miR-218, which we showed is a critical genetic regulator needed for motor neuron survival (see Amin et al., 2015; paper included in supporting documentation). This discovery raises the possibility that miR-218 processing and/or function in motor neurons may be impacted by ALS-causing mutations or environmental factors. Our discovery of a motor neuron-specific microRNA is also consistent with the possibility that motor neurons, more so than other neuron types, might be particularly sensitive to disruption of pathways involved in microRNA processing. These findings have led us to speculate that increasing miR-218 levels in ALS will restore regulatory control and homeostasis to afflicted motor neurons resulting in improved cell survival and disease outcome. We hypothesize that restoration of miR-218 levels in motor neurons would positively affect ALS outcomes. In this proposal, we will: (1) build a detailed understanding of miR-218 expression and the molecules it regulates in motor neurons, and will link it to activity of miR-218 in the organism; (2) perform preliminary tests on Relay218 candidates (mRNAs that are indirectly regulated by miR-218) as therapeutic agents in mouse models of ALS; and (3) study whether miR-218 mimic molecules improve ALS symptoms in mouse models. Although risky because miR-218 is a novel target, this proposal represents an opportunity to develop an entirely new class of drugs for ALS patients that may provide benefits to many forms of the disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810120
Entities
People
- Samuel L Pfaff
Organizations
- Salk Institute for Biological Studies
- United States Army