Albee Messing, VMD, PhD – Slide of the Week

Albee Messing, VMD, PhD – Slide of the Week

Title: Elimination of GFAP from the Central Nervous System (CNS) in Mouse Models of Alexander Disease

Legend: A single injection of antisense oligonucleotides into the lateral ventricle of adult mice leads to nearly complete elimination of GFAP throughout the CNS (GFAP quantitation by ELISA). Mice given saline as a control show the natural elevation of GFAP that occurs in the mutant mice. Mutants (red), wild type (black), 8 weeks post-treatment.

Citation: Hagemann, T.L., Powers, B., Mazur, C., Kim, A., Wheeler, S., Hung, G., Swayze, E., and Messing, A. (2018). Antisense suppression of GFAP as a treatment for Alexander disease. Ann Neurol 83, 27-39. PMID: 29226998

Abstract: Objective: Alexander disease is a fatal leukodystrophy caused by autosomal dominant gain-of-function mutations in the gene for glial fibrillary acidic protein (GFAP), an intermediate filament protein primarily expressed in astrocytes of the CNS. A key feature of pathogenesis is over-expression and accumulation of GFAP, with formation of characteristic cytoplasmic aggregates known as Rosenthal fibers. Here we investigate whether suppressing GFAP with antisense oligonucleotides could provide a therapeutic strategy for treating Alexander disease. Methods: In this study we use GFAP mutant mouse models of Alexander disease to test the efficacy of antisense suppression and evaluate the effects on molecular and cellular phenotypes and non-cell autonomous toxicity. Antisense oligonucleotides were designed to target the murine Gfap transcript, and screened using primary mouse cortical cultures. Lead oligonucleotides were then tested for their ability to reduce GFAP transcripts and protein, first in wild-type mice with normal levels of GFAP, and then in adult mutant mice with established pathology and elevated levels of GFAP. Results: Nearly complete and long-lasting elimination of GFAP occurred in brain and spinal cord following single bolus intracerebroventricular injections, with a striking reversal of Rosenthal fibers and downstream markers of microglial and other stress related responses. GFAP protein was also cleared from cerebrospinal fluid, demonstrating its potential utility as a biomarker in future clinical applications. Finally, treatment led to improved body condition and rescue of hippocampal neurogenesis. Interpretation: These results demonstrate the efficacy of antisense suppression for an astrocyte target, and provide a compelling therapeutic approach for Alexander disease.

About the Lab: Albee Messing’s lab is focused on understanding developmental and pathological aspects of glial cell biology in the nervous system of the mouse, with a particular focus on astrocytes and their major intermediate filament protein, GFAP. Main strategies involve genetic manipulation of glial gene expression using transgenic techniques, and gene targeting in embryonic stem cells to generate mutant strains of mice. Current projects address a variety of topics, such as regulation of gene expression, and the role of GFAP mutations and accumulation in the pathogenesis of AxD. A major effort is devoted to devising novel therapeutic strategies for treatment of this disorder, and identifying biomarkers to permit monitoring severity or progression of the disease.

Slide of the Week Archives