RARE DISEASE
Maple syrup urine disease
Maple syrup urine disease
Maple syrup urine disease
Synonyms: BCKD deficiency, BCKDH deficiency, Branched-chain 2-ketoacid dehydrogenase deficiency, Branched-chain ketoaciduria, MSUD
Synonyms: BCKD deficiency, BCKDH deficiency, Branched-chain 2-ketoacid dehydrogenase deficiency, Branched-chain ketoaciduria, MSUD
Synonyms: BCKD deficiency, BCKDH deficiency, Branched-chain 2-ketoacid dehydrogenase deficiency, Branched-chain ketoaciduria, MSUD
Drug discovery
5
drugs
With orphan designations
Overview
Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive disorder caused by deficient activity of the branched-chain α-ketoacid dehydrogenase complex, leading to toxic accumulation of leucine, isoleucine, and valine. Classic neonatal presentation includes encephalopathy, feeding difficulties, and a distinctive maple syrup odor in bodily fluids. Early diagnosis via newborn screening and prompt dietary intervention are critical to prevent irreversible neurological damage or death. Lifelong management involves a protein-restricted diet, metabolic monitoring, and emergency protocols for decompensation. Liver transplantation remains a curative option but carries surgical risks [1][2][5].
Burden
Clinical: Risk of neurodevelopmental delays, psychiatric comorbidities, and acute metabolic crises triggered by catabolic stressors (e.g., infections) [6][9][17].
Management: Strict dietary adherence, frequent hospitalizations, and specialized care impose significant psychosocial and economic strain [6][16].
Mortality: Untreated cases are fatal within weeks; treated individuals face lifelong disability risks [1][5][16].
Therapies
Dietary management: Protein restriction with synthetic formulas lacking branched-chain amino acids (BCAAs) [1][5][16].
Monitoring: Regular blood leucine, isoleucine, and valine quantification [1][16].
Transplantation: Liver transplant resolves metabolic defects but requires lifelong immunosuppression [3][9][14].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
456 drug discovery papers about Maple syrup urine disease, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
456 drug discovery papers about Maple syrup urine disease, 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
2026-06-22 | Treatment strategies, radiological recovery, and neurodevelopmental outcomes in paediatric Maple Syrup Urine Disease: a 20-year single-centre experience from Türkiye.
Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive metabolic disorder characterised by defective branched-chain amino acid (BCAA) catabolism, leading to neurotoxicity, recurrent metabolic crises, and neurodevelopmental impairment. Evidence on long-term outcomes in paediatric cohorts, particularly with pharmacological adjuncts such as sodium phenylbutyrate (NaPBA) and radiological recovery, remains limited. We undertook a retrospective review of 13 paediatric patients with MSUD (69.2% classic phenotype, 30.8% intermittent) followed at a tertiary metabolic centre in Türkiye between 2003 and 2022. Demographic, biochemical, neurodevelopmental, neuroimaging, and genetic data were evaluated, with specific attention to dietary management, haemodialysis during acute decompensation, and NaPBA therapy. All patients exhibited neurodevelopmental delay, which was more pronounced in the classic phenotype. Milestone-level analysis demonstrated delays in walking (85%), sentence formation (92.3%), and toilet training (92.3%). One year after dietary intervention, mean plasma concentrations of leucine, isoleucine, and valine decreased by 60.9%, 55.9%, and 65.0%, respectively (p < 0.01). Haemodialysis during metabolic crises rapidly reduced leucine (- 73.8%) and ammonia (- 66%), though was more frequently required in patients with the classic phenotype. NaPBA treatment was associated with lower leucine levels during follow-up (p < 0.05). Baseline MRI abnormalities were identified in 87% of patients; 57% showed complete resolution post-treatment, with partial radiological improvement observed alongside clinical follow-up. A phenotype-specific approach combining early dietary intervention, timely haemodialysis in acute crises, and selective use of NaPBA may support metabolic stabilisation and radiological improvement in selected patients. Larger multicentre studies are warranted to validate these findings and refine management protocols.
2026-06-07 | Management of acute metabolic decompensation in maple syrup urine disease: guidance based on international clinical practice.
Maple syrup urine disease (MSUD) is an autosomal recessive inborn error of metabolism caused by a deficiency of branched-chain ketoacid dehydrogenase, the enzyme involved in the second step of branched-chain amino acid catabolism. Of the three branched-chain amino acids (leucine, valine, and isoleucine), accumulation of leucine is the predominant factor causing acute metabolic decompensation in patients with MSUD. In February 2025, eight expert physicians met to discuss the management of acute metabolic decompensation and propose recommendations after literature review (four guidelines and 20 other articles of interest). A practical clinical algorithm was established. Newborn screening was acknowledged to be a successful method of diagnosing MSUD at birth, facilitating early intervention to prospectively manage MSUD and reduce the frequency and severity of acute metabolic decompensation, although it was noted that infants with severe MSUD often present with acute metabolic decompensation before being diagnosed. The experts also identified several barriers to and gaps in the management of acute metabolic decompensation, and MSUD more generally, proposing potential actions to improve clinical outcomes. Acute metabolic decompensation requires prompt, effective treatment by a multidisciplinary team to ensure that circulating plasma leucine levels are rapidly reduced without causing complications (particularly cerebral edema). Where available, intravenous branched chain amino acid-free solutions (e.g., Maapliv, now approved in Europe) may represent an important treatment option. Adequate resources (treatments, laboratory services, dialysis units) are essential for effective management of acute metabolic decompensation. Liver transplantation is an accepted viable option for the long-term prevention of acute metabolic decompensation in eligible patients. Research is ongoing into new treatment options for MSUD, such as gene therapy. Optimal management of acute metabolic decompensation in patients with MSUD requires prompt, effective treatment to reduce leucine levels without causing complications. A ready-to-use branched chain amino acid-free intravenous solution has been recently approved in Europe and research into new treatment options is ongoing.
2026-05-21 | The role of essential fatty acid deficiencies in cognitive function among patients with organic acidemias
Objective: Organic acidemias (OAs) are metabolic disorders characterized by enzyme deficiencies that impair amino acid catabolism, leading to metabolic imbalances. Essential fatty acids (EFAs), particularly Omega-3 and Omega-6, are vital for cellular and neurological functions but are often affected by protein-restricted diets used in OA management. The aim of this study was to evaluate the plasma EFA levels in OA patients and explores their clinical relevance. Materials and Methods: A prospective, case-control design was adopted, including 26 OA patients (methylmalonic acidemia, propionic acidemia, isovaleric acidemia, maple syrup urine disease) and 22 healthy age- and gender-matched controls. Plasma EFA levels were quantified via gas chromatography-mass spectrometry. Cognitive and psychiatric evaluations were performed using standardized tests, including DSM-V-TR criteria, Wechsler Intelligence Scale for Children, and other psychometric tools. Statistical analyses assessed the relationships between EFA levels and clinical findings. Results: Organic acidemias patients exhibited significantly lower levels of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) + DHA, and Omega-3 compared to controls, with higher Omega-6/Omega-3 ratios. Despite these findings, no significant correlations emerged between EFA levels and cognitive or psychiatric outcomes. Conclusion: EFA deficiencies are prevalent among OA patients on protein-restricted diets, underscoring the potential need for targeted nutritional interventions. However, the absence of a direct association with clinical findings suggests multifactorial influences on disease outcomes. Future research should explore the longitudinal effects of EFA supplementation and its role in mitigating neurodevelopmental impairments in OA.
2026-04-02 | Simplifying supplementation in MSUD: tolerance and acceptability of liquid valine and isoleucine supplements in maple syrup urine disease
Abstract Introduction Maple Syrup Urine Disease (MSUD) is a rare metabolic disorder requiring lifelong restriction of branched-chain amino acids (BCAAs), and targeted supplementation with valine and isoleucine to maintain metabolic stability. Methods A prospective, open-label, observational study was conducted over 56 days in 5 paediatric patients mean age 8.8 years (range 3–14) with classical MSUD. In Phase 1 (Days 0–28), participants received the ready to use (RTU) liquid valine formulation, while continuing their usual powdered isoleucine supplement. In Phase 2 (Days 29–56), participants returned to powdered valine and changed to the ready to use RTU liquid isoleucine supplement. Weekly plasma BCAAs were monitored. Acceptability, gastrointestinal tolerance, adherence, and dietary intake were assessed through questionnaires and food diaries. Results RTU liquid valine and isoleucine supplements were well tolerated and accepted by all participants. Plasma leucine decreased when taking both liquid valine (mean leucine 253 µmol/L) and isoleucine (mean leucine 219 µmol/L) compared to baseline (mean leucine 356 µmol/L). Required doses of valine and isoleucine decreased by 30% and 18%, respectively, suggesting improved adherence or enhanced efficacy. Palatability and ease of use were rated more favourably for the RTU products, with no adverse effects or adherence issues reported. Dietary intake remained stable throughout the study. Discussion These preliminary findings suggest that RTU valine and isoleucine formulations may offer potential advantages in MSUD management, simplifying administration, and enhancing user satisfaction. While limited by sample size and short-term evaluation, their practicality and patient-centered design warrant further investigation in larger, more diverse populations to establish long-term efficacy and broader applicability.
2026-03-24 | Alterations in gut microbiota composition in children with methylmalonic acidemia, propionic acidemia, and maple syrup urine disease.
Methylmalonic acidemia (MMA), propionic acidemia (PA), and maple syrup urine disease (MSUD) are rare monogenic disorders that are described as intoxication-type inborn errors of metabolism (IEMs). They usually present in early life, and long-term management requires strict dietary protein restriction, which may significantly alter gut microbiota composition. Despite growing interest in microbiome research, limited data exist on gut microbiota in these disorders, and no study is available for MMA and MSUD. We aimed to describe the gut microbiota compositions in children with MMA, PA, and MSUD. A total of eight patients (Five MMA, one PA, and two MSUD), and 11age-matched healthy controls were enrolled. All patients were following a medically supervised, protein-restricted diet. Fecal sample was collected from each participant, and gut microbiota composition was evaluated with 16S rRNA sequencing. Patients with MMA, PA, and MSUD exhibited significantly altered gut microbiota composition compared to healthy controls. Alpha diversity analysis revealed reduced microbial richness in patients, with significantly lower Chao1 and observed OTU indices (p < 0.05). Beta diversity metrics demonstrated distinct clustering between groups, indicating significantly different microbial community structures. Higher relative abundances of opportunistic or dysbiotic taxa have been seen in patient group, while controls were enriched in beneficial taxa like Faecalibacterium prausnitzii, Ruminococcus, and Lactobacillus. LEfSe analysis identified 17 taxa enriched in patients-including members of Proteobacteria, Sphingobacteriia, and Streptococcus anginosus-and 6 taxa enriched in controls, notably Faecalibacterium prausnitzi. This is the first descriptive study of the gut microbiota composition of MMA, PA, and MSUD patients. These findings indicate an association between long-term dietary management and altered microbiota composition, although causality cannot be inferred due to the cross-sectional study design. The observed alterations suggest that the gut microbiota may represent a novel therapeutic target in the management of IEMs.
cell therapies
2026-02-25 | Clinical Profiles, Genetic Variants, and Neurodevelopmental Outcomes Following Liver Transplantation in Maple Syrup Urine Disease: A Study From Palestine.
Maple syrup urine disease (MSUD) is a rare, autosomal recessive metabolic disorder resulting from a deficiency of the branched-chain α-ketoacid dehydrogenase complex. This leads to the accumulation of branched-chain amino acids and their corresponding ketoacids, causing acute metabolic crises and progressive neurological damage if untreated. The impact of founder variants, high consanguinity, and limited access to metabolic care pose challenges in medically underserved populations, such as in Palestine. We conducted a retrospective analysis of 11 patients from eight Palestinian families referred to the main Metabolic Unit in the West Bank. Clinical data, biochemical profiles, and molecular findings were reviewed to characterize the presentation and outcomes of MSUD. Management strategies, including dietary intervention and liver transplantation, were also evaluated. Acute metabolic crises were the initial presentation in 91% of cases, typically within the first days of life. Diagnostic delay averaged 47 days in families without prior MSUD history, compared to 2.3 days in those with affected siblings. Founder pathogenic variants were identified in multiple unrelated families, reflecting genetic homogeneity due to community structure; novel variants were also detected. Timely diagnosis facilitated early referral and improved outcomes. Patients who underwent liver transplantation, especially when performed early, exhibited favorable developmental trajectories, increased leucine tolerance, and fewer hospitalizations. One participant diagnosed prenatally remained free of metabolic crises until transplantation at age six, with excellent neurocognitive outcomes. This study highlights the importance of integrating prenatal screening and early diagnosis, timely dietary intervention, and liver transplantation to improve MSUD outcomes in resource-limited settings.
2026-01-15 | Pediatric Full and In-situ Split Domino Living Donor Liver Transplants Experience.
Domino liver transplantation (DLT) is a method in which an explanted liver from a patient with metabolic disease is transplanted to another recipient. In cases where the liver is split and used for two recipients, the technique is termed domino split liver transplantation. This study presents our experience with three pediatric DLT cases, in which liver grafts from two donor-recipient patients with maple syrup urine disease (MSUD) were transplanted to separate recipients. First donor recipient's liver was splitted in situ, while the other was transplanted as a full-sized graft. Demographics, surgical techniques, biliary reconstruction methods, and posttransplant outcomes were analyzed. All recipients were discharged uneventfully following transplantation. No vascular or biliary complications were observed, and de novo MSUD did not develop in any recipient. This confirms that MSUD livers are safe for DLT, particularly in pediatric cases. DLT using MSUD donor livers is a viable option for expanding the organ pool for pediatric transplantation. Advancements in surgical techniques and perioperative care contribute to improved patient outcomes, making DLT a valuable strategy in liver transplantation programs.
2025-12-26 | Pediatric liver transplant for maple syrup urine disease a single center experience.
Maple syrup urine disease (MSUD) is an autosomal recessive inborn error of branched-chain amino acid metabolism caused by an inherited deficiency of branched-chain alpha-ketoacid dehydrogenase (BCKDH) activity that degrades isoleucine, leucine, and valine. Liver transplantation (LT) is a therapeutic option to treat the classical severe type of MSUD. This study aimed to assess and compare liver biochemical outcomes and amino BCAAs levels post-LT according to different types of donors. Retrospective cohort analysis of 10 patient medical records diagnosed as MSUD who underwent LT in King Fahad Specialist Hospital-Dammam between January 2013 and May 2023. Ten pediatric patients diagnosed with MSUD who had finished 1 year of follow-up after LT were included in the study. The median age of diagnosis among the pediatric patients was 1 month (as it is included in the national neonatal screening). Besides, the median age for LT was 123 months (10 years 3 months) (with a range of 9-173 months). Availability of milk formula, prevention of further neurological insult, and difficulty in controlling the protein intake were the main indications for LT. Post LT, six patients (60%) were immediately initiated on a regular diet, and four patients (40%) waited for 3 months before starting a regular diet. All the patients were on Tacrolimus as immunosuppression, with three patients started on Mycophenolate because of biopsy-proven acute cellular rejection. Our result showed 100% 1-year graft survival and 100% until the time of report, with no donor complications. 70% of the explanted liver had been re-transplanted as a domino liver transplant. No clinical or laboratory difference when comparing living-related to living-unrelated or deceased donor liver transplant. 100% of our patients and families showed satisfaction with the decision of liver transplant. MSUD post liver transplant showed a 100% graft survival rate, and all patients and families showed satisfaction. In settings with limited deceased donor organs, living-related donor LT (even from heterozygous carriers) is a viable option for MSUD, yielding comparable metabolic control and graft outcomes to other donor types.
2025-12-18 | Domino Hepatectomy and Implantation With Innovative Outflow Reconstruction for an Adult Patient With Maple Syrup Urine Disease and Type 1 Diabetes Mellitus: Surgical Technique.
Maple syrup urine disease is characterized by deficient metabolism of branched chain amino acids leading to neurological and developmental delays. Because livers with maple syrup urine disease are histologically normal except for a single enzyme deficiency, which is also present in other organs, liver transplant provides adequate enzymes for metabolism of branched chain amino acids, and the explanted liver can be used as a domino graft for another person needing a liver transplant. We report on the case of a rare individual who survived into adulthood with ante-natal diagnosis and strict dietary management. His recent clinical course was complicated by the development of diabetes mellitus leading to recurrent instances of diabetic ketoacidosis or maple syrup urine disease crisis necessitating liver transplant. Our technical modifications enabled a safe and quick domino hepatectomy by minimizing anesthesia time and the anhepatic phase and timely preparation of the domino graft for an uneventful implantation.
2025-11-17 | Design and pharmacodynamic study of live biotherapeutic products with efficient degradation of branched-chain amino acids.
The homeostasis of branched-chain amino acids (BCAAs) plays a crucial role in maintaining health, and the accumulation of BCAAs can lead to various diseases. Therefore, exogenous degradation or conversion of excessive BCAAs may help alleviate diseases caused by BCAA accumulation, such as maple syrup urine disease. This study utilized synthetic biology approaches to engineer two strains for efficient BCAA catabolism successfully-ECN-Deg and ECN-Tra-by integrating specific metabolic pathways into the chassis strain, Escherichia coli Nissle 1917 (ECN). ECN-Deg integrates a metabolic module for BCAA degradation, while ECN-Tra integrates a metabolic module for BCAA transformation. Both engineered strains demonstrate efficient BCAA catabolism in vitro and in vivo. In a high-BCAA mouse model, ECN-Deg and ECN-Tra alleviated liver and ileal damage caused by excessive BCAAs and reduced systemic inflammation levels. Furthermore, ECN-Deg and ECN-Tra were able to modulate the gut microbiota, increasing the richness of Akkermansia muciniphila and Mucispirillum schaedleri, which are associated with health benefits. Additionally, they reduced the richness of the pathogenic bacterium Streptococcus pasteurianus. Thus, this study lays the foundation for the development of probiotics for the treatment of BCAAs metabolic disorders and BCAAs-related chronic diseases.
gene therapies
2026-05-15 | Systemic dual-gene therapy reverses biochemical intoxication in the central metabolic compartment of Bckdha-/- mice.
Branched-chain 2-ketoacid dehydrogenase (BCKDH) deficiency (maple syrup urine disease; MSUD) causes lethal encephalopathy by disrupting cerebral metabolism, a process imperfectly reflected by circulating biomarkers. Diet and liver transplantation stabilize peripheral metabolites but fail to restore brain neurochemistry, demarcating the central nervous system as the decisive therapeutic compartment. To define the pathogenesis of intoxication and its therapeutic response, we performed paired serum-brain metabolomics in Bckdha-/- mice treated with a systemic AAV9 dual-gene vector encoding human BCKDHA and BCKDHB (A-BiP-B). Untreated neonates exhibited a 9-fold elevation of brain 2-ketoisocaproate accompanied by cerebral depletion of glutamate and glutamine, as well as shifts in tricarboxylic acid cycle and ketone body metabolism. These disturbances originated from reversal of branched-chain aminotransferase 2 flux and destabilization of glutamate-2-ketoglutarate mass balance, producing divergent metabolic endophenotypes in blood versus brain. A single intravenous injection of A-BiP-B rescued mice from fatal encephalopathy, partially restored cerebral BCKDHA mRNA expression, and brought core brain neurochemical endpoints within wild-type range despite persistent elevation of serum 2-ketoacids. These findings expose limitations of current MSUD management and establish systemic dual-gene therapy as a means of restoring neurochemical homeostasis while enabling survival on unrestricted protein intake.
2026-05-14 | Trial-ready external controls for gene therapy: The MATCH cohort in maple syrup urine disease.
Maple syrup urine disease (MSUD) is a life-threatening metabolic disorder for which randomized trials are infeasible. We present the MSUD Age-matched Standard Treatment Cohort (MATCH), a prospective natural history study of 11 infants with classic MSUD followed from neonatal diagnosis to liver transplantation. Aligned with Food and Drug Administration (FDA) guidance and International Council for Harmonisation (ICH) E9(R1), MATCH applies prespecified eligibility criteria, fixed visit cadence, adjudicated outcomes, and explicit handling of intercurrent events. Three of six outcome measures-proportional intact protein equivalent (PIPE), crisis management days (CMDs), and blood alloisoleucine concentration-are prespecified as estimands. Monte Carlo simulations show that a single-arm trial comparing 11 treated participants to MATCH controls achieves ≥90% power (p ≤ 0.025) to detect 64% fewer CMDs (3.0% vs. 8.4%), a 57% increase in PIPE (19.3% vs. 12.3%), and a 36% reduction in alloisoleucine (117 vs. 183 μM). MATCH demonstrates how protocolized natural history data serve as regulatory-grade external controls for single-arm trials.
2025-11-20 | Health Implications of Incomplete Metabolism
The important effects of incomplete metabolism on human health are examined in this work, with particular attention to how it may play a role in the etiology of long-term conditions like diabetes, obesity, and mitochondrial diseases. Nutritional deficits, the buildup of hazardous metabolites, and a disturbance of biochemical equilibrium are all consequences of metabolic pathway disruption. The classic cases of phenylketonuria (PKU) and maple syrup urine disease (MSUD) are the grave neurological and developmental effects of metabolic pathway disruption. G6PD insufficiency is an example of how incomplete drug metabolism, which can be caused by genetic polymorphisms, enzyme deficiencies, or hepatic/renal impairments, can lead to metabolic toxicity and drug buildup. Deficiencies in vital vitamins (B12, D, A, K) and minerals (calcium, iron) result in metabolic inefficiencies and clinical aftereffects, such as anemia and neurotoxicity. Nutrient metabolism is also compromised. Lipid intermediate buildup, oxidative stress, and systemic inflammation are all influenced by lipid metabolic abnormalities, which are especially prevalent in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). By affecting ATP synthesis and redox equilibrium, mitochondrial dysfunction aggravates metabolic diseases further. Oxidative stress aggravates illnesses, such as myopathies and lactic acidosis. Novel therapeutic approaches, such as enzyme replacement therapy (ERT), CRISPR-Cas9 gene therapy, and nanotechnology-based methods, present intriguing paths toward pharmacogenomics-driven enzyme regulation and metabolic function restoration, as well as toward precision medicine.
2025-09-27 | Adenine base editing rescues disrupted BCKDH function and reduces BCAAs toxic accumulation in maple syrup urine disease patient iPSC-hepatic organoids.
Maple syrup urine disease (MSUD) is an inherited metabolic disorder caused by a deficiency in the activity of the hepatic branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which leads to the toxic accumulation of three branched-chain amino acids (BCAAs) and their respective α-ketoacid, resulting in severe neurotoxicity, coma and even death without effective therapeutic measures. In this study, we established the patient induced pluripotent stem cells (iPSC)-derived hepatic organoids (HOs), analyzed the characteristics, and applied adenine base editor (ABE8e) to correct a mutation (T322I) of the BCKDHB (branched chain keto acid dehydrogenase E1, beta polypeptide) gene in patient induced pluripotent stem cells (iPSC)-derived hepatic organoids (HOs). qRT-PCR and western blot analysis were performed to assess the expression level of BCKDHA (branched chain keto acid dehydrogenase E1, alpha polypeptide) and BCKDHB. The effects of base editing were comprehensively analyzed using both bulk RNA sequencing and single-cell RNA sequencing (scRNA-Seq). Immunofluorescence and RT-PCR arrayed the high expression of hepatoblast specific proteins in HOs, such as α-1-anti-trypsin (A1AT), hepatocyte nuclear factor-4-alpha (HNF4A), cytokeratin18 (CK18), albumin (ALB), cytochrome P450 family 3 subfamily A member 4 (CYP3A4) and cytochrome P450 family 3 subfamily A member 7(CYP3A7). Functional experiments indicated that these HOs recapitulated characteristics of hepatocytes like glycogen accumulation, low-density lipoprotein (LDL) uptake, indocyanine green (ICG) uptake and release as well as quantitation of ALB and urea from HOs. The levels of BCKDHA and BCKDHB were dramatically decreased in MSUD-HOs compared with control-HOs (P < 0.01) detected by qRT-PCR, western blot and immunofluorescence. Deep sequencing and whole genome sequencing (WGS) demonstrated that the correction of BCKDHB mutation in patient iPSC-derived HOs caused high on-target gene editing without any detectable off-target effects. Moreover, the corrected MSUD-HOs exhibited restored BCKDH enzymatic function and reduced BCAAs level. The transcriptome analysis indicates that the MSUD-HOs with BCKDHB mutation reduced mRNA level of regulating metabolism associated with liver mitochondrial function, while the corrected MSUD-HOs rescued those processes after ABE8e correction. The scRNA-Seq analysis further validated the rescue effects of BCKDH function after gene editing. Our study provides reliable evidence that ABE8e is highly efficient and safe in correcting patient-derived HOs from MSUD, indicating the feasibility to be a transformative treatment for genetic hepatic diseases like MSUD.
2025-02-26 | BCKDHA-BCKDHB digenic gene therapy restores metabolic homeostasis in two mouse models and a calf with classic maple syrup urine disease.
Classic maple syrup urine disease (MSUD) results from biallelic mutations in genes that encode the branched-chain α-ketoacid dehydrogenase E1α (BCKDHA), E1β (BCKDHB), or dihydrolipoamide branched-chain transacylase (DBT) subunits, which interact to form the mitochondrial BCKDH complex that decarboxylates ketoacid derivatives of leucine, isoleucine, and valine. MSUD is an inborn error of metabolism characterized by recurrent life-threatening neurologic crises and progressive brain injury that can only be managed with an exacting prescription diet or allogeneic liver transplant. To develop a gene replacement therapy for MSUD, we designed a dual-function recombinant adeno-associated virus serotype 9 (rAAV9) vector to deliver codon-optimized BCKDHA and BCKDHB (rAAV9.hA-BiP-hB) to the liver, muscle, heart, and brain. rAAV9.hA-BiP-hB restored coexpression of BCKDHA and BCKDHB as well as BCKDH holoenzyme activity in BCKDHA-/- HEK293T cells and did not perturb physiologic branched-chain amino acid homeostasis in wild-type mice at a systemic dose of 2.7 × 1014 vector genomes per kilogram. In two models of severe MSUD (Bckdha-/- and Bckdhb-/- mice) and a newborn calf homozygous for BCKDHA c.248C>T, one postnatal injection prevented perinatal death, normalized growth, restored coordinated expression of BCKDHA and BCKDHB in the skeletal muscle, liver, heart, and brain, and stabilized MSUD biomarkers in the face of high protein ingestion. In summary, we developed a one-time BCKDHA-BCKDHB systemic dual-gene replacement strategy that holds promise as a therapeutic alternative to prescription diet and liver transplant for treatment of MSUD types 1A and 1B, the two most common forms of MSUD in humans.
small molecules
2026-06-22 | Treatment strategies, radiological recovery, and neurodevelopmental outcomes in paediatric Maple Syrup Urine Disease: a 20-year single-centre experience from Türkiye.
Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive metabolic disorder characterised by defective branched-chain amino acid (BCAA) catabolism, leading to neurotoxicity, recurrent metabolic crises, and neurodevelopmental impairment. Evidence on long-term outcomes in paediatric cohorts, particularly with pharmacological adjuncts such as sodium phenylbutyrate (NaPBA) and radiological recovery, remains limited. We undertook a retrospective review of 13 paediatric patients with MSUD (69.2% classic phenotype, 30.8% intermittent) followed at a tertiary metabolic centre in Türkiye between 2003 and 2022. Demographic, biochemical, neurodevelopmental, neuroimaging, and genetic data were evaluated, with specific attention to dietary management, haemodialysis during acute decompensation, and NaPBA therapy. All patients exhibited neurodevelopmental delay, which was more pronounced in the classic phenotype. Milestone-level analysis demonstrated delays in walking (85%), sentence formation (92.3%), and toilet training (92.3%). One year after dietary intervention, mean plasma concentrations of leucine, isoleucine, and valine decreased by 60.9%, 55.9%, and 65.0%, respectively (p < 0.01). Haemodialysis during metabolic crises rapidly reduced leucine (- 73.8%) and ammonia (- 66%), though was more frequently required in patients with the classic phenotype. NaPBA treatment was associated with lower leucine levels during follow-up (p < 0.05). Baseline MRI abnormalities were identified in 87% of patients; 57% showed complete resolution post-treatment, with partial radiological improvement observed alongside clinical follow-up. A phenotype-specific approach combining early dietary intervention, timely haemodialysis in acute crises, and selective use of NaPBA may support metabolic stabilisation and radiological improvement in selected patients. Larger multicentre studies are warranted to validate these findings and refine management protocols.
2026-06-07 | Management of acute metabolic decompensation in maple syrup urine disease: guidance based on international clinical practice.
Maple syrup urine disease (MSUD) is an autosomal recessive inborn error of metabolism caused by a deficiency of branched-chain ketoacid dehydrogenase, the enzyme involved in the second step of branched-chain amino acid catabolism. Of the three branched-chain amino acids (leucine, valine, and isoleucine), accumulation of leucine is the predominant factor causing acute metabolic decompensation in patients with MSUD. In February 2025, eight expert physicians met to discuss the management of acute metabolic decompensation and propose recommendations after literature review (four guidelines and 20 other articles of interest). A practical clinical algorithm was established. Newborn screening was acknowledged to be a successful method of diagnosing MSUD at birth, facilitating early intervention to prospectively manage MSUD and reduce the frequency and severity of acute metabolic decompensation, although it was noted that infants with severe MSUD often present with acute metabolic decompensation before being diagnosed. The experts also identified several barriers to and gaps in the management of acute metabolic decompensation, and MSUD more generally, proposing potential actions to improve clinical outcomes. Acute metabolic decompensation requires prompt, effective treatment by a multidisciplinary team to ensure that circulating plasma leucine levels are rapidly reduced without causing complications (particularly cerebral edema). Where available, intravenous branched chain amino acid-free solutions (e.g., Maapliv, now approved in Europe) may represent an important treatment option. Adequate resources (treatments, laboratory services, dialysis units) are essential for effective management of acute metabolic decompensation. Liver transplantation is an accepted viable option for the long-term prevention of acute metabolic decompensation in eligible patients. Research is ongoing into new treatment options for MSUD, such as gene therapy. Optimal management of acute metabolic decompensation in patients with MSUD requires prompt, effective treatment to reduce leucine levels without causing complications. A ready-to-use branched chain amino acid-free intravenous solution has been recently approved in Europe and research into new treatment options is ongoing.
2026-05-21 | The role of essential fatty acid deficiencies in cognitive function among patients with organic acidemias
Objective: Organic acidemias (OAs) are metabolic disorders characterized by enzyme deficiencies that impair amino acid catabolism, leading to metabolic imbalances. Essential fatty acids (EFAs), particularly Omega-3 and Omega-6, are vital for cellular and neurological functions but are often affected by protein-restricted diets used in OA management. The aim of this study was to evaluate the plasma EFA levels in OA patients and explores their clinical relevance. Materials and Methods: A prospective, case-control design was adopted, including 26 OA patients (methylmalonic acidemia, propionic acidemia, isovaleric acidemia, maple syrup urine disease) and 22 healthy age- and gender-matched controls. Plasma EFA levels were quantified via gas chromatography-mass spectrometry. Cognitive and psychiatric evaluations were performed using standardized tests, including DSM-V-TR criteria, Wechsler Intelligence Scale for Children, and other psychometric tools. Statistical analyses assessed the relationships between EFA levels and clinical findings. Results: Organic acidemias patients exhibited significantly lower levels of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) + DHA, and Omega-3 compared to controls, with higher Omega-6/Omega-3 ratios. Despite these findings, no significant correlations emerged between EFA levels and cognitive or psychiatric outcomes. Conclusion: EFA deficiencies are prevalent among OA patients on protein-restricted diets, underscoring the potential need for targeted nutritional interventions. However, the absence of a direct association with clinical findings suggests multifactorial influences on disease outcomes. Future research should explore the longitudinal effects of EFA supplementation and its role in mitigating neurodevelopmental impairments in OA.
2026-04-02 | Simplifying supplementation in MSUD: tolerance and acceptability of liquid valine and isoleucine supplements in maple syrup urine disease
Abstract Introduction Maple Syrup Urine Disease (MSUD) is a rare metabolic disorder requiring lifelong restriction of branched-chain amino acids (BCAAs), and targeted supplementation with valine and isoleucine to maintain metabolic stability. Methods A prospective, open-label, observational study was conducted over 56 days in 5 paediatric patients mean age 8.8 years (range 3–14) with classical MSUD. In Phase 1 (Days 0–28), participants received the ready to use (RTU) liquid valine formulation, while continuing their usual powdered isoleucine supplement. In Phase 2 (Days 29–56), participants returned to powdered valine and changed to the ready to use RTU liquid isoleucine supplement. Weekly plasma BCAAs were monitored. Acceptability, gastrointestinal tolerance, adherence, and dietary intake were assessed through questionnaires and food diaries. Results RTU liquid valine and isoleucine supplements were well tolerated and accepted by all participants. Plasma leucine decreased when taking both liquid valine (mean leucine 253 µmol/L) and isoleucine (mean leucine 219 µmol/L) compared to baseline (mean leucine 356 µmol/L). Required doses of valine and isoleucine decreased by 30% and 18%, respectively, suggesting improved adherence or enhanced efficacy. Palatability and ease of use were rated more favourably for the RTU products, with no adverse effects or adherence issues reported. Dietary intake remained stable throughout the study. Discussion These preliminary findings suggest that RTU valine and isoleucine formulations may offer potential advantages in MSUD management, simplifying administration, and enhancing user satisfaction. While limited by sample size and short-term evaluation, their practicality and patient-centered design warrant further investigation in larger, more diverse populations to establish long-term efficacy and broader applicability.
2026-03-24 | Alterations in gut microbiota composition in children with methylmalonic acidemia, propionic acidemia, and maple syrup urine disease.
Methylmalonic acidemia (MMA), propionic acidemia (PA), and maple syrup urine disease (MSUD) are rare monogenic disorders that are described as intoxication-type inborn errors of metabolism (IEMs). They usually present in early life, and long-term management requires strict dietary protein restriction, which may significantly alter gut microbiota composition. Despite growing interest in microbiome research, limited data exist on gut microbiota in these disorders, and no study is available for MMA and MSUD. We aimed to describe the gut microbiota compositions in children with MMA, PA, and MSUD. A total of eight patients (Five MMA, one PA, and two MSUD), and 11age-matched healthy controls were enrolled. All patients were following a medically supervised, protein-restricted diet. Fecal sample was collected from each participant, and gut microbiota composition was evaluated with 16S rRNA sequencing. Patients with MMA, PA, and MSUD exhibited significantly altered gut microbiota composition compared to healthy controls. Alpha diversity analysis revealed reduced microbial richness in patients, with significantly lower Chao1 and observed OTU indices (p < 0.05). Beta diversity metrics demonstrated distinct clustering between groups, indicating significantly different microbial community structures. Higher relative abundances of opportunistic or dysbiotic taxa have been seen in patient group, while controls were enriched in beneficial taxa like Faecalibacterium prausnitzii, Ruminococcus, and Lactobacillus. LEfSe analysis identified 17 taxa enriched in patients-including members of Proteobacteria, Sphingobacteriia, and Streptococcus anginosus-and 6 taxa enriched in controls, notably Faecalibacterium prausnitzi. This is the first descriptive study of the gut microbiota composition of MMA, PA, and MSUD patients. These findings indicate an association between long-term dietary management and altered microbiota composition, although causality cannot be inferred due to the cross-sectional study design. The observed alterations suggest that the gut microbiota may represent a novel therapeutic target in the management of IEMs.
cell therapies
2026-02-25 | Clinical Profiles, Genetic Variants, and Neurodevelopmental Outcomes Following Liver Transplantation in Maple Syrup Urine Disease: A Study From Palestine.
Maple syrup urine disease (MSUD) is a rare, autosomal recessive metabolic disorder resulting from a deficiency of the branched-chain α-ketoacid dehydrogenase complex. This leads to the accumulation of branched-chain amino acids and their corresponding ketoacids, causing acute metabolic crises and progressive neurological damage if untreated. The impact of founder variants, high consanguinity, and limited access to metabolic care pose challenges in medically underserved populations, such as in Palestine. We conducted a retrospective analysis of 11 patients from eight Palestinian families referred to the main Metabolic Unit in the West Bank. Clinical data, biochemical profiles, and molecular findings were reviewed to characterize the presentation and outcomes of MSUD. Management strategies, including dietary intervention and liver transplantation, were also evaluated. Acute metabolic crises were the initial presentation in 91% of cases, typically within the first days of life. Diagnostic delay averaged 47 days in families without prior MSUD history, compared to 2.3 days in those with affected siblings. Founder pathogenic variants were identified in multiple unrelated families, reflecting genetic homogeneity due to community structure; novel variants were also detected. Timely diagnosis facilitated early referral and improved outcomes. Patients who underwent liver transplantation, especially when performed early, exhibited favorable developmental trajectories, increased leucine tolerance, and fewer hospitalizations. One participant diagnosed prenatally remained free of metabolic crises until transplantation at age six, with excellent neurocognitive outcomes. This study highlights the importance of integrating prenatal screening and early diagnosis, timely dietary intervention, and liver transplantation to improve MSUD outcomes in resource-limited settings.
2026-01-15 | Pediatric Full and In-situ Split Domino Living Donor Liver Transplants Experience.
Domino liver transplantation (DLT) is a method in which an explanted liver from a patient with metabolic disease is transplanted to another recipient. In cases where the liver is split and used for two recipients, the technique is termed domino split liver transplantation. This study presents our experience with three pediatric DLT cases, in which liver grafts from two donor-recipient patients with maple syrup urine disease (MSUD) were transplanted to separate recipients. First donor recipient's liver was splitted in situ, while the other was transplanted as a full-sized graft. Demographics, surgical techniques, biliary reconstruction methods, and posttransplant outcomes were analyzed. All recipients were discharged uneventfully following transplantation. No vascular or biliary complications were observed, and de novo MSUD did not develop in any recipient. This confirms that MSUD livers are safe for DLT, particularly in pediatric cases. DLT using MSUD donor livers is a viable option for expanding the organ pool for pediatric transplantation. Advancements in surgical techniques and perioperative care contribute to improved patient outcomes, making DLT a valuable strategy in liver transplantation programs.
2025-12-26 | Pediatric liver transplant for maple syrup urine disease a single center experience.
Maple syrup urine disease (MSUD) is an autosomal recessive inborn error of branched-chain amino acid metabolism caused by an inherited deficiency of branched-chain alpha-ketoacid dehydrogenase (BCKDH) activity that degrades isoleucine, leucine, and valine. Liver transplantation (LT) is a therapeutic option to treat the classical severe type of MSUD. This study aimed to assess and compare liver biochemical outcomes and amino BCAAs levels post-LT according to different types of donors. Retrospective cohort analysis of 10 patient medical records diagnosed as MSUD who underwent LT in King Fahad Specialist Hospital-Dammam between January 2013 and May 2023. Ten pediatric patients diagnosed with MSUD who had finished 1 year of follow-up after LT were included in the study. The median age of diagnosis among the pediatric patients was 1 month (as it is included in the national neonatal screening). Besides, the median age for LT was 123 months (10 years 3 months) (with a range of 9-173 months). Availability of milk formula, prevention of further neurological insult, and difficulty in controlling the protein intake were the main indications for LT. Post LT, six patients (60%) were immediately initiated on a regular diet, and four patients (40%) waited for 3 months before starting a regular diet. All the patients were on Tacrolimus as immunosuppression, with three patients started on Mycophenolate because of biopsy-proven acute cellular rejection. Our result showed 100% 1-year graft survival and 100% until the time of report, with no donor complications. 70% of the explanted liver had been re-transplanted as a domino liver transplant. No clinical or laboratory difference when comparing living-related to living-unrelated or deceased donor liver transplant. 100% of our patients and families showed satisfaction with the decision of liver transplant. MSUD post liver transplant showed a 100% graft survival rate, and all patients and families showed satisfaction. In settings with limited deceased donor organs, living-related donor LT (even from heterozygous carriers) is a viable option for MSUD, yielding comparable metabolic control and graft outcomes to other donor types.
2025-12-18 | Domino Hepatectomy and Implantation With Innovative Outflow Reconstruction for an Adult Patient With Maple Syrup Urine Disease and Type 1 Diabetes Mellitus: Surgical Technique.
Maple syrup urine disease is characterized by deficient metabolism of branched chain amino acids leading to neurological and developmental delays. Because livers with maple syrup urine disease are histologically normal except for a single enzyme deficiency, which is also present in other organs, liver transplant provides adequate enzymes for metabolism of branched chain amino acids, and the explanted liver can be used as a domino graft for another person needing a liver transplant. We report on the case of a rare individual who survived into adulthood with ante-natal diagnosis and strict dietary management. His recent clinical course was complicated by the development of diabetes mellitus leading to recurrent instances of diabetic ketoacidosis or maple syrup urine disease crisis necessitating liver transplant. Our technical modifications enabled a safe and quick domino hepatectomy by minimizing anesthesia time and the anhepatic phase and timely preparation of the domino graft for an uneventful implantation.
2025-11-17 | Design and pharmacodynamic study of live biotherapeutic products with efficient degradation of branched-chain amino acids.
The homeostasis of branched-chain amino acids (BCAAs) plays a crucial role in maintaining health, and the accumulation of BCAAs can lead to various diseases. Therefore, exogenous degradation or conversion of excessive BCAAs may help alleviate diseases caused by BCAA accumulation, such as maple syrup urine disease. This study utilized synthetic biology approaches to engineer two strains for efficient BCAA catabolism successfully-ECN-Deg and ECN-Tra-by integrating specific metabolic pathways into the chassis strain, Escherichia coli Nissle 1917 (ECN). ECN-Deg integrates a metabolic module for BCAA degradation, while ECN-Tra integrates a metabolic module for BCAA transformation. Both engineered strains demonstrate efficient BCAA catabolism in vitro and in vivo. In a high-BCAA mouse model, ECN-Deg and ECN-Tra alleviated liver and ileal damage caused by excessive BCAAs and reduced systemic inflammation levels. Furthermore, ECN-Deg and ECN-Tra were able to modulate the gut microbiota, increasing the richness of Akkermansia muciniphila and Mucispirillum schaedleri, which are associated with health benefits. Additionally, they reduced the richness of the pathogenic bacterium Streptococcus pasteurianus. Thus, this study lays the foundation for the development of probiotics for the treatment of BCAAs metabolic disorders and BCAAs-related chronic diseases.
gene therapies
2026-05-15 | Systemic dual-gene therapy reverses biochemical intoxication in the central metabolic compartment of Bckdha-/- mice.
Branched-chain 2-ketoacid dehydrogenase (BCKDH) deficiency (maple syrup urine disease; MSUD) causes lethal encephalopathy by disrupting cerebral metabolism, a process imperfectly reflected by circulating biomarkers. Diet and liver transplantation stabilize peripheral metabolites but fail to restore brain neurochemistry, demarcating the central nervous system as the decisive therapeutic compartment. To define the pathogenesis of intoxication and its therapeutic response, we performed paired serum-brain metabolomics in Bckdha-/- mice treated with a systemic AAV9 dual-gene vector encoding human BCKDHA and BCKDHB (A-BiP-B). Untreated neonates exhibited a 9-fold elevation of brain 2-ketoisocaproate accompanied by cerebral depletion of glutamate and glutamine, as well as shifts in tricarboxylic acid cycle and ketone body metabolism. These disturbances originated from reversal of branched-chain aminotransferase 2 flux and destabilization of glutamate-2-ketoglutarate mass balance, producing divergent metabolic endophenotypes in blood versus brain. A single intravenous injection of A-BiP-B rescued mice from fatal encephalopathy, partially restored cerebral BCKDHA mRNA expression, and brought core brain neurochemical endpoints within wild-type range despite persistent elevation of serum 2-ketoacids. These findings expose limitations of current MSUD management and establish systemic dual-gene therapy as a means of restoring neurochemical homeostasis while enabling survival on unrestricted protein intake.
2026-05-14 | Trial-ready external controls for gene therapy: The MATCH cohort in maple syrup urine disease.
Maple syrup urine disease (MSUD) is a life-threatening metabolic disorder for which randomized trials are infeasible. We present the MSUD Age-matched Standard Treatment Cohort (MATCH), a prospective natural history study of 11 infants with classic MSUD followed from neonatal diagnosis to liver transplantation. Aligned with Food and Drug Administration (FDA) guidance and International Council for Harmonisation (ICH) E9(R1), MATCH applies prespecified eligibility criteria, fixed visit cadence, adjudicated outcomes, and explicit handling of intercurrent events. Three of six outcome measures-proportional intact protein equivalent (PIPE), crisis management days (CMDs), and blood alloisoleucine concentration-are prespecified as estimands. Monte Carlo simulations show that a single-arm trial comparing 11 treated participants to MATCH controls achieves ≥90% power (p ≤ 0.025) to detect 64% fewer CMDs (3.0% vs. 8.4%), a 57% increase in PIPE (19.3% vs. 12.3%), and a 36% reduction in alloisoleucine (117 vs. 183 μM). MATCH demonstrates how protocolized natural history data serve as regulatory-grade external controls for single-arm trials.
2025-11-20 | Health Implications of Incomplete Metabolism
The important effects of incomplete metabolism on human health are examined in this work, with particular attention to how it may play a role in the etiology of long-term conditions like diabetes, obesity, and mitochondrial diseases. Nutritional deficits, the buildup of hazardous metabolites, and a disturbance of biochemical equilibrium are all consequences of metabolic pathway disruption. The classic cases of phenylketonuria (PKU) and maple syrup urine disease (MSUD) are the grave neurological and developmental effects of metabolic pathway disruption. G6PD insufficiency is an example of how incomplete drug metabolism, which can be caused by genetic polymorphisms, enzyme deficiencies, or hepatic/renal impairments, can lead to metabolic toxicity and drug buildup. Deficiencies in vital vitamins (B12, D, A, K) and minerals (calcium, iron) result in metabolic inefficiencies and clinical aftereffects, such as anemia and neurotoxicity. Nutrient metabolism is also compromised. Lipid intermediate buildup, oxidative stress, and systemic inflammation are all influenced by lipid metabolic abnormalities, which are especially prevalent in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). By affecting ATP synthesis and redox equilibrium, mitochondrial dysfunction aggravates metabolic diseases further. Oxidative stress aggravates illnesses, such as myopathies and lactic acidosis. Novel therapeutic approaches, such as enzyme replacement therapy (ERT), CRISPR-Cas9 gene therapy, and nanotechnology-based methods, present intriguing paths toward pharmacogenomics-driven enzyme regulation and metabolic function restoration, as well as toward precision medicine.
2025-09-27 | Adenine base editing rescues disrupted BCKDH function and reduces BCAAs toxic accumulation in maple syrup urine disease patient iPSC-hepatic organoids.
Maple syrup urine disease (MSUD) is an inherited metabolic disorder caused by a deficiency in the activity of the hepatic branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which leads to the toxic accumulation of three branched-chain amino acids (BCAAs) and their respective α-ketoacid, resulting in severe neurotoxicity, coma and even death without effective therapeutic measures. In this study, we established the patient induced pluripotent stem cells (iPSC)-derived hepatic organoids (HOs), analyzed the characteristics, and applied adenine base editor (ABE8e) to correct a mutation (T322I) of the BCKDHB (branched chain keto acid dehydrogenase E1, beta polypeptide) gene in patient induced pluripotent stem cells (iPSC)-derived hepatic organoids (HOs). qRT-PCR and western blot analysis were performed to assess the expression level of BCKDHA (branched chain keto acid dehydrogenase E1, alpha polypeptide) and BCKDHB. The effects of base editing were comprehensively analyzed using both bulk RNA sequencing and single-cell RNA sequencing (scRNA-Seq). Immunofluorescence and RT-PCR arrayed the high expression of hepatoblast specific proteins in HOs, such as α-1-anti-trypsin (A1AT), hepatocyte nuclear factor-4-alpha (HNF4A), cytokeratin18 (CK18), albumin (ALB), cytochrome P450 family 3 subfamily A member 4 (CYP3A4) and cytochrome P450 family 3 subfamily A member 7(CYP3A7). Functional experiments indicated that these HOs recapitulated characteristics of hepatocytes like glycogen accumulation, low-density lipoprotein (LDL) uptake, indocyanine green (ICG) uptake and release as well as quantitation of ALB and urea from HOs. The levels of BCKDHA and BCKDHB were dramatically decreased in MSUD-HOs compared with control-HOs (P < 0.01) detected by qRT-PCR, western blot and immunofluorescence. Deep sequencing and whole genome sequencing (WGS) demonstrated that the correction of BCKDHB mutation in patient iPSC-derived HOs caused high on-target gene editing without any detectable off-target effects. Moreover, the corrected MSUD-HOs exhibited restored BCKDH enzymatic function and reduced BCAAs level. The transcriptome analysis indicates that the MSUD-HOs with BCKDHB mutation reduced mRNA level of regulating metabolism associated with liver mitochondrial function, while the corrected MSUD-HOs rescued those processes after ABE8e correction. The scRNA-Seq analysis further validated the rescue effects of BCKDH function after gene editing. Our study provides reliable evidence that ABE8e is highly efficient and safe in correcting patient-derived HOs from MSUD, indicating the feasibility to be a transformative treatment for genetic hepatic diseases like MSUD.
2025-02-26 | BCKDHA-BCKDHB digenic gene therapy restores metabolic homeostasis in two mouse models and a calf with classic maple syrup urine disease.
Classic maple syrup urine disease (MSUD) results from biallelic mutations in genes that encode the branched-chain α-ketoacid dehydrogenase E1α (BCKDHA), E1β (BCKDHB), or dihydrolipoamide branched-chain transacylase (DBT) subunits, which interact to form the mitochondrial BCKDH complex that decarboxylates ketoacid derivatives of leucine, isoleucine, and valine. MSUD is an inborn error of metabolism characterized by recurrent life-threatening neurologic crises and progressive brain injury that can only be managed with an exacting prescription diet or allogeneic liver transplant. To develop a gene replacement therapy for MSUD, we designed a dual-function recombinant adeno-associated virus serotype 9 (rAAV9) vector to deliver codon-optimized BCKDHA and BCKDHB (rAAV9.hA-BiP-hB) to the liver, muscle, heart, and brain. rAAV9.hA-BiP-hB restored coexpression of BCKDHA and BCKDHB as well as BCKDH holoenzyme activity in BCKDHA-/- HEK293T cells and did not perturb physiologic branched-chain amino acid homeostasis in wild-type mice at a systemic dose of 2.7 × 1014 vector genomes per kilogram. In two models of severe MSUD (Bckdha-/- and Bckdhb-/- mice) and a newborn calf homozygous for BCKDHA c.248C>T, one postnatal injection prevented perinatal death, normalized growth, restored coordinated expression of BCKDHA and BCKDHB in the skeletal muscle, liver, heart, and brain, and stabilized MSUD biomarkers in the face of high protein ingestion. In summary, we developed a one-time BCKDHA-BCKDHB systemic dual-gene replacement strategy that holds promise as a therapeutic alternative to prescription diet and liver transplant for treatment of MSUD types 1A and 1B, the two most common forms of MSUD in humans.
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Drug Discovery Landscape
5 orphan drug designations for Maple syrup urine disease, including 1 approved therapy.
5 orphan drug designations for Maple syrup urine disease, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant AAV9 vector expressing functional, codon-optimized, human BCKDHA and BCKDHB genes which encode for catalytic E1alpha and E1beta subunits, respectively, of the BCKDH holoenzyme | gene therapies | FDA | 2025-05-15 | — | Plowshare Therapies LLC |
a modified version of a leucine decarboxylase enzyme from Planctomycetaceae bacterium | proteins | FDA | 2022-12-20 | — | Codexis, Inc. |
Sodium phenylbutyrate | small molecules | EMA | 2022-07-18 | — | Renantos Pharmavertriebsgesellschaft mbH |
Glycine, L-alanine, L-arginine, L-aspartic acid, L-cysteine, L-glutamic acid, L-histidine, L-lysine monohydrate, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, taurine [Maapliv] | other | EMA | 2018-10-26 | 2025-07-29 | Recordati Rare Diseases |
sodium phenylbutyrate | small molecules | FDA | 2014-08-19 | — | Acer Therapeutics, Inc. |
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