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-218are required in mature motor neurons. In preliminary experiments we have found that the reporter encoded by tg-miR-218-rep detects miR-218 in SOD1(G93A) mice (n=2), whereas miR-218 activity is reduced in ALS caused by Fig4 mutation (n=1). This result needs to be confirmed, but suggests that different forms of ALS may impact miR-218 function differently. We are now testing whether miR-218 function is perturbed in TDP43(Q331K) and PFN1(C71G) mouse models. We have hypothesized that elevated miR-218 may be protective against some ALS-causing mutations. To test this 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 miR-218 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
- Sep 01, 2019
- Accession Number
- AD1106782
Entities
People
- Samuel L Pfaff
Organizations
- Salk Institute for Biological Studies