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Business Update
NurOwn®-Derived Exosomes Show Promise in COVID-19 ARDS
On January 20, 2021, BrainStorm Cell Therapeutics, Inc. (NASDAQ:BCLI) announced the publication of results from a preclinical study that evaluated NurOwn-derived exosomes in a mouse model of acute respiratory distress syndrome (ARDS) (Kaspi et al., 2021). The publication, entitled “MSC-NTF (NurOwn®) exosomes: a novel therapeutic modality in the mouse LPS-induced ARDS model”, described results showing that treatment with intratracheal administration of NurOwn-derived exosomes results in a statistically significant reduction in the lung disease severity score and improvements in a number of other ARDS markers, including lung function, fibrin, neutrophils, and blood oxygenation.
ARDS results in the small blood vessels of the lung leaking fluid that fills up the alveoli, thus preventing proper oxygen exchange (Stevens et al., 2018). There are many causes of ARDS, including infections (e.g., pneumonia), severe burns, pancreatitis, inhalation of smoke or chemicals, or other serious illnesses, including COVID-19. An excessive inflammatory response appears to be involved in the pathogenesis of ARDS (Li et al., 2019). Current treatment options involve supportive care while the lungs heal, which involves oxygen therapy supplied through a ventilator. There are no pharmacological treatments specifically for ARDS and approximately 40% of hospitalized patients die from it (Siegel et al., 2020).
In this preclinical study, exosomes derived from both bone marrow mesenchymal stem cells (MSCs) and neurotrophic factor secreting MSCs (MSC-NTF; NurOwn) were studied for their effectiveness in a lipopolysaccharide (LPS)-induced ARDS model (Chen et al., 2010). Exosomes are nano-sized extracellular vesicles that are secreted by various cells, including MSCs, and are responsible for cell-cell communication through delivery of miRNA, mRNA, lipids, and proteins (Yanez-Mo et al., 2015). Exosomes can be administered in a number of different ways, including intratracheally, and have numerous advantages over traditional cell therapy including low immunogenicity, high stability, no potential for differentiation, and enhanced tissue penetration. Evaluation of the exosomes produced for this study showed similarity between MSC and MSC-NTF-derived exosomes in regards to median size (146 nm vs. 114 nm) and expression of CD44 and CD29 (MSC markers). Exosomes are thought to exhibit their therapeutic effect through immunomodulation, and while there was a similar level of interferon gamma (IFN-γ) inhibition (lower left figure), MSC-NTF-derived exosomes were statistically significantly more effective at inhibiting tumor necrosis alpha (TNF-α) secretion compared to MSC-derived exosomes (lower right figure, P<0.05) from activated peripheral blood mononuclear cells (PBMCs).
The following figure on the left shows a timeline for the LPS-induced ARDS model, in which LPS is administered followed by treatment at 3, 24, and 48 hours with all animals sacrificed at 72 hours. The following figure on the right shows that both MSC-derived and MSC-NTF-derived exosomes increased blood oxygen saturation compared to administration of LPS and placebo.
LPS treatment resulted in significant lung damage 72 hours after administration. Lung damage was quantified according to the criteria from the American Thoracic Society (Matute-Bello et al., 2011), which includes assessing alveolar wall thickness, presence of fibrin, and neutrophil count along with a total severity score. The following figure shows that treatment with MSC-NTF-derived exosomes significantly lowered the total severity score along with alveolar wall thickness, fibrin accumulation, and neutrophil accumulation. MSC-derived exosomes did not significantly affect any of those parameters but did somewhat reduce neutrophil count.
In order to understand the differences between MSC-NTF and MSC-derived exosomes the researchers examined the protein content of each type of exosome from three different donors. They focused on proteins that had previously been shown to be upregulated in MSC-NTF cells compared to naïve MSCs, proteins that were reported in the exosome database ExoCarta (Keerthikumar et al., 2016), and were reported to have a positive effect in models of ARDS. Four proteins met these criteria and were subsequently analyzed by ELISA. The following figure shows that AREG was 16-fold more prevalent in MSC-NTF exosomes compared to MSC-exosomes (P=0.013) and LIF was >3-fold more abundant in MSC-NTF exosomes compared to MSC exosomes (P=0.015).
Conclusion
The data published by BrainStorm shows the potential application of their exosome technology as a treatment for ARDS, which in the near term could be utilized in the battle against coronavirus and in the long term could be used for ARDS caused by other ailments, for which there continues to be a pressing need for better therapies. While the company is excited about the exosome technology, the main focus continues to be on identifying a regulatory path forward for NurOwn in ALS. We anticipate an update on this process in the next few months. With no changes to our model the valuation remains at $10.
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