AI Article Synopsis
- Methylmalonic aciduria cblB type is a severe metabolic disorder caused by a deficiency in the ATP:cob(I)alamin adenosyltransferase enzyme, leading to poor treatment outcomes.
- Researchers have successfully generated hepatocyte-like cells (HLCs) from both healthy and MMAB-induced pluripotent stem cell lines to test the effects of pharmacological chaperones (PCs).
- Treatment with PCs combined with vitamin B increased enzyme activity and reduced methylmalonic acid levels in MMAB cells, demonstrating the potential of this HLC model for future drug testing and development.
Article Abstract
Methylmalonic aciduria cblB type (MMA cblB type, MMAB OMIM #251110), caused by a deficiency in the enzyme ATP:cob(I)alamin adenosyltransferase (ATR, E.C_2. 5.1.17), is a severe metabolic disorder with a poor prognosis despite treatment. We recently described the potential therapeutic use of pharmacological chaperones (PCs) after increasing the residual activity of ATR in patient-derived fibroblasts. The present work reports the successful generation of hepatocyte-like cells (HLCs) differentiated from two healthy and two MMAB induced pluripotent stem cell (iPSC) lines, and the use of this platform for testing the effects of PCs. The MMAB cells produced little ATR, showed reduced residual ATR activity, and had higher concentrations of methylmalonic acid compared to healthy HLCs. Differential proteome analysis revealed the two MMAB HCLs to show reproducible differentiation, but this was not so for the healthy HLCs. Interestingly, PC treatment in combination with vitamin B increased the amount of ATR available, and subsequently ATR activity, in both MMAB HLCs. More importantly, the treatment significantly reduced the methylmalonic acid content of both. In summary, the HLC model would appear to be an excellent candidate for the pharmacological testing of the described PCs, for analyzing the effects of new drugs, and investigating the repurposing of older drugs, before testing in animal models.
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| http://dx.doi.org/10.1016/j.bbadis.2022.166433 | DOI Listing |
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