Contributions
Abstract: P579
Type: Poster Sessions
Abstract Category: Therapy - Neuroprotection and Repair
Chronic multiple sclerosis (MS) lesions contain significant numbers of quiescent oligodendrocyte precursors cells (OPCs). The failure of these OPCs to differentiate into mature oligodendrocytes and subsequently remyelinate neurons within MS lesions is believed to contribute to the progression of the disease. Therefore, one therapeutic strategy to address demyelination, and ultimately axonal loss, in multiple sclerosis is to stimulate OPC differentiation into mature OLs to enable remyelination.
We have developed a novel electro-crystallization method that produces clean-surfaced, faceted gold nanocrystals in aqueous suspension. Our previous work demonstrated the therapeutic value of oral administration of these gold nanocrystals (CNM-Au8) in the in vivo cuprizone and lysolecithin demyelination animal models. To further characterize the effect of CNM-Au8 on OPC differentiation, we conducted an in vitro RNAseq expression study using isolated, purified OPC cultures, with each treatment condition performed in triplicate. Here we show that 1 µg/mL and 10 µg/mL CNM-Au8 treatment of mouse OPCs in primary culture for 72 hours results in differential expression (DE) of genes involved in myelination. Markers of oligodendrocyte (OL) maturation such as MAG, MBP, GJC2, NKX6.2, and SOX10 mRNAs were elevated at least 2-fold over untreated vehicle controls. We conducted Multidimensional Scaling Analyses to examine distances between samples according to their gene expression profiles. These analyses demonstrated that CNM-Au8-treated OPC expression profiles were more similar to the expression profile of differentiated OLs treated with a promoter of OPC differentiation, triiodothyronine (T3), than to the profile of proliferating OPCs treated with platelet derived growth factor (PDGF). Furthermore, there was an enrichment of mRNA transcripts with gene ontology terms related to lipid metabolism uniquely present in the DE gene profile for CNM-Au8-treated OPCs. These included a panel of genes encoding proteins involved in long chain fatty acid synthesis, which is essential to the generation of lipids that comprise ~70% of myelin. In contrast, the DE gene profiles for the T3 and PDGF controls did not demonstrate enrichment in long chain fatty acid synthesis mRNAs. Taken together, these data demonstrate that treatment with CNM-Au8 promotes OPC differentiation and OL maturation. CNM-Au8 represents a promising potential remyelinating treatment for demyelinating disorders such as MS.
Disclosure: D.F., H.E.T., A.P.R., and S.D.M. have nothing to disclose. M.T.H., G.S.F., K.S.H., and M.G.M are full time employees of Clene Nanomedicine and as such receive salary and stock options. M.T.H. and M.G.M own stock in Clene.
Abstract: P579
Type: Poster Sessions
Abstract Category: Therapy - Neuroprotection and Repair
Chronic multiple sclerosis (MS) lesions contain significant numbers of quiescent oligodendrocyte precursors cells (OPCs). The failure of these OPCs to differentiate into mature oligodendrocytes and subsequently remyelinate neurons within MS lesions is believed to contribute to the progression of the disease. Therefore, one therapeutic strategy to address demyelination, and ultimately axonal loss, in multiple sclerosis is to stimulate OPC differentiation into mature OLs to enable remyelination.
We have developed a novel electro-crystallization method that produces clean-surfaced, faceted gold nanocrystals in aqueous suspension. Our previous work demonstrated the therapeutic value of oral administration of these gold nanocrystals (CNM-Au8) in the in vivo cuprizone and lysolecithin demyelination animal models. To further characterize the effect of CNM-Au8 on OPC differentiation, we conducted an in vitro RNAseq expression study using isolated, purified OPC cultures, with each treatment condition performed in triplicate. Here we show that 1 µg/mL and 10 µg/mL CNM-Au8 treatment of mouse OPCs in primary culture for 72 hours results in differential expression (DE) of genes involved in myelination. Markers of oligodendrocyte (OL) maturation such as MAG, MBP, GJC2, NKX6.2, and SOX10 mRNAs were elevated at least 2-fold over untreated vehicle controls. We conducted Multidimensional Scaling Analyses to examine distances between samples according to their gene expression profiles. These analyses demonstrated that CNM-Au8-treated OPC expression profiles were more similar to the expression profile of differentiated OLs treated with a promoter of OPC differentiation, triiodothyronine (T3), than to the profile of proliferating OPCs treated with platelet derived growth factor (PDGF). Furthermore, there was an enrichment of mRNA transcripts with gene ontology terms related to lipid metabolism uniquely present in the DE gene profile for CNM-Au8-treated OPCs. These included a panel of genes encoding proteins involved in long chain fatty acid synthesis, which is essential to the generation of lipids that comprise ~70% of myelin. In contrast, the DE gene profiles for the T3 and PDGF controls did not demonstrate enrichment in long chain fatty acid synthesis mRNAs. Taken together, these data demonstrate that treatment with CNM-Au8 promotes OPC differentiation and OL maturation. CNM-Au8 represents a promising potential remyelinating treatment for demyelinating disorders such as MS.
Disclosure: D.F., H.E.T., A.P.R., and S.D.M. have nothing to disclose. M.T.H., G.S.F., K.S.H., and M.G.M are full time employees of Clene Nanomedicine and as such receive salary and stock options. M.T.H. and M.G.M own stock in Clene.