Pleiotropic activity of systemically delivered angiogenin in the SOD1G93A mouse model. (1st May 2018)

• Record Type: Journal Article
• Authors: Crivello, Martin; O'Riordan, Saidhbhe L.; Woods, Ina; Cannon, Sarah; Halang, Luise; Coughlan, Karen S.; Hogg, Marion C.; Lewandowski, Sebastian A.; Prehn, Jochen H.M.
• Is Part Of: Neuropharmacology. Volume 133(2018)
• Page Start: 503
• Page End: 511
• Publication Date: 2018-05-01
• Subjects: Amyotrophic lateral sclerosis -- Preclinical study -- Neurotherapeutic -- Angiogenic factor -- Endothelium -- Motor function; ALS Amyotrophic Lateral Sclerosis -- PND post-natal day -- huANG human angiogenin -- ASMA alpha smooth muscle actin -- SMC smooth muscle cell -- GFAP glial fibrillary acidic protein -- NO nitric oxide; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2018.02.022
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Loss-of-function mutations in the angiogenin ( ANG ) gene have been identified in familial and sporadic ALS patients. Previous work from our group identified human ANG (huANG) to protect motoneurons in vitro, and provided proof-of-concept that daily intraperitoneal (i.p.) huANG injections post-symptom onset increased lifespan and delayed disease progression in SOD1 G93A mice. huANG's mechanism of action remains less well understood. Here, we implemented a preclinical in vivo design to validate our previous results, provide pharmacokinetic and protein distribution data after systemic administration, and explore potential pleiotropic activities of huANG in vivo. SOD1 G93A mice (n = 45) and non-transgenic controls (n = 31) were sex- age- and litter-matched according to the 2010 European ALS/MND group guidelines, and treated with huANG (1 μg, i.p., 3 times/week) or vehicle from 90 days on. huANG treatment increased survival and delayed motor dysfunction as assessed by rotarod in SOD1 G93A mice. Increased huANG serum levels were detectable 2 and 24 h after i.p. injection equally in transgenic and non-transgenic mice. Exogenous huANG localized to spinal cord astrocytes, supporting a glia-mediated, paracrine mechanism of action; uptake into endothelial cells was also observed. 1 μg huANG or vehicle were administered from 90 to 115 days of age for histological analysis. Vehicle-treated SOD1 G93A mice showed decreased motoneuron numbers and vascular length per ventral horn area, while huANG treatment resulted in improved vascular network maintenance and motoneuron survival. Our data suggest huANG represents a new class of pleiotropic ALS therapeutic that acts on the spinal cord vasculature and glia to delay motoneuron degeneration and disease progression. Highlights: IP huANG delivery increased survival and delayed motor dysfunction in SOD1 G93A mice. Pharmacokinetics after IP huANG delivery showed the protein accumulated in serum. huANG was taken up by lumbar spinal cord astrocytes and endothelial cells. huANG treatment counteracted motoneuron loss and vascular network regression. huANG represents a new class of pleiotropic neuroprotectants for the treatment of ALS.