RARE DISEASE
Homocystinuria due to cystathionine beta-synthase deficiency
Homocystinuria due to cystathionine beta-synthase deficiency
Homocystinuria due to cystathionine beta-synthase deficiency
Synonyms: CBS-deficient HCU, Cystathionine beta-synthase deficiency, Cystathionine beta-synthase-deficient homocystinuria, Homocystinuria due to CBS deficiency
Synonyms: CBS-deficient HCU, Cystathionine beta-synthase deficiency, Cystathionine beta-synthase-deficient homocystinuria, Homocystinuria due to CBS deficiency
Synonyms: CBS-deficient HCU, Cystathionine beta-synthase deficiency, Cystathionine beta-synthase-deficient homocystinuria, Homocystinuria due to CBS deficiency
Drug discovery
9
drugs
With orphan designations
Overview
Homocystinuria due to cystathionine beta-synthase (CBS) deficiency is an autosomal recessive disorder of methionine metabolism caused by pathogenic variants in the CBS gene. This results in elevated homocysteine and methionine levels, leading to multisystem complications including ectopia lentis, thromboembolism, osteoporosis, marfanoid habitus, and neurodevelopmental impairment. Early diagnosis via newborn screening and prompt treatment (e.g., vitamin B6, methionine restriction) can prevent severe outcomes, though clinical heterogeneity persists based on residual enzyme activity and therapeutic responsiveness [1][2][4][6].
Burden
Untreated patients face high morbidity: 30–50% risk of thromboembolic events, progressive lens dislocation, and intellectual disability [5][6][12].
Even treated individuals with total homocysteine ≥50 µM exhibit elevated risks of vascular, skeletal, and ocular complications [5][10].
Late diagnosis correlates with irreversible damage, emphasizing the critical role of neonatal screening and lifelong biochemical monitoring [2][6][12].
Therapies
Pyridoxine (vitamin B6): High doses (100–500 mg/day) for responsive patients, combined with folate/B12 supplementation [2][3][6].
Dietary management: Methionine-restricted diet with cysteine supplementation for non-responders; protein substitutes (e.g., methionine-free formulas) are often required [2][12].
Adjunctive therapies: Betaine (6–9 g/day) to enhance homocysteine remethylation, alongside anticoagulation (e.g., aspirin) for thromboprophylaxis [3][6][12].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders
Research Papers
495 drug discovery papers about Homocystinuria due to cystathionine beta-synthase deficiency, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
495 drug discovery papers about Homocystinuria due to cystathionine beta-synthase deficiency, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-06 | Homocystinuria presenting with cerebral venous thrombosis: a case report highlighting progressive thrombosis.
Homocystinuria is a hereditary metabolic disorder primarily caused by defects in enzymes involved in methionine metabolism, resulting in excessive accumulation of homocysteine and its metabolites in the blood and urine. Cerebral venous sinus thrombosis (CVST), premature atherosclerosis, and other thromboembolic events are among the most serious clinical manifestations of homocystinuria. We report a 13-year-old boy who initially presented with headache, followed by progressive disturbance of consciousness and status epilepticus. Cranial magnetic resonance imaging (MRI) revealed superior sagittal sinus thrombosis. He was transferred to a tertiary hospital, where he underwent emergency thrombus aspiration under digital subtraction angiography (DSA) guidance and received low-molecular-weight heparin (LMWH) anticoagulation. Although endovascular aspiration combined with LMWH controlled the seizures, his venous thrombosis continued to progress. He subsequently developed lower-extremity deep vein thrombosis, acute pulmonary embolism, and ventricular fibrillation. Clinical biochemical evaluation and genetic testing confirmed classic homocystinuria. Targeted therapy with warfarin, aspirin, vitamin B6, folic acid, and betaine resulted in a favorable prognosis. Early etiological screening, including genetic testing, should be prioritized in young patients with unexplained or recurrent thrombosis to optimize treatment and prognosis. Rational use of anticoagulants combined with targeted metabolic therapy (vitamin B6, folic acid, betaine) and antiplatelet therapy is critical for improving outcomes in such patients.
2026-06-06 | Structural basis for a filamentous morpheein model of human cystathionine beta-synthase.
Human cystathionine beta-synthase (CBS) is a vital enzyme that regulates sulfur amino acid metabolism, hydrogen sulfide production, and cellular redox balance. Using a multidisciplinary approach, we demonstrate that CBS functions as a filamentous morpheein, with its stability, turnover, and activity governed by dynamic quaternary structural transitions. Three distinct filamentous assemblies were resolved by cryo-EM and are mediated by the oligomerization loop (residues 516-525): (i) ligand-free trans-dimers that form trans-basal filaments with basal stability and activity, (ii) adenosylornithine-bound cis-dimers that assemble into stabilized cis-basal filaments and (iii) S-adenosylmethionine-bound allo-dimers, which, together with cis-dimers, form highly stable, allo-activated stacked filaments. These reversible filamentous assemblies redefine CBS biology by integrating oligomerization and allosteric regulation within a morpheein framework. These findings provide a transformative perspective on CBS function and open avenues for pharmacological targeting of dysregulated CBS in various diseases including homocystinuria, cancer, and Down syndrome.
2026-05-11 | Homocystinuria in a consanguineous indigenous family from rural Honduras: a ten-year follow up and literature review of familial cases.
Homocystinuria (HCU) is a rare autosomal recessive metabolic disorder, characterized by a mutation in the enzyme cystathionine beta-synthase and abnormally high levels of homocysteine in the blood. HCU that runs in a family is rare; prior to this report, there have been only 150 familial cases described in the literature. Here, we describe a familial cluster of HCU in four children in "Family V," a consanguineous indigenous family from rural Honduras with a 10-year clinical follow up. We describe the diagnosis, presentation and progression of three patients who were diagnosed in 2015; critical findings include substantial vision loss in Patients 1 and 2, and a significant decline in language ability in Patient 3. We also describe the presentation of Patient 4, a grandchild who we diagnosed with probable HCU based on symptoms very similar to his siblings and highly suspicious for HCU. Additionally, we completed a narrative review of previously published familial HCU cases, using PubMed and Google Scholar, to highlight common phenotypic trends in familial HCU patients. In the reported familial cases, 57% had CNS complications, 48% had ocular complications, and 30% had cardiovascular complications.
2026-03-07 | Assessing the nutritional value and health risks of special low‑protein foods: narrative review.
Special low-protein foods (SLPFs) are essential for patients with disorders of inherited amino acid metabolism that require lifelong dietary protein restriction to prevent severe neurocognitive effects and even death. Conditions such as phenylketonuria (PKU), tyrosinemia (TYR), maple syrup urine disease (MSUD), homocystinuria (HCU), and urea cycle disorders (UCD) depend on these foods to support metabolic control and dietary adherence. SLPFs provide satiety, energy, and help prevent catabolism, but their nutritional composition poses challenges. Most SLPFs are formulated using isolated starches as the primary macronutrient base. Hydrocolloid fibers are commonly added to improve texture, consistency, shelf life, and water or gas retention. These ingredients form the backbone of SLPFs production and are consistently used across different regions worldwide, reflecting a standardized approach to their formulation. However, their potential adverse effects include suppression of gut microbiota, gut dysbiosis, increased inflammatory markers, overweight, and obesity, all of which raise cardio‑metabolic risks. Strengthening the nutritional quality of SLPFs through natural plant sources may help mitigate their potential adverse outcomes while ensuring patients’ dietary needs are met. Therefore, it is important to explore natural low‑protein alternatives that can both support sustainable food production and promote long‑term health benefits.
2026-01-28 | Modulating One-Carbon Metabolism with B-Vitamins to Protect the Retinal Barrier and Prevent Retinal Degeneration.
Vitamin B12 deficiency is increasingly recognized as a contributor in both vascular and neurodegenerative aging-related disorders. Its deficiency disrupts one-carbon metabolism, leading to impaired homocysteine (Hcy) cycling. Elevated Hcy is a well-established risk factor for vascular dysfunction. Previously, we established that elevated Hcy contributes to aging retinal diseases and plays a central role in blood retinal barrier (BRB) dysfunction. Building on this foundation, the present study examines how B-vitamin deficiency disrupts one-carbon metabolism and whether restoring these vitamins can serve as a preventive or therapeutic strategy. Since B-vitamins (B6, B9, and B12) are crucial cofactors in the metabolism of Hcy, we investigated how dietary changes in these vitamins affect serum Hcy levels and retinal vascular integrity in mice. C57BL/6- Wild-type (WT) and cbs+/- mice (Cystathionine Beta-Synthase heterozygotes, common mouse model for elevated Hcy) were fed specially formulated diets, which contained different levels of B-vitamins (normal, deficient (B-Vit (-)) or enriched (B-Vit (+)). Initially, two groups of mice were placed on either a normal or a deficient diet. After 12-16 weeks, the success of the diet regimes was confirmed by observing serum B12 deficiency in the B-Vit (-) group, along with elevated Hcy levels. Subsequently, a subgroup of the B-Vit (-) mice was switched to an enriched diet. The BRB integrity was evaluated in living mice using fluorescein angiography (FA), optical coherence tomography (OCT), and in the perfused mice retinas with Western blot analysis of leaked retinal albumin and tight junction proteins (occludin and ZO-1) levels. The B-vitamin deficiency caused significant drop in serum vitamin B12 and an increase in plasma Hcy, leading to vascular leakage, altered retinal thickness, choroidal neovascular changes, increased retinal albumin leak, and decreased tight junction protein expression, indicating BRB disruption, which was restored with B-vitamin supplementation. a long-term deficiency of vitamins B6, B9, and B12 can lead to disruptions in the BRB. However, supplementation with these B-vitamins has the potential to reverse these effects and help maintain the integrity of BRB. This under-score the significance of one-carbon metabolism for retinal health and suggests that ensuring adequate levels of B-vitamins may aid in preventing aging retinal diseases with BRB disruption such as diabetic retinopathy and age-related macular degeneration.
cell therapies
2025-01-09 | Parental Living Donor Liver Transplantation as a Solution in Medical Treatment-Resistant Cystathionine-β-Synthase Deficiency: A Single-Center Case Series.
Cystathionine-β-synthase deficiency (CBSd) is an inherited metabolic liver disease causing morbidities in eyes, skeleton, brain, and vasculature. Despite its potential lethality due to thromboembolism and liver failure, sole diagnosis of CBSd seemed not to fulfill the enlistment criteria for deceased donor liver transplantation in previous reports. We retrospectively reviewed three cases of living donor liver transplantation (LDLT) for pediatric CBSd patients responding poorly to conservative treatment in Beijing Friendship Hospital, and a literature review was performed. Patients 1 and 3 received donated partial liver from heterozygous carrier parents, and Patient 2 received donated partial liver from a CBS-competent parent. Patient 2 developed portal thrombus 1 day after LDLT, which was resolved with surgical thrombectomy and reconstruction. Patients 1 and 3 had their resected liver donated to other patients with advanced liver cancer, and the domino grafts functioned well until the death due to tumor recurrence. Parental LDLT, whether from carriers or not, is an appropriate alternative for CBSd patients resistant to medical treatment. Risk of peri-operative thromboembolism might be higher in CBSd than in other LDLT cases, and explanted livers with CBSd could serve as domino grafts.
2024-03-18 | Conquering homocystinuria with engineered probiotics.
Pyridoxine-unresponsive homocystinuria has lifelong implications for health. In this issue, Perreault and colleagues present evidence that orally delivered engineered probiotic Escherichia Coli Nissle SYNB1353 is a promising candidate in reducing homocysteine, with successful trials in mice, monkeys, and humans. However, further probiotic optimization and safety assessments are required.
2022-06-08 | [Clinical characteristics and CBS gene analysis of 13 cases with classic homocystinuria].
Objective: To analyze the clinical features and CBS gene variants of 13 patients with classic homocystinuria, and the strategies of individual treatment and prevention were explored. Methods: The general information, clinical manifestations, laboratory tests, cranial images, CBS gene variants, diagnosis and therapeutic strategies of 13 patients with classic homocystinuria admitted to the Department of Pediatrics of Children's Hospital Affiliated to Zhengzhou University and Peking University First Hospital from November 2013 to June 2021 were analyzed retrospectively. Results: There were 13 patients diagnosed at the age of 10 days to 14 years, 6 were male and 7 were female. There were 3 patients detected by newborn screening and received treatment at the asymptomatic stage. There were 10 patients clinically diagnosed at the age of 5 to 14 years. Their symptoms appeared at age of 1 to 6 years. The major clinical manifestations were marfanoid features, lens dislocation and (or) myopia, developmental delay, osteoporosis, and cardiovascular diseases. Brain magnetic resonance imaging showed asymmetric infarcts in 4 patients and hypomyelination in 1 case. Increased blood methionine, plasma total homocysteine and urinary total homocysteine with normal urinary methylmalonic acid were found in 13 patients. The biochemical features were consistent with classic homocystinuria. Totally 18 variants were identified in CBS gene of 13 patients, 10 variants were novel and 8 were reported. only 1 patient was partially responsive to vitamin B6 treatment, while 12 cases were non-responsive. They were mainly treated with low methionine diet and betaine supplement. Three vitamin B6 non-responsive cases received liver transplantation at age of 3, 8 and 8 years, respectively. Their blood methionine and total homocysteine returned to normal within a week after liver transplantation. One patient died. Prenatal diagnosis was performed for a fetus when the mother was pregnant again. Two pathogenic CBS gene variants were identified from the amniocytes as same as the proband. Conclusions: The clinical manifestations of classic homocystinuria are complex and variable. Blood amino acid analysis, serum or urine total homocysteine assay and gene analysis are critical for its diagnosis. There were 10 novel CBS gene varients were identified expanding the CBS gene varient spectrum. Liver transplantation is an effective treatment. Prenatal diagnosis is important to prevent classic homocysteinuria. 目的： 分析经典型同型半胱氨酸尿症患儿的临床特点和CBS基因变异情况，探讨个体化治疗方法及预防。 方法： 回顾性分析2013年11月至2021年6月就诊于郑州大学附属儿童医院及北京大学第一医院儿科的13例经典型同型半胱氨酸尿症患儿的一般情况、临床表现、实验室检查、头颅影像学、CBS基因变异特点、诊断及治疗等资料。 结果： 13例患儿中男6例，女7例，确诊年龄为10日龄至14岁。3例为新生儿筛查检出，无症状时开始治疗，余10例于1~6岁发病，5~14岁时确诊，主要表现为马凡综合征样体型、晶状体脱位和（或）近视、发育落后、骨质疏松及心脑血管疾病。4例脑磁共振成像示不对称梗死灶，1例示髓鞘形成低下。13例患儿血清蛋氨酸、血清总同型半胱氨酸及尿液总同型半胱氨酸均增高，尿液甲基丙二酸正常，符合经典型同型半胱氨酸尿症。13例患儿CBS基因共检出18种变异，其中10种为新变异、8种为已知变异。仅1例为维生素B6部分反应型，12例为维生素B6无反应型，均以低蛋氨酸饮食及甜菜碱治疗为主，3例疗效不良患儿分别于3、8、8岁进行了肝移植治疗，术后1周内血液蛋氨酸及同型半胱氨酸恢复正常。1例患儿死亡。1例患儿母亲再孕时进行产前诊断，羊水细胞CBS基因存在与患儿相同的致病变异。 结论： 经典型同型半胱氨酸尿症临床表现复杂多样，血氨基酸、血清及尿液总同型半胱氨酸和基因分析是诊断的关键。检出10种CBS基因新变异，扩展了CBS基因变异谱。肝移植为有效的治疗办法。产前诊断是防控经典型同型半胱氨酸尿症的重要措施。.
2019-10-01 | Feasibility of domino liver transplantation from hyperhomocsyteinemia
Hyperhomocysteinemia, resulting from a cystathionine beta synthase (CBS) deficiency, is an autosomal recessive disease associated with high levels of homocysteine. Such patients can present with severe mental retardation, ectopia lentis and osteoporosis and thromboembolic disease. To the best of our knowledge, only two cases of liver transplantation for CBS deficiency have been published. Here, we report a case of an 8-year-old male with a CBS deficiency that underwent living donor liver transplantation. The postoperative course was uneventful and homocysteine levels remained normal. The liver of this CBS deficiency patient was then successfully used in domino transplantation. The domino liver transplantation recipient was a 41-year-old male diagnosed with acute liver failure following hemi-liver resection due to cholangiocarcinoma. The domino recipient developed acquired hyperhomocysteinemia, which was controlled with a special regimen of medications. No complications relative to CBS deficiency were observed up to 11 months post-transplant. At this time, the patient expired as a result of cholangiocarcinoma recurrence. In conclusion, our data suggest that liver transplantation for CBS deficiency can be effective, safe and beneficial. It is possible to be both safe and beneficial to use a CBS deficiency patient as a domino donor for salvage liver transplantation in a selective category of recipients.
2015-09-14 | Hyperhomocysteinemia suppresses bone marrow CD34+/VEGF receptor 2+ cells and inhibits progenitor cell mobilization and homing to injured vasculature-a role of β1-integrin in progenitor cell migration and adhesion.
Hyperhomocysteinemia (HHcy) impairs re-endothelialization and accelerates vascular remodeling. The role of CD34(+)/VEGF receptor (VEGFR) 2(+) progenitor cells (PCs) in vascular repair in HHcy is unknown. We studied the effect of HHcy on PCs and its role in vascular repair in severe HHcy (∼150 μM), which was induced in cystathionine-β synthase heterozygous mice fed a high-methionine diet for 8 weeks. Vascular injury was introduced by carotid air-dry endothelium denudation. CD34(+)/VEGFR2(+) cells were examined by flow cytometry. HHcy reduced bone marrow (BM) CD34(+)/VEGFR2(+) cells and suppressed replenishment of postinjury CD34(+)/VEGFR2(+) cells in peripheral blood (PB). Donor green fluorescent protein-positive PC homing to the injured vessel was reduced in HHcy after CD34(+) PCs from enhanced green fluorescent protein mice were adoptively transferred following carotid injury. CD34(+) PC transfusion partially reversed HHcy-suppressed re-endothelialization and HHcy-induced neointimal formation. Furthermore, homocysteine (Hcy) inhibited proliferation, adhesion, and migration and suppressed β1-integrin expression and activity in human CD34(+) endothelial colony-forming cells (ECFCs) isolated from PBs in a dose-dependent manner. A functional-activating β1-integrin antibody rescued Hcy-suppressed adhesion and migration in CD34(+) ECFCs. In conclusion, HHcy reduces BM CD34(+)/VEGFR2(+) generation and suppresses CD34(+)/VEGFR2(+) cell mobilization and homing to the injured vessel via β1-integrin inhibition, which partially contributes to impaired re-endothelialization and vascular remodeling.
gene therapies
2026-04-14 | Liver-Targeted AAV-DJ-hCBS Therapy Achieves Long-Term Correction of Metabolic Imbalance in CBS-Deficient Mice.
Cystathionine β-synthase (CBS) deficiency causes classical homocystinuria with severe hyperhomocysteinemia (HHcy) that is inadequately controlled by current therapies. We tested whether liver-targeted CBS gene therapy provides durable biochemical and phenotypic rescue. Using a Cre-inducible adult mouse model of whole-body CBS loss, a single intravenous dose of AAV-DJ-hCBS (3 × 1012 or 3 × 1013 vg/kg) was administered, and the animals were followed for 12 months. Vector biodistribution showed ~100-fold hepatic enrichment over the kidney and spleen. Both doses rapidly normalized plasma homocysteine (<8 µM), maintaining correction throughout the study while preventing alopecia, weight loss, and loss of adiposity. Liver histology showed resolution of inflammation, and only 2 of 19 mice developed anti-hCBS antibodies. Liver proteomics (3998 proteins quantified) revealed CBS deficiency-associated suppression of tRNA aminoacylation and dysregulation of lipid and carbon metabolism with an HNF4A transcriptional signature, all normalized by therapy. Liver metabolomics demonstrated accumulation of S-adenosylmethionine and S-adenosylhomocysteine and disruption of phosphatidylcholine synthesis, also corrected by treatment. Plasma metabolomics revealed systemic disturbances fully normalized by hepatic CBS restoration. These findings identify the liver as the central metabolic control point in CBS deficiency and support liver-targeted gene therapy as a durable corrective strategy.
2024-06-14 | Komrower Memorial Lecture 2023. Molecular basis of phenotype expression in homocystinuria: Where are we 30 years later?
This review summarises progress in the research of homocystinuria (HCU) in the past three decades. HCU due to cystathionine β-synthase (CBS) was discovered in 1962, and Prof. Jan Peter Kraus summarised developments in the field in the first-ever Komrower lecture in 1993. In the past three decades, significant advancements have been achieved in the biology of CBS, including gene organisation, tissue expression, 3D structures, and regulatory mechanisms. Renewed interest in CBS arose in the late 1990s when this enzyme was implicated in biogenesis of H2S. Advancements in genetic and biochemical techniques enabled the identification of several hundreds of pathogenic CBS variants and the misfolding of missense mutations as a common mechanism. Several cellular, invertebrate and murine HCU models allowed us to gain insights into functional and metabolic pathophysiology of the disease. Establishing the E-HOD consortium and patient networks, HCU Network Australia and HCU Network America, offered new possibilities for acquiring clinical data in registries and data on patients' quality of life. A recent analysis of data from the E-HOD registry showed that the clinical variability of HCU is broad, extending from severe childhood disease to milder (late) adulthood forms, which typically respond to pyridoxine. Pyridoxine responsiveness appears to be the key factor determining the clinical course of HCU. Increased awareness about HCU played a role in developing novel therapies, such as gene therapy, correction of misfolding by chaperones, removal of methionine from the gut and enzyme therapies that decrease homocysteine or methionine in the circulation.
2023-01-06 | Recent therapeutic approaches to cystathionine beta-synthase-deficient homocystinuria.
Cystathionine beta-synthase (CBS)-deficient homocystinuria (HCU) is the most common inborn error of sulfur amino acid metabolism. The pyridoxine non-responsive form of the disease manifests itself by massively increasing plasma and tissue concentrations of homocysteine, a toxic intermediate of methionine metabolism that is thought to be the major cause of clinical complications including skeletal deformities, connective tissue defects, thromboembolism and cognitive impairment. The current standard of care involves significant dietary interventions that, despite being effective, often adversely affect quality of life of HCU patients, leading to poor adherence to therapy and inadequate biochemical control with clinical complications. In recent years, the unmet need for better therapeutic options has resulted in development of novel enzyme and gene therapies and exploration of pharmacological approaches to rescue CBS folding defects caused by missense pathogenic mutations. Here, we review scientific evidence and current state of affairs in development of recent approaches to treat HCU.
2022-02-03 | Long-term functional correction of cystathionine β-synthase deficiency in mice by adeno-associated viral gene therapy.
Cystathionine β-synthase (CBS) deficiency is a recessive inborn error of sulfur metabolism characterized by elevated blood levels of total homocysteine (tHcy). Patients diagnosed with CBS deficiency are currently treated by a combination of vitamin supplementation and restriction of foods containing the homocysteine precursor methionine, but the effectiveness of this therapy is limited due to poor compliance. A mouse model for CBS deficiency (Tg-I278T Cbs-/- ) was used to evaluate a potential gene therapy approach to treat CBS deficiency utilizing an AAVrh.10-based vector containing the human CBS cDNA downstream of the constitutive, strong CAG promoter (AAVrh.10hCBS). Mice were administered a single dose of virus and followed for up to 1 year. The data demonstrated a dose-dependent increase in liver CBS activity and a dose-dependent decrease in serum tHcy. Liver CBS enzyme activity at 1 year was similar to Cbs+/- control mice. Mice given the highest dose (5.6 × 1011 genomes/mouse) had mean serum tHcy decrease of 97% 1 week after injection and an 81% reduction 1 year after injection. Treated mice had either full- or substantial correction of alopecia, bone loss, and fat mass phenotypes associated with Cbs deficiency in mice. Our findings show that AAVrh.10-based gene therapy is highly effective in treating CBS deficiency in mice and supports additional pre-clinical testing for eventual use human trials.
2021-08-03 | Liver transplant as a curative treatment in a pediatric patient with classic homocystinuria: A case report.
We report a patient with homocystinuria and hyperoxaluria who was cured of homocystinuria-related disease following liver transplant. The patient was diagnosed with homocystinuria as a newborn and was treated with dietary modifications and supplements. At 22 months, he passed a calcium oxalate stone and was found to have numerous bilateral kidney stones. Genetic testing confirmed primary hyperoxaluria, type 1. He underwent preemptive liver transplant at age four to treat primary hyperoxaluria. Following transplant, his serum methionine and homocysteine levels normalized, thus, demonstrating resolution of homocystinuria. Methionine and homocysteine levels remained normal 6 years later. Homocystinuria is associated with ophthalmologic, skeletal, neurologic, and thromboembolic complications. As cystathionine beta-synthase resides in the liver, transplant was hypothesized to be an effective treatment. Primary hyperoxaluria generally progresses to chronic kidney disease and is treated with combined kidney-liver transplant at the time of end stage kidney disease. Given this patient's dual diagnoses, we proceeded with preemptive liver transplantation. Three prior cases of patients with homocystinuria treated with liver transplantation have been reported. In all cases, transplant resolved metabolic effects. However, our case represents a pediatric patient without disease-related complications prior to transplant. This case supports liver-targeted gene therapies as an effective treatment for homocystinuria.
proteins
2025-11-14 | 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.
2025-05-18 | Safety and efficacy of pegtibatinase enzyme replacement therapy in adults with classical homocystinuria in the COMPOSE phase 1/2 randomized trial.
Because the standard-of-care treatment for classical homocystinuria (HCU) often cannot achieve adequate metabolic control, the phase 1/2 COMPOSE trial (NCT03406611) evaluated pegtibatinase enzyme replacement therapy. Participants with HCU aged 12 to 65 years with elevated total plasma homocysteine (tHcy) receiving standard-of-care treatment were randomized 3:1 into 6 increasing dose cohorts (each n ≈ 4) of subcutaneous pegtibatinase (≤2.5 mg/kg twice weekly [BIW]) or placebo. Primary end points included adverse event incidence and immunogenicity. Secondary end points included tHcy change from baseline to posttreatment (geometric mean of weeks 6-12). Overall, 24 participants were enrolled. Pegtibatinase was generally well tolerated at all doses with no anaphylaxis or severe immune reactions; 15 participants (62.5%) experienced ≥1 treatment-related treatment-emergent adverse event (most commonly injection-site reactions; 1 serious [acute urticaria]). At the 2 highest doses, substantial tHcy reductions were observed after treatment (relative reduction: 57% for 1.5 mg/kg BIW; 67% for 2.5 mg/kg BIW), and all participants maintained tHcy < 100 μM. One participant receiving 2.5 mg/kg BIW achieved tHcy < 15 μM (normal) and methionine < 14 μM (below normal), enabling increased dietary intact protein intake. Changes in other metabolites aligned with tHcy. Pegtibatinase was generally well tolerated and substantially reduced tHcy levels, demonstrating potential as a treatment for HCU.
2023-10-23 | An orally administered enzyme therapeutic for homocystinuria that suppresses homocysteine by metabolizing methionine in the gastrointestinal tract.
Classical homocystinuria (HCU) is a rare inborn error of amino acid metabolism characterized by accumulation of homocysteine, an intermediate product of methionine metabolism, leading to significant systemic toxicities, particularly within the vascular, skeletal, and ocular systems. Most patients require lifelong dietary therapy with severe restriction of natural protein to minimize methionine intake, and many patients still struggle to maintain healthy homocysteine levels. Since eliminating methionine from the diet reduces homocysteine levels, we hypothesized that an enzyme that can degrade methionine within the gastrointestinal (GI) tract could help HCU patients maintain healthy levels while easing natural protein restrictions. We describe the preclinical development of CDX-6512, a methionine gamma lyase (MGL) enzyme that was engineered for stability and activity within the GI tract for oral administration to locally degrade methionine. CDX-6512 is stable to low pH and intestinal proteases, enabling it to survive the harsh GI environment without enteric coating and to degrade methionine freed from dietary protein within the small intestine. Administering CDX-6512 to healthy non-human primates following a high protein meal led to a dose-dependent suppression of plasma methionine. In Tg-I278T Cbs-/- mice, an animal model that recapitulates aspects of HCU disease including highly elevated serum homocysteine levels, oral dosing of CDX-6512 after a high protein meal led to suppression in serum levels of both methionine and homocysteine. When animals received a daily dose of CDX-6512 with a high protein meal for two weeks, the Tg-I278T Cbs-/- mice maintained baseline homocysteine levels, whereas homocysteine levels in untreated animals increased by 39%. These preclinical data demonstrate the potential of CDX-6512 as an oral enzyme therapy for HCU.
2022-03-01 | Characterization and application of l-methionine γ-lyase Q349S mutant enzyme with an enhanced activity toward l-homocysteine.
l-Methionine γ-lyse (MGL), a pyridoxal 5'-phosphate-dependent enzyme, catalyzes the α,γ-elimination of l-methionine (l-Met) and l-homocysteine (l-Hcy) to produce α-keto acids, thiols, and ammonia. Previously, various mutant enzymes of Pseudomonas putida MGL (PpMGL) were prepared to identify a homocysteine (Hcy)-specific enzyme that would assist the diagnosis of homocystinuria. Among the mutat enzymes the Q349S mutant exhibited high degradation activity toward l-Hcy. In the present study, PpMGL Q349S was characterized; the results suggested that it could be applied to determine the amount of l-Hcy. Compared to the wild-type PpMGL, specific activities of the Q349S mutant with l-Hcy and l-Met were 1.5 and 0.7 times, respectively. Additionally, we confirmed that l-Hcy in plasma samples could be accurately detected using the Q349S mutant by preincubating it with cysteine desulfurase (CsdA). Furthermore, we determined the X-ray crystal structure of PpMGL Q349S l-Met or l-Hcy complexes Michaelis complex, germinal diamine, and external aldimine at 2.25-2.40 Å. These 3D structures showed that the interaction partner of the β-hydroxyl group of Thr355 in the wild-type PpMGL was changed to the carboxyl group of the Hcy-PLP external aldimine in the Q349S mutant. The interaction of Ser349 and Arg375 was different between l-Met and l-Hcy recognition, indicating that it was important for the recognition of the carboxyl group of the substrate.
2020-07-24 | Hypermethioninemia Leads to Fatal Bleeding and Increased Mortality in a Transgenic I278T Mouse Model of Homocystinuria
Severely elevated plasma homocysteine and methionine lead to thromboembolic events and strokes in homocystinuric (HCU) patients. Mouse models of HCU failed to exhibit prothrombotic phenotype, presumably due to lack of hypermethioninemia. We evaluated the impact of hypermethioninemia together with hyperhomocysteinemia on murine HCU phenotype and compared the efficacy of the current and novel therapies for HCU. High methionine intake decreased survival of I278T mice, which died from intestinal bleeding with hepatic and pancreatic failure. I278T mice on normal or increased methionine intake developed endothelial dysfunction, but paradoxically demonstrated delayed occlusion in an induced arterial thrombosis model. RNA-seq analysis suggested that expression of coagulation factor XI (FXI) is downregulated in livers of I278T mice. Indeed, plasma concentrations of FXI were decreased in I278T mice on normal diet and further reduced by increased methionine intake. Dietary methionine restriction normalized the observed phenotype. Similarly, treatment with OT-58, a novel enzyme therapy for HCU, corrected the phenotype in I278T mice regardless of their dietary methionine intake. Hypermethioninemia does not contribute to prothrombotic phenotype in murine HCU. Downregulation of FXI may contribute to the lack of prothrombotic tendency in I278T mice. Methionine restriction or treatment with OT-58 corrects vascular disease in the I278T mouse model of HCU.
small molecules
2026-07-06 | Homocystinuria presenting with cerebral venous thrombosis: a case report highlighting progressive thrombosis.
Homocystinuria is a hereditary metabolic disorder primarily caused by defects in enzymes involved in methionine metabolism, resulting in excessive accumulation of homocysteine and its metabolites in the blood and urine. Cerebral venous sinus thrombosis (CVST), premature atherosclerosis, and other thromboembolic events are among the most serious clinical manifestations of homocystinuria. We report a 13-year-old boy who initially presented with headache, followed by progressive disturbance of consciousness and status epilepticus. Cranial magnetic resonance imaging (MRI) revealed superior sagittal sinus thrombosis. He was transferred to a tertiary hospital, where he underwent emergency thrombus aspiration under digital subtraction angiography (DSA) guidance and received low-molecular-weight heparin (LMWH) anticoagulation. Although endovascular aspiration combined with LMWH controlled the seizures, his venous thrombosis continued to progress. He subsequently developed lower-extremity deep vein thrombosis, acute pulmonary embolism, and ventricular fibrillation. Clinical biochemical evaluation and genetic testing confirmed classic homocystinuria. Targeted therapy with warfarin, aspirin, vitamin B6, folic acid, and betaine resulted in a favorable prognosis. Early etiological screening, including genetic testing, should be prioritized in young patients with unexplained or recurrent thrombosis to optimize treatment and prognosis. Rational use of anticoagulants combined with targeted metabolic therapy (vitamin B6, folic acid, betaine) and antiplatelet therapy is critical for improving outcomes in such patients.
2026-06-06 | Structural basis for a filamentous morpheein model of human cystathionine beta-synthase.
Human cystathionine beta-synthase (CBS) is a vital enzyme that regulates sulfur amino acid metabolism, hydrogen sulfide production, and cellular redox balance. Using a multidisciplinary approach, we demonstrate that CBS functions as a filamentous morpheein, with its stability, turnover, and activity governed by dynamic quaternary structural transitions. Three distinct filamentous assemblies were resolved by cryo-EM and are mediated by the oligomerization loop (residues 516-525): (i) ligand-free trans-dimers that form trans-basal filaments with basal stability and activity, (ii) adenosylornithine-bound cis-dimers that assemble into stabilized cis-basal filaments and (iii) S-adenosylmethionine-bound allo-dimers, which, together with cis-dimers, form highly stable, allo-activated stacked filaments. These reversible filamentous assemblies redefine CBS biology by integrating oligomerization and allosteric regulation within a morpheein framework. These findings provide a transformative perspective on CBS function and open avenues for pharmacological targeting of dysregulated CBS in various diseases including homocystinuria, cancer, and Down syndrome.
2026-05-11 | Homocystinuria in a consanguineous indigenous family from rural Honduras: a ten-year follow up and literature review of familial cases.
Homocystinuria (HCU) is a rare autosomal recessive metabolic disorder, characterized by a mutation in the enzyme cystathionine beta-synthase and abnormally high levels of homocysteine in the blood. HCU that runs in a family is rare; prior to this report, there have been only 150 familial cases described in the literature. Here, we describe a familial cluster of HCU in four children in "Family V," a consanguineous indigenous family from rural Honduras with a 10-year clinical follow up. We describe the diagnosis, presentation and progression of three patients who were diagnosed in 2015; critical findings include substantial vision loss in Patients 1 and 2, and a significant decline in language ability in Patient 3. We also describe the presentation of Patient 4, a grandchild who we diagnosed with probable HCU based on symptoms very similar to his siblings and highly suspicious for HCU. Additionally, we completed a narrative review of previously published familial HCU cases, using PubMed and Google Scholar, to highlight common phenotypic trends in familial HCU patients. In the reported familial cases, 57% had CNS complications, 48% had ocular complications, and 30% had cardiovascular complications.
2026-03-07 | Assessing the nutritional value and health risks of special low‑protein foods: narrative review.
Special low-protein foods (SLPFs) are essential for patients with disorders of inherited amino acid metabolism that require lifelong dietary protein restriction to prevent severe neurocognitive effects and even death. Conditions such as phenylketonuria (PKU), tyrosinemia (TYR), maple syrup urine disease (MSUD), homocystinuria (HCU), and urea cycle disorders (UCD) depend on these foods to support metabolic control and dietary adherence. SLPFs provide satiety, energy, and help prevent catabolism, but their nutritional composition poses challenges. Most SLPFs are formulated using isolated starches as the primary macronutrient base. Hydrocolloid fibers are commonly added to improve texture, consistency, shelf life, and water or gas retention. These ingredients form the backbone of SLPFs production and are consistently used across different regions worldwide, reflecting a standardized approach to their formulation. However, their potential adverse effects include suppression of gut microbiota, gut dysbiosis, increased inflammatory markers, overweight, and obesity, all of which raise cardio‑metabolic risks. Strengthening the nutritional quality of SLPFs through natural plant sources may help mitigate their potential adverse outcomes while ensuring patients’ dietary needs are met. Therefore, it is important to explore natural low‑protein alternatives that can both support sustainable food production and promote long‑term health benefits.
2026-01-28 | Modulating One-Carbon Metabolism with B-Vitamins to Protect the Retinal Barrier and Prevent Retinal Degeneration.
Vitamin B12 deficiency is increasingly recognized as a contributor in both vascular and neurodegenerative aging-related disorders. Its deficiency disrupts one-carbon metabolism, leading to impaired homocysteine (Hcy) cycling. Elevated Hcy is a well-established risk factor for vascular dysfunction. Previously, we established that elevated Hcy contributes to aging retinal diseases and plays a central role in blood retinal barrier (BRB) dysfunction. Building on this foundation, the present study examines how B-vitamin deficiency disrupts one-carbon metabolism and whether restoring these vitamins can serve as a preventive or therapeutic strategy. Since B-vitamins (B6, B9, and B12) are crucial cofactors in the metabolism of Hcy, we investigated how dietary changes in these vitamins affect serum Hcy levels and retinal vascular integrity in mice. C57BL/6- Wild-type (WT) and cbs+/- mice (Cystathionine Beta-Synthase heterozygotes, common mouse model for elevated Hcy) were fed specially formulated diets, which contained different levels of B-vitamins (normal, deficient (B-Vit (-)) or enriched (B-Vit (+)). Initially, two groups of mice were placed on either a normal or a deficient diet. After 12-16 weeks, the success of the diet regimes was confirmed by observing serum B12 deficiency in the B-Vit (-) group, along with elevated Hcy levels. Subsequently, a subgroup of the B-Vit (-) mice was switched to an enriched diet. The BRB integrity was evaluated in living mice using fluorescein angiography (FA), optical coherence tomography (OCT), and in the perfused mice retinas with Western blot analysis of leaked retinal albumin and tight junction proteins (occludin and ZO-1) levels. The B-vitamin deficiency caused significant drop in serum vitamin B12 and an increase in plasma Hcy, leading to vascular leakage, altered retinal thickness, choroidal neovascular changes, increased retinal albumin leak, and decreased tight junction protein expression, indicating BRB disruption, which was restored with B-vitamin supplementation. a long-term deficiency of vitamins B6, B9, and B12 can lead to disruptions in the BRB. However, supplementation with these B-vitamins has the potential to reverse these effects and help maintain the integrity of BRB. This under-score the significance of one-carbon metabolism for retinal health and suggests that ensuring adequate levels of B-vitamins may aid in preventing aging retinal diseases with BRB disruption such as diabetic retinopathy and age-related macular degeneration.
cell therapies
2025-01-09 | Parental Living Donor Liver Transplantation as a Solution in Medical Treatment-Resistant Cystathionine-β-Synthase Deficiency: A Single-Center Case Series.
Cystathionine-β-synthase deficiency (CBSd) is an inherited metabolic liver disease causing morbidities in eyes, skeleton, brain, and vasculature. Despite its potential lethality due to thromboembolism and liver failure, sole diagnosis of CBSd seemed not to fulfill the enlistment criteria for deceased donor liver transplantation in previous reports. We retrospectively reviewed three cases of living donor liver transplantation (LDLT) for pediatric CBSd patients responding poorly to conservative treatment in Beijing Friendship Hospital, and a literature review was performed. Patients 1 and 3 received donated partial liver from heterozygous carrier parents, and Patient 2 received donated partial liver from a CBS-competent parent. Patient 2 developed portal thrombus 1 day after LDLT, which was resolved with surgical thrombectomy and reconstruction. Patients 1 and 3 had their resected liver donated to other patients with advanced liver cancer, and the domino grafts functioned well until the death due to tumor recurrence. Parental LDLT, whether from carriers or not, is an appropriate alternative for CBSd patients resistant to medical treatment. Risk of peri-operative thromboembolism might be higher in CBSd than in other LDLT cases, and explanted livers with CBSd could serve as domino grafts.
2024-03-18 | Conquering homocystinuria with engineered probiotics.
Pyridoxine-unresponsive homocystinuria has lifelong implications for health. In this issue, Perreault and colleagues present evidence that orally delivered engineered probiotic Escherichia Coli Nissle SYNB1353 is a promising candidate in reducing homocysteine, with successful trials in mice, monkeys, and humans. However, further probiotic optimization and safety assessments are required.
2022-06-08 | [Clinical characteristics and CBS gene analysis of 13 cases with classic homocystinuria].
Objective: To analyze the clinical features and CBS gene variants of 13 patients with classic homocystinuria, and the strategies of individual treatment and prevention were explored. Methods: The general information, clinical manifestations, laboratory tests, cranial images, CBS gene variants, diagnosis and therapeutic strategies of 13 patients with classic homocystinuria admitted to the Department of Pediatrics of Children's Hospital Affiliated to Zhengzhou University and Peking University First Hospital from November 2013 to June 2021 were analyzed retrospectively. Results: There were 13 patients diagnosed at the age of 10 days to 14 years, 6 were male and 7 were female. There were 3 patients detected by newborn screening and received treatment at the asymptomatic stage. There were 10 patients clinically diagnosed at the age of 5 to 14 years. Their symptoms appeared at age of 1 to 6 years. The major clinical manifestations were marfanoid features, lens dislocation and (or) myopia, developmental delay, osteoporosis, and cardiovascular diseases. Brain magnetic resonance imaging showed asymmetric infarcts in 4 patients and hypomyelination in 1 case. Increased blood methionine, plasma total homocysteine and urinary total homocysteine with normal urinary methylmalonic acid were found in 13 patients. The biochemical features were consistent with classic homocystinuria. Totally 18 variants were identified in CBS gene of 13 patients, 10 variants were novel and 8 were reported. only 1 patient was partially responsive to vitamin B6 treatment, while 12 cases were non-responsive. They were mainly treated with low methionine diet and betaine supplement. Three vitamin B6 non-responsive cases received liver transplantation at age of 3, 8 and 8 years, respectively. Their blood methionine and total homocysteine returned to normal within a week after liver transplantation. One patient died. Prenatal diagnosis was performed for a fetus when the mother was pregnant again. Two pathogenic CBS gene variants were identified from the amniocytes as same as the proband. Conclusions: The clinical manifestations of classic homocystinuria are complex and variable. Blood amino acid analysis, serum or urine total homocysteine assay and gene analysis are critical for its diagnosis. There were 10 novel CBS gene varients were identified expanding the CBS gene varient spectrum. Liver transplantation is an effective treatment. Prenatal diagnosis is important to prevent classic homocysteinuria. 目的： 分析经典型同型半胱氨酸尿症患儿的临床特点和CBS基因变异情况，探讨个体化治疗方法及预防。 方法： 回顾性分析2013年11月至2021年6月就诊于郑州大学附属儿童医院及北京大学第一医院儿科的13例经典型同型半胱氨酸尿症患儿的一般情况、临床表现、实验室检查、头颅影像学、CBS基因变异特点、诊断及治疗等资料。 结果： 13例患儿中男6例，女7例，确诊年龄为10日龄至14岁。3例为新生儿筛查检出，无症状时开始治疗，余10例于1~6岁发病，5~14岁时确诊，主要表现为马凡综合征样体型、晶状体脱位和（或）近视、发育落后、骨质疏松及心脑血管疾病。4例脑磁共振成像示不对称梗死灶，1例示髓鞘形成低下。13例患儿血清蛋氨酸、血清总同型半胱氨酸及尿液总同型半胱氨酸均增高，尿液甲基丙二酸正常，符合经典型同型半胱氨酸尿症。13例患儿CBS基因共检出18种变异，其中10种为新变异、8种为已知变异。仅1例为维生素B6部分反应型，12例为维生素B6无反应型，均以低蛋氨酸饮食及甜菜碱治疗为主，3例疗效不良患儿分别于3、8、8岁进行了肝移植治疗，术后1周内血液蛋氨酸及同型半胱氨酸恢复正常。1例患儿死亡。1例患儿母亲再孕时进行产前诊断，羊水细胞CBS基因存在与患儿相同的致病变异。 结论： 经典型同型半胱氨酸尿症临床表现复杂多样，血氨基酸、血清及尿液总同型半胱氨酸和基因分析是诊断的关键。检出10种CBS基因新变异，扩展了CBS基因变异谱。肝移植为有效的治疗办法。产前诊断是防控经典型同型半胱氨酸尿症的重要措施。.
2019-10-01 | Feasibility of domino liver transplantation from hyperhomocsyteinemia
Hyperhomocysteinemia, resulting from a cystathionine beta synthase (CBS) deficiency, is an autosomal recessive disease associated with high levels of homocysteine. Such patients can present with severe mental retardation, ectopia lentis and osteoporosis and thromboembolic disease. To the best of our knowledge, only two cases of liver transplantation for CBS deficiency have been published. Here, we report a case of an 8-year-old male with a CBS deficiency that underwent living donor liver transplantation. The postoperative course was uneventful and homocysteine levels remained normal. The liver of this CBS deficiency patient was then successfully used in domino transplantation. The domino liver transplantation recipient was a 41-year-old male diagnosed with acute liver failure following hemi-liver resection due to cholangiocarcinoma. The domino recipient developed acquired hyperhomocysteinemia, which was controlled with a special regimen of medications. No complications relative to CBS deficiency were observed up to 11 months post-transplant. At this time, the patient expired as a result of cholangiocarcinoma recurrence. In conclusion, our data suggest that liver transplantation for CBS deficiency can be effective, safe and beneficial. It is possible to be both safe and beneficial to use a CBS deficiency patient as a domino donor for salvage liver transplantation in a selective category of recipients.
2015-09-14 | Hyperhomocysteinemia suppresses bone marrow CD34+/VEGF receptor 2+ cells and inhibits progenitor cell mobilization and homing to injured vasculature-a role of β1-integrin in progenitor cell migration and adhesion.
Hyperhomocysteinemia (HHcy) impairs re-endothelialization and accelerates vascular remodeling. The role of CD34(+)/VEGF receptor (VEGFR) 2(+) progenitor cells (PCs) in vascular repair in HHcy is unknown. We studied the effect of HHcy on PCs and its role in vascular repair in severe HHcy (∼150 μM), which was induced in cystathionine-β synthase heterozygous mice fed a high-methionine diet for 8 weeks. Vascular injury was introduced by carotid air-dry endothelium denudation. CD34(+)/VEGFR2(+) cells were examined by flow cytometry. HHcy reduced bone marrow (BM) CD34(+)/VEGFR2(+) cells and suppressed replenishment of postinjury CD34(+)/VEGFR2(+) cells in peripheral blood (PB). Donor green fluorescent protein-positive PC homing to the injured vessel was reduced in HHcy after CD34(+) PCs from enhanced green fluorescent protein mice were adoptively transferred following carotid injury. CD34(+) PC transfusion partially reversed HHcy-suppressed re-endothelialization and HHcy-induced neointimal formation. Furthermore, homocysteine (Hcy) inhibited proliferation, adhesion, and migration and suppressed β1-integrin expression and activity in human CD34(+) endothelial colony-forming cells (ECFCs) isolated from PBs in a dose-dependent manner. A functional-activating β1-integrin antibody rescued Hcy-suppressed adhesion and migration in CD34(+) ECFCs. In conclusion, HHcy reduces BM CD34(+)/VEGFR2(+) generation and suppresses CD34(+)/VEGFR2(+) cell mobilization and homing to the injured vessel via β1-integrin inhibition, which partially contributes to impaired re-endothelialization and vascular remodeling.
gene therapies
2026-04-14 | Liver-Targeted AAV-DJ-hCBS Therapy Achieves Long-Term Correction of Metabolic Imbalance in CBS-Deficient Mice.
Cystathionine β-synthase (CBS) deficiency causes classical homocystinuria with severe hyperhomocysteinemia (HHcy) that is inadequately controlled by current therapies. We tested whether liver-targeted CBS gene therapy provides durable biochemical and phenotypic rescue. Using a Cre-inducible adult mouse model of whole-body CBS loss, a single intravenous dose of AAV-DJ-hCBS (3 × 1012 or 3 × 1013 vg/kg) was administered, and the animals were followed for 12 months. Vector biodistribution showed ~100-fold hepatic enrichment over the kidney and spleen. Both doses rapidly normalized plasma homocysteine (<8 µM), maintaining correction throughout the study while preventing alopecia, weight loss, and loss of adiposity. Liver histology showed resolution of inflammation, and only 2 of 19 mice developed anti-hCBS antibodies. Liver proteomics (3998 proteins quantified) revealed CBS deficiency-associated suppression of tRNA aminoacylation and dysregulation of lipid and carbon metabolism with an HNF4A transcriptional signature, all normalized by therapy. Liver metabolomics demonstrated accumulation of S-adenosylmethionine and S-adenosylhomocysteine and disruption of phosphatidylcholine synthesis, also corrected by treatment. Plasma metabolomics revealed systemic disturbances fully normalized by hepatic CBS restoration. These findings identify the liver as the central metabolic control point in CBS deficiency and support liver-targeted gene therapy as a durable corrective strategy.
2024-06-14 | Komrower Memorial Lecture 2023. Molecular basis of phenotype expression in homocystinuria: Where are we 30 years later?
This review summarises progress in the research of homocystinuria (HCU) in the past three decades. HCU due to cystathionine β-synthase (CBS) was discovered in 1962, and Prof. Jan Peter Kraus summarised developments in the field in the first-ever Komrower lecture in 1993. In the past three decades, significant advancements have been achieved in the biology of CBS, including gene organisation, tissue expression, 3D structures, and regulatory mechanisms. Renewed interest in CBS arose in the late 1990s when this enzyme was implicated in biogenesis of H2S. Advancements in genetic and biochemical techniques enabled the identification of several hundreds of pathogenic CBS variants and the misfolding of missense mutations as a common mechanism. Several cellular, invertebrate and murine HCU models allowed us to gain insights into functional and metabolic pathophysiology of the disease. Establishing the E-HOD consortium and patient networks, HCU Network Australia and HCU Network America, offered new possibilities for acquiring clinical data in registries and data on patients' quality of life. A recent analysis of data from the E-HOD registry showed that the clinical variability of HCU is broad, extending from severe childhood disease to milder (late) adulthood forms, which typically respond to pyridoxine. Pyridoxine responsiveness appears to be the key factor determining the clinical course of HCU. Increased awareness about HCU played a role in developing novel therapies, such as gene therapy, correction of misfolding by chaperones, removal of methionine from the gut and enzyme therapies that decrease homocysteine or methionine in the circulation.
2023-01-06 | Recent therapeutic approaches to cystathionine beta-synthase-deficient homocystinuria.
Cystathionine beta-synthase (CBS)-deficient homocystinuria (HCU) is the most common inborn error of sulfur amino acid metabolism. The pyridoxine non-responsive form of the disease manifests itself by massively increasing plasma and tissue concentrations of homocysteine, a toxic intermediate of methionine metabolism that is thought to be the major cause of clinical complications including skeletal deformities, connective tissue defects, thromboembolism and cognitive impairment. The current standard of care involves significant dietary interventions that, despite being effective, often adversely affect quality of life of HCU patients, leading to poor adherence to therapy and inadequate biochemical control with clinical complications. In recent years, the unmet need for better therapeutic options has resulted in development of novel enzyme and gene therapies and exploration of pharmacological approaches to rescue CBS folding defects caused by missense pathogenic mutations. Here, we review scientific evidence and current state of affairs in development of recent approaches to treat HCU.
2022-02-03 | Long-term functional correction of cystathionine β-synthase deficiency in mice by adeno-associated viral gene therapy.
Cystathionine β-synthase (CBS) deficiency is a recessive inborn error of sulfur metabolism characterized by elevated blood levels of total homocysteine (tHcy). Patients diagnosed with CBS deficiency are currently treated by a combination of vitamin supplementation and restriction of foods containing the homocysteine precursor methionine, but the effectiveness of this therapy is limited due to poor compliance. A mouse model for CBS deficiency (Tg-I278T Cbs-/- ) was used to evaluate a potential gene therapy approach to treat CBS deficiency utilizing an AAVrh.10-based vector containing the human CBS cDNA downstream of the constitutive, strong CAG promoter (AAVrh.10hCBS). Mice were administered a single dose of virus and followed for up to 1 year. The data demonstrated a dose-dependent increase in liver CBS activity and a dose-dependent decrease in serum tHcy. Liver CBS enzyme activity at 1 year was similar to Cbs+/- control mice. Mice given the highest dose (5.6 × 1011 genomes/mouse) had mean serum tHcy decrease of 97% 1 week after injection and an 81% reduction 1 year after injection. Treated mice had either full- or substantial correction of alopecia, bone loss, and fat mass phenotypes associated with Cbs deficiency in mice. Our findings show that AAVrh.10-based gene therapy is highly effective in treating CBS deficiency in mice and supports additional pre-clinical testing for eventual use human trials.
2021-08-03 | Liver transplant as a curative treatment in a pediatric patient with classic homocystinuria: A case report.
We report a patient with homocystinuria and hyperoxaluria who was cured of homocystinuria-related disease following liver transplant. The patient was diagnosed with homocystinuria as a newborn and was treated with dietary modifications and supplements. At 22 months, he passed a calcium oxalate stone and was found to have numerous bilateral kidney stones. Genetic testing confirmed primary hyperoxaluria, type 1. He underwent preemptive liver transplant at age four to treat primary hyperoxaluria. Following transplant, his serum methionine and homocysteine levels normalized, thus, demonstrating resolution of homocystinuria. Methionine and homocysteine levels remained normal 6 years later. Homocystinuria is associated with ophthalmologic, skeletal, neurologic, and thromboembolic complications. As cystathionine beta-synthase resides in the liver, transplant was hypothesized to be an effective treatment. Primary hyperoxaluria generally progresses to chronic kidney disease and is treated with combined kidney-liver transplant at the time of end stage kidney disease. Given this patient's dual diagnoses, we proceeded with preemptive liver transplantation. Three prior cases of patients with homocystinuria treated with liver transplantation have been reported. In all cases, transplant resolved metabolic effects. However, our case represents a pediatric patient without disease-related complications prior to transplant. This case supports liver-targeted gene therapies as an effective treatment for homocystinuria.
proteins
2025-11-14 | 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.
2025-05-18 | Safety and efficacy of pegtibatinase enzyme replacement therapy in adults with classical homocystinuria in the COMPOSE phase 1/2 randomized trial.
Because the standard-of-care treatment for classical homocystinuria (HCU) often cannot achieve adequate metabolic control, the phase 1/2 COMPOSE trial (NCT03406611) evaluated pegtibatinase enzyme replacement therapy. Participants with HCU aged 12 to 65 years with elevated total plasma homocysteine (tHcy) receiving standard-of-care treatment were randomized 3:1 into 6 increasing dose cohorts (each n ≈ 4) of subcutaneous pegtibatinase (≤2.5 mg/kg twice weekly [BIW]) or placebo. Primary end points included adverse event incidence and immunogenicity. Secondary end points included tHcy change from baseline to posttreatment (geometric mean of weeks 6-12). Overall, 24 participants were enrolled. Pegtibatinase was generally well tolerated at all doses with no anaphylaxis or severe immune reactions; 15 participants (62.5%) experienced ≥1 treatment-related treatment-emergent adverse event (most commonly injection-site reactions; 1 serious [acute urticaria]). At the 2 highest doses, substantial tHcy reductions were observed after treatment (relative reduction: 57% for 1.5 mg/kg BIW; 67% for 2.5 mg/kg BIW), and all participants maintained tHcy < 100 μM. One participant receiving 2.5 mg/kg BIW achieved tHcy < 15 μM (normal) and methionine < 14 μM (below normal), enabling increased dietary intact protein intake. Changes in other metabolites aligned with tHcy. Pegtibatinase was generally well tolerated and substantially reduced tHcy levels, demonstrating potential as a treatment for HCU.
2023-10-23 | An orally administered enzyme therapeutic for homocystinuria that suppresses homocysteine by metabolizing methionine in the gastrointestinal tract.
Classical homocystinuria (HCU) is a rare inborn error of amino acid metabolism characterized by accumulation of homocysteine, an intermediate product of methionine metabolism, leading to significant systemic toxicities, particularly within the vascular, skeletal, and ocular systems. Most patients require lifelong dietary therapy with severe restriction of natural protein to minimize methionine intake, and many patients still struggle to maintain healthy homocysteine levels. Since eliminating methionine from the diet reduces homocysteine levels, we hypothesized that an enzyme that can degrade methionine within the gastrointestinal (GI) tract could help HCU patients maintain healthy levels while easing natural protein restrictions. We describe the preclinical development of CDX-6512, a methionine gamma lyase (MGL) enzyme that was engineered for stability and activity within the GI tract for oral administration to locally degrade methionine. CDX-6512 is stable to low pH and intestinal proteases, enabling it to survive the harsh GI environment without enteric coating and to degrade methionine freed from dietary protein within the small intestine. Administering CDX-6512 to healthy non-human primates following a high protein meal led to a dose-dependent suppression of plasma methionine. In Tg-I278T Cbs-/- mice, an animal model that recapitulates aspects of HCU disease including highly elevated serum homocysteine levels, oral dosing of CDX-6512 after a high protein meal led to suppression in serum levels of both methionine and homocysteine. When animals received a daily dose of CDX-6512 with a high protein meal for two weeks, the Tg-I278T Cbs-/- mice maintained baseline homocysteine levels, whereas homocysteine levels in untreated animals increased by 39%. These preclinical data demonstrate the potential of CDX-6512 as an oral enzyme therapy for HCU.
2022-03-01 | Characterization and application of l-methionine γ-lyase Q349S mutant enzyme with an enhanced activity toward l-homocysteine.
l-Methionine γ-lyse (MGL), a pyridoxal 5'-phosphate-dependent enzyme, catalyzes the α,γ-elimination of l-methionine (l-Met) and l-homocysteine (l-Hcy) to produce α-keto acids, thiols, and ammonia. Previously, various mutant enzymes of Pseudomonas putida MGL (PpMGL) were prepared to identify a homocysteine (Hcy)-specific enzyme that would assist the diagnosis of homocystinuria. Among the mutat enzymes the Q349S mutant exhibited high degradation activity toward l-Hcy. In the present study, PpMGL Q349S was characterized; the results suggested that it could be applied to determine the amount of l-Hcy. Compared to the wild-type PpMGL, specific activities of the Q349S mutant with l-Hcy and l-Met were 1.5 and 0.7 times, respectively. Additionally, we confirmed that l-Hcy in plasma samples could be accurately detected using the Q349S mutant by preincubating it with cysteine desulfurase (CsdA). Furthermore, we determined the X-ray crystal structure of PpMGL Q349S l-Met or l-Hcy complexes Michaelis complex, germinal diamine, and external aldimine at 2.25-2.40 Å. These 3D structures showed that the interaction partner of the β-hydroxyl group of Thr355 in the wild-type PpMGL was changed to the carboxyl group of the Hcy-PLP external aldimine in the Q349S mutant. The interaction of Ser349 and Arg375 was different between l-Met and l-Hcy recognition, indicating that it was important for the recognition of the carboxyl group of the substrate.
2020-07-24 | Hypermethioninemia Leads to Fatal Bleeding and Increased Mortality in a Transgenic I278T Mouse Model of Homocystinuria
Severely elevated plasma homocysteine and methionine lead to thromboembolic events and strokes in homocystinuric (HCU) patients. Mouse models of HCU failed to exhibit prothrombotic phenotype, presumably due to lack of hypermethioninemia. We evaluated the impact of hypermethioninemia together with hyperhomocysteinemia on murine HCU phenotype and compared the efficacy of the current and novel therapies for HCU. High methionine intake decreased survival of I278T mice, which died from intestinal bleeding with hepatic and pancreatic failure. I278T mice on normal or increased methionine intake developed endothelial dysfunction, but paradoxically demonstrated delayed occlusion in an induced arterial thrombosis model. RNA-seq analysis suggested that expression of coagulation factor XI (FXI) is downregulated in livers of I278T mice. Indeed, plasma concentrations of FXI were decreased in I278T mice on normal diet and further reduced by increased methionine intake. Dietary methionine restriction normalized the observed phenotype. Similarly, treatment with OT-58, a novel enzyme therapy for HCU, corrected the phenotype in I278T mice regardless of their dietary methionine intake. Hypermethioninemia does not contribute to prothrombotic phenotype in murine HCU. Downregulation of FXI may contribute to the lack of prothrombotic tendency in I278T mice. Methionine restriction or treatment with OT-58 corrects vascular disease in the I278T mouse model of HCU.
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Drug Discovery Landscape
9 orphan drug designations for Homocystinuria due to cystathionine beta-synthase deficiency, including 1 approved therapy.
9 orphan drug designations for Homocystinuria due to cystathionine beta-synthase deficiency, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
betaine | small molecules | FDA | 2026-07-17 | — | Cycle Pharmaceuticals Ltd. |
Modified human cystathionine beta synthase messenger ribonucleic acid encapsulated in a lipid nanoparticle | RNAs | FDA | 2024-07-18 | — | INNORNA USA INC. |
live biotherapeutic consisting of metP and metDC genes which are incorporated into the genome of a probiotic strain of E. coli Nissie 1917 | other | FDA | 2022-11-22 | — | Synlogic Operating Company, Inc. |
Poly(oxy-1,2-ethanediyl), alpha-(carboxymethyl)-omega-methoxy-, amide with cystathionine γ-lyase [Pyridoxal 5’-phosphate cofactor] (synthetic engineered human), tetramer | proteins | EMA | 2020-10-19 | — | Aeglea Ireland Limited |
Polyethylene glycol-modified human recombinant truncated cystathionine beta-synthase | proteins | EMA | 2016-05-30 | — | Travere Therapeutics Ireland Limited |
polyethylene glycol modified recombinant C-terminal truncate of human cystathionine beta-synthase | proteins | FDA | 2015-03-17 | — | Travere Therapeutics Switzerland GmbH |
taurine | small molecules | FDA | 2010-03-22 | — | Johan L. Van Hove, MD, PhD |
Betaine [Cystadane] | small molecules | EMA | 2001-07-09 | — | Recordati Rare Diseases |
Betaine [Cystadane] | small molecules | FDA | 1994-05-16 | 1996-10-25 | Orphan Europe SARL |
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