| First Author | Majtan T | Year | 2019 |
| Journal | FASEB J | Volume | 33 |
| Issue | 11 | Pages | 12477-12486 |
| PubMed ID | 31450979 | Mgi Jnum | J:299166 |
| Mgi Id | MGI:6457686 | Doi | 10.1096/fj.201901203R |
| Citation | Majtan T, et al. (2019) Behavior, body composition, and vascular phenotype of homocystinuric mice on methionine-restricted diet or enzyme replacement therapy. FASEB J 33(11):12477-12486 |
| abstractText | Classic homocystinuria (HCU) is an inherited disorder characterized by elevated homocysteine (Hcy) in plasma and tissues resulting from cystathionine beta-synthase (CBS) deficiency. There is no cure, and patients are predominantly managed by methionine-restricted diet (MRD) to limit the production of Hcy. In this study, we used the I278T mouse model of HCU to evaluate the long-term impact of a novel enzyme replacement therapy [truncated human CBS C15S mutant modified with linear 20-kDa N-hydroxysuccinimide ester polyethylene glycol (OT-58)] on clinical end points relevant to human patients with HCU. In addition, we compared its efficacy on a background of either MRD or normal methionine intake [regular diet (REG)] to that of MRD alone. We found that, compared with untreated I278T mice, OT-58 treatment of I278T mice fed with the REG diet resulted in a 90% decrease in plasma Hcy concentrations and correction of learning/cognition, endothelial dysfunction, hemostasis, bone mineralization, and body composition. On background of the MRD, OT-58 performed equally well with plasma Hcy entirely normalized. The MRD alone decreased plasma Hcy by 67% and corrected the HCU phenotype in I278T mice. However, the MRD increased anxiety and reduced bone mineral content in both I278T mice and wild-type controls. This study shows that OT-58 is a highly efficacious novel treatment for HCU on the background of either normal or restricted methionine intake.-Majtan, T., Park, I., Cox, A., Branchford, B. R., di Paola, J., Bublil, E. M., Kraus, J. P. Behavior, body composition, and vascular phenotype of homocystinuric mice on methionine-restricted diet or enzyme replacement therapy. |
