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Genetic Rescue Reverses Microglial Activation in Preclinical Models of Retinitis Pigmentosa
- Publication Year :
- 2018
- Publisher :
- American Society of Gene & Cell Therapy, 2018.
-
Abstract
- Microglia cells (MGCs) play a key role in scavenging pathogens and phagocytosing cellular debris in the central nervous system and retina. Their activation, however, contributes to the progression of multiple degenerative diseases. Given the potential damage created by MGCs, it is important to better understand their mechanism of activation. Here, we explored the role of MGCs in the context of retinitis pigmentosa (RP) by using four independent preclinical mouse models. For therapeutic modeling, tamoxifen-inducible CreER was introduced to explore changes in MGCs when RP progression halted. The phenotypes of the MGCs were observed using live optical coherence tomography, live autofluorescence, and immunohistochemistry. We found that, regardless of genetic background, MGCs were activated in neurodegenerative conditions and migrated beyond the layers where they are typically found to the inner and outer segments, where degeneration was ongoing. Genetic rescue not only halted degeneration but also deactivated MGCs, regardless of whether the intervention occurred at the early, middle, or late stage of the disease. These findings suggest that halting long-term disease progression may be more successful by downregulating MGC activity while co-administering the therapeutic intervention.
- Subjects :
- 0301 basic medicine
Central nervous system
CX3C Chemokine Receptor 1
Context (language use)
Degeneration (medical)
Disease
03 medical and health sciences
Mice
0302 clinical medicine
Drug Discovery
Retinitis pigmentosa
Genetics
medicine
Animals
Humans
Molecular Biology
Pharmacology
Retina
Microglia
business.industry
Phosphoric Diester Hydrolases
Genetic Therapy
medicine.disease
Phenotype
Disease Models, Animal
Tamoxifen
030104 developmental biology
medicine.anatomical_structure
Cancer research
Molecular Medicine
Original Article
business
030217 neurology & neurosurgery
Retinitis Pigmentosa
Tomography, Optical Coherence
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....7bed3af6301e6308c4b84c55a6a1208c