Intravenously Administered, Retinoid Activating Nanoparticles Increase Lifespan and Reduce Neurodegeneration in the SOD1G93A Mouse Model of ALS

David X Medina; Eugene P Chung; Collin D Teague; Robert Bowser; Rachael W Sirianni

doi:10.3389/fbioe.2020.00224

Intravenously Administered, Retinoid Activating Nanoparticles Increase Lifespan and Reduce Neurodegeneration in the SOD1^G93A Mouse Model of ALS

Front Bioeng Biotechnol. 2020 Mar 27:8:224. doi: 10.3389/fbioe.2020.00224. eCollection 2020.

Authors

David X Medina^{1

2}, Eugene P Chung², Collin D Teague², Robert Bowser¹, Rachael W Sirianni^{2

3}

Affiliations

¹ Gregory W. Fulton ALS Center, Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ, United States.
² Barrow Brain Tumor Research Center, Barrow Neurological Institute, Phoenix, AZ, United States.
³ Vivian L. Smith Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, TX, United States.

Abstract

Dysregulation of the retinoic acid (RA) signaling pathway is observed in amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Here, we investigated the therapeutic potential of retinoid activation via the RA receptor β (RARβ) in the SOD1 ^G93A mouse model of ALS. Our approach utilized the RARβ agonist adapalene, which we previously found to be neuroprotective in vitro. Adapalene, like most retinoids, is poorly water soluble, which has thus far prevented effective drug delivery in vivo. To address this challenge, we encapsulated adapalene within nanoparticles (Adap-NPs) composed of poly(lactic acid)-poly(ethylene glycol) (PLA-PEG). Our data demonstrate that intravenous administration of Adap-NPs robustly activates retinoid signaling in the CNS. Chronic administration of Adap-NPs resulted in improved motor performance, prolonged lifespan, and neuroprotection in SOD1 ^G93A mice. This study highlights retinoid signaling as a valuable therapeutic approach and presents a novel nanoparticle platform for the treatment of ALS.

Keywords: amyotrophic lateral sclerosis (ALS); drug delivery; nanoparticle; neurodegeneration and neuroprotection; retinoic acid signaling.