MicroRNA Replacement Therapy for ALS Treatment
Abstract
The overall goal of this grant is to determine whether ALS affects the expression and/or function of a critical microRNA-218(miR-218) using mouse genetics. We have generated a novel mouse line that detects miR-218 activity (tg-miR-218-rep)and used it to establish that we can induce deletion of miR-218 in adult motor neurons using a novel intercross of the following animals: miR-218-1 -/- ; miR-218-2 CreER/fl; tg-miR-218-rep +/-. This inducible system for eliminating miR-218 will help to establish for the first time whether both alleles of miR-218 are required in mature motor neurons. We have determined that our reporter detects levels of miR-218 in SOD1(G93A) and PFN1(C71G) mice at end-stage, as well as in advanced disease TDP43(Q331K) and aging, asymptomatic BAC500 mice. The sensitivity of our reporter gene suggests that motor neurons maintain detectable levels of miR-218 at late stages of disease. We have hypothesized that elevatedmiR-218 may be protective against some ALS-causing mutations. To test this hypothesis, we have generated a new self-complementing retroAAV virus carrying miR-218 that will be injected into ALS mouse models. Finally, we have tested and identified a miR218 mimic molecule using cell culture screens. This modified oligonucleotide can be used as an alternative approach to increase miR-218 in ALS.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2021
- Accession Number
- AD1174930
Entities
People
- Samuel L Pfaff
Organizations
- Salk Institute for Biological Studies