Interplay of Enzyme Therapy and Dietary Management of Murine Homocystinuria

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.

Current and Novel Therapeutical Approaches of Classical Homocystinuria in Childhood With Special Focus on Enzyme Replacement Therapy, Liver-Directed Therapy and Gene Therapy

“…Enzyme replacement therapy includes studies with pegtibatinase (OT-58, TVT-058). The application includes regime twice per week, 1.5 mg/kg subcutaneously [ 1 , 33 , 46 ]. It is a PEG-ylated recombinant enzyme replacement therapy [ 33 , 46 ].…”

“…The application includes regime twice per week, 1.5 mg/kg subcutaneously [ 1 , 33 , 46 ]. It is a PEG-ylated recombinant enzyme replacement therapy [ 33 , 46 ]. In 2019, a double blind, randomized, placebo-controlled, phase 1 and phase 2 study to analyze the safety, tolerance, pharmacological aspects pharmacodynamics, and analysis of clinical outcome of pegtibatinase (TVT-058) was initiated [ 47 ].…”

Recent therapeutic approaches to cystathionine beta‐synthase‐deficient homocystinuria

“…Patients with HCU should be monitored for levels of these two B vitamins, and possible deficiency should be corrected. Importance of Cys supplementation remains unclear with recent preclinical data showing no additional benefit of three times increased Cys intake compared to normal diet on metabolic profile and phenotype of HCU mouse models (Park, Bublil, et al, 2020).…”