Abstract
Albeit effective, methionine/protein restriction in the management of classical homocystinuria (HCU) is suboptimal and hard to follow. To address unmet need, we developed an enzyme therapy (OT-58), which effectively corrected disease symptoms in various mouse models of HCU in the absence of methionine restriction. Here we evaluated short- and long-term efficacy of OT-58 on the background of current dietary management of HCU. Methionine restriction resulted in the lowering of total homocysteine (tHcy) by 38–63% directly proportional to a decreased methionine intake (50–12.5% of normal). Supplemental betaine resulted in additional lowering of tHcy. OT-58 successfully competed with betaine and normalized tHcy on the background of reduced methionine intake, while substantially lowering tHcy in mice on normal methionine intake. Betaine was less effective in lowering tHcy on the background of normal or increased methionine intake, while exacerbating hypermethioninemia. OT-58 markedly reduced both hyperhomocysteinemia and hypermethioninemia caused by the diets and betaine in HCU mice. Withdrawal of betaine did not affect improved metabolic balance, which was established and solely maintained by OT-58 during periods of fluctuating dietary methionine intake. Taken together, OT-58 may represent novel, highly effective enzyme therapy for HCU performing optimally in the presence or absence of dietary management of HCU.
Highlights
Classical homocystinuria (HCU; OMIM# 236200) is a rare inborn error of sulfur amino acid metabolism caused by substantially reduced or entirely missing cystathionine beta-synthase (CBS)activity [1]
A lack of CBS activity leads to extremely elevated plasma and tissue Hcy concentrations, which represent a biochemical hallmark of HCU
All procedures were performed at the University of Colorado Anschutz Medical Campus under the Institutional Animal Care and Use Committee (IACUC)-approved protocol# 81, which complied with the Guide for the Care and Use of Laboratory Animals
Summary
Classical homocystinuria (HCU; OMIM# 236200) is a rare inborn error of sulfur amino acid metabolism caused by substantially reduced or entirely missing cystathionine beta-synthase (CBS)activity [1]. Human CBS is a complex enzyme with intricate regulation responsible for the condensation of homocysteine (Hcy), a toxic intermediate of methionine (Met) metabolism, with serine to form cystathionine (Cth), directing the flux of organic sulfur irreversibly toward the biosynthesis of cysteine (Cys) [2] (Figure 1). A lack of CBS activity leads to extremely elevated plasma and tissue Hcy concentrations, which represent a biochemical hallmark of HCU. The major objective of treatment is to reduce the accumulation of Hcy and maintain it as close as possible to normal levels (5–15 μM; Figure 1). Recent guidelines for the management of HCU recommend maintaining plasma total Hcy (tHcy) below the 100 μM threshold, which, rather than being an ideal target for Hcy levels, represents a high but achievable target that may help in reducing some of the clinical complications [3].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
