Homocystinuria: Advances in metabolic and molecular therapies targeting homocysteine pathways (Review)

Homocystinuria (HCU) is a rare inherited metabolic disorder caused by deficiencies of cystathionine β‑synthase (CBS), methylenetetrahydrofolate reductase or methionine synthase, leading to elevated homocysteine and methionine concentrations in blood and urine. If untreated, HCU can result in notable multi‑organ complications, including ectopia lentis, thromboembolism, skeletal abnormalities and cognitive impairment. The global prevalence is estimated to be 1 in 300,000, although rates vary regionally with genetic mutation patterns and consanguinity. Current therapies include: i) Vitamin B6, B12 and folate supplementation; ii) methionine‑restricted diets; and iii) betaine. These therapies have important limitations, including variable responsiveness and challenges in long‑term adherence, and often fail to prevent complications. Novel therapeutic approaches are advancing rapidly. Enzyme replacement therapies such as pegtibatinase, pegtarviliase and CDX‑6512 have shown promise in preclinical and early clinical studies, achieving notable homocysteine reduction. Gene therapies using adeno‑associated virus serotype rh.10‑CBS or minicircle DNA‑CBS constructs offer the potential for durable metabolic correction. Pharmacological chaperones, including S‑adenosylmethionine and heme arginate, aim to restore CBS activity in mutation‑specific contexts, while orthotopic liver transplantation remains the only definitive treatment for severe pyridoxine‑non‑responsive cases. The present review summarizes these emerging therapeutic strategies, highlighting their potential to correct metabolic imbalances in HCU, improve clinical outcomes, and address the limitations of both conventional and novel treatments. The present review also incorporates novel epidemiological findings, integrates the foundational enzymology of HCU with current genotype‑phenotype associations and updates the therapeutic landscape through early 2025 with key developments such as the discontinuation of the pegtarviliase program and the rebranding of CDX‑6512 as SYNT‑202.