A new treatment for stroke that reduces brain damage and accelerates the brain’s natural healing tendencies in animal models has been developed by researchers at the University of Georgia’s Regenerative Bioscience Center and ArunA Biomedical, a UGA startup company.
The research team, led by UGA professor Steven Stice and Nasrul Hoda of Augusta University, created a treatment called AB126 using extracellular vesicles (EV), fluid-filled structures known as exosomes, which are generated from human neural stem cells.
Able to completely cloak itself within the bloodstream, this type of regenerative EV therapy appears to be the most promising in overcoming the limitations of many cell therapies-with the ability for exosomes to carry and deliver multiple doses-as well as the ability to store and administer treatment. Small in size, the tiny tubular shape of an exosome allows EV therapy to cross barriers that cells cannot.
Stice, Georgia Research Alliance Eminent Scholar and D.W. Brooks Distinguished Professor in the College of Agricultural and Environmental Sciences, said:
“This is truly exciting evidence, because exosomes provide a stealth-like characteristic, invisible even to the body’s own defenses. When packaged with therapeutics, these treatments can actually change cell progression and improve functional recovery."
Following the administration of AB126, the researchers used MRI scans to measure brain atrophy rates in preclinical, age-matched stroke models, which showed an approximately 35 percent decrease in the size of injury and 50 percent reduction in brain tissue loss - something not observed acutely in previous studies of exosome treatment for stroke.
[caption id=“attachment_94503” align=“aligncenter” width=“680”] NSC EVs outperform MSC EVs in the murine embolic stroke model and indicate acute benefits may be modulated by augmenting the systemic immune response.
One hour after stroke induction either free In-111 or labeled EVs (b, left and right, respectively) were administered into mice via tail vein injection and analyzed by SPECT.
EVs were present in the infarct region 1 h after injection (b, red circles, left brain panels), but were largely cleared by 24 h (b, red circles, right brain panels).
Systemic presence in the lungs, liver, and spleen are in agreement with other EV biodistribution studies (b, body panels).
Based on rapid clearance, animals received three doses of EVs (MSC EV, NSC EV, or vehicle control; N = 12/group), at 2, 14, and 28 h after TE-MCAO, (as outlined in a).
Neurological deficit 48 h post-TE-MCAO (c) indicated that animals that received MSC EVs were indistinguishable from controls, while NSC EV evaluation trended toward significance (p = 0.055).
Adhesive tape test indicated improved somatosensory function after NSC EV treatment compared to either MSC EV or control (d)
Acute effects on neural tissue were analyzed by 2,3,5-triphenyltetrazolium Chloride (TTC) differentiated metabolically active (live, red) and inactive (dead, colorless) tissue indicated significantly decreased injury and infarct following NSC EV treatment (e, f)
Credit: Robin L. Webb, et al. CC-BY.[/caption]
Outside of rodents, the results were replicated by Franklin West, associate professor of animal and dairy science, and fellow RBC members using a porcine model of stroke - the only one of its kind in the U.S.
Based on these pre-clinical results, ArunA Biomedical plans to begin human studies in 2019, said Stice, who is also chief scientific officer of ArunA Biomedical.
“Until now, we had very little evidence specific to neural exosome treatment and the ability to improve motor function,” said Stice. “Just days after stroke, we saw better mobility, improved balance and measurable behavioral benefits in treated animal models."
ArunA recently unveiled advances to the company’s proprietary neural cell platform for the production of exosome manufacturing. Today, ArunA’s manufacturing process positions the company to produce AB126 exosomes at a scale to meet early clinical demand.
The company has plans to expand this initiative beyond stroke for preclinical studies in epilepsy, traumatic brain and spinal cord injuries later this year.
“Over 700 drugs have failed in stroke clinical trials, an unprecedented rate thought to be attributed in part to limited and isolated testing often solely in “young” rodent models and focusing on a single secondary injury mechanism. Here, extracellular vesicles (EVs), nanometer-sized cell signaling particles, were tested in a mouse thromboembolic (TE) stroke model.
Neural stem cell (NSC) and mesenchymal stem cell (MSC) EVs derived from the same pluripotent stem cell (PSC) line were evaluated for changes in infarct volume as well as sensorimotor function. NSC EVs improved cellular, tissue, and functional outcomes in middle-aged rodents, whereas MSC EVs were less effective. Acute differences in lesion volume following NSC EV treatment were corroborated by MRI in 18-month-old aged rodents.
NSC EV treatment has a positive effect on motor function in the aged rodent as indicated by beam walk, instances of foot faults, and strength evaluated by hanging wire test. Increased time with a novel object also indicated that NSC EVs improved episodic memory formation in the rodent.
The therapeutic effect of NSC EVs appears to be mediated by altering the systemic immune response. These data strongly support further preclinical development of a NSC EV-based stroke therapy and warrant their testing in combination with FDA-approved stroke therapies.”
Webb, R.L., Kaiser, E.E., Scoville, S.L. et al. Human Neural Stem Cell Extracellular Vesicles Improve Tissue and Functional Recovery in the Murine Thromboembolic Stroke Model Transl. Stroke Res. (2017). https://doi.org/10.1007/s12975-017-0599-2
Top Image: Robin L. Webb, et al. CC-BY. Ipsilateral hemisphere atrophy in NSC EV-treated mice relative to non-treated mice at 30 days.