RARE DISEASE
Rare disorder potentially indicated for liver transplant
Rare disorder potentially indicated for liver transplant
Rare disorder potentially indicated for liver transplant
Drug discovery
1
drug
With orphan designation
Overview
Rare liver disorders requiring transplantation primarily include metabolic disorders (e.g., Wilson disease, familial amyloidotic polyneuropathy), congenital conditions (e.g., Byler disease, Caroli’s disease), vascular abnormalities (e.g., Budd-Chiari syndrome), and select malignancies (e.g., unresectable neuroendocrine tumors) [1][13][18]. These diseases often present with progressive liver dysfunction, extrahepatic complications, or refractory symptoms despite medical therapy, necessitating transplant for curative intent or improved survival [9][13].
Therapies
Categories: rare transplant-related disorders
Research Papers
42 drug discovery papers about Rare disorder potentially indicated for liver transplant, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
42 drug discovery papers about Rare disorder potentially indicated for liver transplant, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-01-10 | Does Gamma-Glutamyl Transpeptidase Serum Level Play a Role as a Prognostic Marker in Biliary Atresia, an Immune-Mediated Cholangiopathy in Children?
Background: Biliary atresia (BA) is a rare, immune-mediated cholangiopathy in children and a leading cause of neonatal cholestasis and pediatric liver transplantation (LT). Gamma-glutamyl transpeptidase (GGT) is commonly elevated in BA and is used as a diagnostic marker; however, recent studies have suggested that a subset of BA patients present with normal or low GGT levels, potentially indicating a more severe disease course. Methods: This retrospective study evaluated the prognostic value of serum GGT levels in 47 children diagnosed with BA at a single center over 15 years. Patients were stratified by GGT levels at diagnosis, and outcomes were compared, including survival with native liver, need for LT, and mortality. GGT thresholds of 200 U/L and 300 U/L were used to define normal and elevated levels. Results: The study found that 12% of patients had normal or low GGT at diagnosis. Still, there were no statistically significant differences in age at diagnosis, severity of liver fibrosis, age at Kasai portoenterostomy (KPE), or overall outcomes between low and high GGT groups. Although patients with lower GGT tended to require LT at a younger age, this difference was not significant. Receiver operating characteristic (ROC) curve analysis showed that GGT levels at diagnosis, before, and after KPE were not reliable predictors of outcome. Conclusions: The findings contrast with some previous reports suggesting that low GGT is associated with a worse prognosis. Low GGT level alone should not delay diagnosis or surgical intervention in suspected BA. Early referral for KPE remains critical, and patients with low GGT may benefit from earlier LT evaluation. Larger, multicenter studies are needed to clarify the prognostic role of GGT in BA.
2025-05-26 | Therapeutic effect of hUC-MSCs from different transplantation routes on acute liver failure in rats.
Acute liver failure (ALF) is a rare yet serious clinical syndrome. Recent studies have indicated that stem cells can effectively treat this condition. However, the optimal route for stem cell transplantation in the treatment of ALF remains unclear. This study aims to investigate the most effective transplantation route for stem cell therapy in ALF. Human umbilical cord mesenchymal stem cells (hUC-MSCs) expressing both luciferase and green fluorescent protein were generated using a lentiviral vector. The hUC-MSCs were transplanted via the tail vein, portal vein, and abdominal cavity. The survival and distribution of the transplanted hUC-MSCs in rats were assessed through in vivo imaging and immunofluorescence. Furthermore, the therapeutic effects of hUC-MSCs transplanted via different routes on ALF were compared. The survival time of hUC-MSCs transplanted via the tail vein and portal vein was shorter compared to those transplanted intraperitoneally. The distribution of hUC-MSCs varied by transplantation route: those injected via the tail vein and portal vein were primarily found in the lungs and liver, respectively, while intraperitoneally transplanted hUC-MSCs predominantly localized in the abdominal cavity. In ALF rats, hUC-MSCs transplanted via the tail vein and portal vein improved survival rates, enhanced liver pathology, and reduced levels of inflammatory cytokines in liver tissue. In contrast, abdominal transplantation of hUC-MSCs showed no significant therapeutic effect. hUC-MSCs transplanted via the tail vein and portal vein exhibited similar therapeutic effects on ALF; however, abdominal transplantation of hUC-MSCs showed no significant effect.
2024-10-25 | Bone marrow transplantation increases sulfatase activity in somatic tissues in a multiple sulfatase deficiency mouse model.
Multiple Sulfatase Deficiency (MSD) is an ultra-rare autosomal recessive disorder characterized by deficient enzymatic activity of all known sulfatases. MSD patients frequently carry two loss of function mutations in the SUMF1 gene, encoding a formylglycine-generating enzyme (FGE) that activates 17 different sulfatases. MSD patients show common features of other lysosomal diseases like mucopolysaccharidosis and metachromatic leukodystrophy, including neurologic impairments, developmental delay, and visceromegaly. There are currently no approved therapies for MSD patients. Hematopoietic stem cell transplant (HSCT) has been applied with success in the treatment of certain lysosomal diseases. In HSCT, donor-derived myeloid cells are a continuous source of active sulfatase enzymes that can be taken up by sulfatase-deficient host cells. Thus, HSCT could be a potential approach for the treatment of MSD. To test this hypothesis, we used a clinically relevant mouse model for MSD, B6-Sumf1(S153P/S153P) mice, engrafted with bone marrow cells, Sumf1+/+, from B6-PtprcK302E mice (CD45.1 immunoreactive). After 10 months post-transplant, flow cytometric analysis shows an average of 90% of circulating leukocytes of donor origin (Sumf1(+/+)). Enzymatic activity for ARSA, ARSB, and SGSH is significantly increased in spleen of B6-Sumf1(S153P/S153P) recipient mice. In non-lymphoid organs, only liver and heart show a significant correction of sulfatase activity and GAG accumulation. Frequency of inflammatory cells and lysosomal pathology is significantly reduced in liver and heart, while no significant improvement is detected in brain. Our results indicate that HSCT could be a suitable approach to treat MSD-pathology affecting peripheral organs, however that benefit to CNS pathology might be limited.
2024-06-16 | Are Current Educational and Therapeutic Programs, Directed at Rare Disease Transplant Candidates and Recipients, Sufficient to Support Them on the Path From Diagnosis to Life After Allogenic Transplantation?-Recommendations for Member State Policymakers.
For many rare disease (RD) patients, allogenic transplantation represents an effective therapy, improving overall survival rates and quality of life (QoL). Globally, ∼1% of liver transplants are performed for RDs and rare indications. However, patients and carers report unmet needs on their pathway toward treatment-in education and therapeutic measures, oftentimes shouldering expertise-building responsibility themselves. These issues are exacerbated in child patients. Estimates indicate that 6% to 8% of Poland's population (2.3-3 million persons) are burdened by RDs and potentially face such issues. This work aims to identify shortcomings of Polish policy in the field of educational and therapeutic measures for RD transplant candidates and recipients. Based on solutions introduced by pioneers, recommendations are formulated regarding priority actions. An analysis of national, transnational, and individual-center programs, directed at patients during their path from diagnosis to life post-transplant, was conducted. The investigation uncovered measure gaps not addressed by the National Plan for Rare Diseases-in fields of patient and stakeholder education (pre- and post-transplant), psychological care provision, specialized center creation, integration of data scattered among registries with the national insurer's database, and artificial intelligence (AI) tool implementation to support both early diagnostic efforts and tailoring of patient treatment. Programs directed at RD transplant candidates and recipients must aim to ensure that a satisfactory psychosomatic condition of the patient is maintained before and following the procedure, therefore lending credence to success. This necessitates early diagnosis schemes, and personalized medicine, multidisciplinary approaches to the individual, achievable only through big data system creation and AI introduction.
2022-09-22 | ATP7B gene therapy of autologous reprogrammed hepatocytes alleviates copper accumulation in a mouse model of Wilson's disease.
Wilson's disease (WD) is a rare hereditary disorder due to ATP7B gene mutation, causing pathologic copper storage mainly in the liver and neurological systems. Hepatocyte transplantation showed therapeutic potential; however, this strategy is often hindered by a shortage of quality donor cells and by allogeneic immune rejection. In this study, we aimed to evaluate the function and efficacy of autologous reprogrammed, ATP7B gene-restored hepatocytes using a mouse model of WD. Sufficient liver progenitor cells (LPCs) were harvested by reprogramming hepatocytes from ATP7B-/- mice with small molecules, which exhibited strong proliferation and hepatic differentiation capacity in vitro. After lentivirus-mediated mini ATP7B gene transfection and redifferentiation, functional LPC-ATP7B-derived hepatocytes (LPC-ATP7B-Heps) were developed. RNA sequencing data showed that, compared with LPC-green fluorescent protein-Heps (LPC-GFP-Heps) with enrichment of genes that were mainly in pathways of oxidative stress and cell apoptosis, in LPC-ATP7B-Heps under high copper stress, copper ion binding and cell proliferation pathways were enriched. LPC-ATP7B-Heps transplantation into ATP7B-/- mice alleviated deposition of excess liver copper with its associated inflammation and fibrosis, comparable with those observed using normal primary hepatocytes at 4 months after transplantation. We established a system of autologous reprogrammed WD hepatocytes and achieved ATP7B gene therapy in vitro. LPC-ATP7B-Heps transplantation demonstrated therapeutic efficacy on copper homeostasis in a mouse model of WD.
small molecules
2026-06-18 | Post-meal loss of consciousness in an adult patient with carbamoyl phosphate synthetase 1 deficiency and two newly identified heterozygous variants: a case report.
Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive disorder characterized by urea cycle dysfunction and secondary hyperammonemia. Although primarily observed in neonates, adult cases are exceedingly rare and warrant reporting due to their novelty and potential for misdiagnosis. We present a case of a 34-year-old male who presented with post-meal loss of consciousness, a symptom atypical of the disease's usual manifestation. A 34-year-old man was admitted with a 2-day history of general fatigue that escalated to unconsciousness over half a day. He also experienced vomiting, bilateral limb convulsions, and a history of epilepsy. Upon admission, he exhibited coma with a Glasgow Coma Scale score of 5/15. Biochemical investigations revealed normal liver and kidney function but a significantly elevated blood ammonia concentration of 597.6 µmol/L. Cranial imaging showed diffuse swelling of the brain parenchyma indicative of encephalopathy. Gene sequencing identified three heterozygous variants in theCPS1 gene, including two novel variants sites. Despite ammonia-lowering treatments, his condition rapidly deteriorated, and he succumbed to hyperammonemia-induced encephalopathy on day 9 of admission. This case highlights the importance of recognizing CPS1D as a potential diagnosis in adults presenting with neurological symptoms, particularly those involving consciousness changes. The rarity and atypical presentation of adult CPS1D underscore the need for early diagnosis through comprehensive evaluation, including blood ammonia measurement and genetic analysis. This case expands the spectrum of clinical manifestations and genetic variants associated with CPS1D and emphasizes the urgency of ammonia-lowering therapy and consideration for liver transplantation in eligible patients.
2026-04-15 | Central nervous system post-transplant lymphoproliferative disorder relapse after pediatric liver transplantation: a case report and literature review.
Post-transplant lymphoproliferative disorder (PTLD) represents a potentially life-threatening and grave complication that can arise following solid organ transplantation (SOT). Clinically, extranodal involvement in PTLD is frequent, whereas involvement of the central nervous system (CNS) is relatively rare and frequently associated with a poor prognosis. Currently, there is no standardized therapeutic approach for CNS-PTLD. We report a pediatric patient who suffered from multiple recurrences of CNS-PTLD after liver transplantation. The patient was Epstein-Barr virus (EBV)-negative before transplantation but developed PTLD involving lymph node, liver, and multiple bones 2 years after liver transplantation, accompanied by elevated EBV-DNA in peripheral blood (PB). As the lesion was systemic and CD20-positive, we chose to use rituximab (RTX) monotherapy and achieved remission. However, after 3 cycles of RTX, the child developed neurological symptoms such as facial nerve palsy and mouth deviation. Brain magnetic resonance imaging (MRI) revealed a mass in the inner ear and thickening of the facial nerve, suggesting that the disease had invaded the CNS. Therefore, we upgraded the treatment plan to R-CHOP chemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), and achieved a complete remission (CR). Following 2 cycles of R-CHOP, the patient experienced facial nerve palsy again, and brain MRI indicated a lesion in the left cerebellopontine angle region, suggesting disease recurrence. Re-treatment with 4 cycles of R-CHOP provided minimal symptomatic relief, and follow-up MRI demonstrated progressive multiple intracranial lesions. Brain biopsy confirmed CNS-PTLD [EBV-positive Burkitt's lymphoma (BL)]. Due to the patient's resistance to standard chemotherapy (R-CHOP) and the limited location of the lesion in the CNS, we switched to a more central-permeable treatment regimen. Then the patient achieved CR following treatment with high-dose methotrexate (HD-MTX) combined with intrathecal methotrexate (IT-MTX), and subsequently underwent timely chimeric antigen receptor T-cell (CAR-T) therapy to consolidate the therapeutic effect and prevent recurrence. The patient currently maintains sustained CR. We observe that the combination of HD-MTX and intrathecal chemotherapy exhibits remarkable efficacy in managing post-transplant CNS-PTLD that is resistant to conventional R-CHOP chemotherapy. CAR-T therapy emerges as a potential option for patients suffering from relapsed or refractory CNS-PTLD.
2026-02-02 | Beyond pruritus in Alagille syndrome: potential effects of maralixibat on fibrosis and portal hypertension-insights from two case studies.
Alagille syndrome (ALGS) is a genetic disorder primarily affecting the liver, often leading to cholestasis and pruritus. Ileal Bile Acid Transporter inhibitors (IBATi), such as maralixibat, have shown promise in controlling pruritus and potentially modifying disease progression. We report two patients with ALGS treated with maralixibat. Case 1 involved a 10-days-old newborn presenting with cholestasis, jaundice, and acholic stools. Genetic testing confirmed a pathogenic JAG1 mutation. Despite preserved liver function, the patient was evaluated for liver transplantation (LT) due to severe pruritus and portal hypertension. Maralixibat initiation led to marked improvement in pruritus, serum bile acids, bilirubin, and cholesterol. Liver biopsies performed 13 months apart demonstrated fibrosis regression from cirrhosis to stage F2. Elastography showed decreased liver stiffness, reduced splenomegaly, and improved platelet counts. Liver enzymes transiently increased, but treatment continued without dose adjustment. Case 2 involved a 15-years-old female with moderate portal hypertension and mild pruritus. After 24 months of maralixibat, pruritus resolved completely, serum bile acids decreased, liver stiffness and splenomegaly improved, and platelet counts increased. Liver enzymes remained mildly elevated without requiring treatment modification. These findings suggest maralixibat may improve portal hypertension and hepatic injury, even in patients with less severe biochemical abnormalities. In ALGS, maralixibat treatment improved pruritus, lowered serum bile acids, and suggested potential benefits on fibrosis and portal hypertension, indicating a possible role beyond symptomatic relief.
2025-12-15 | Unusual Etiology of Budd-Chiari Syndrome in an Adolescent: A Case of Combined Thrombophilic Disorder.
Budd-Chiari syndrome (BCS) is an uncommon but potentially life-threatening hepatic vascular disorder resulting from obstruction of the hepatic venous outflow. While it predominantly affects adults, pediatric and adolescent presentations are rare, particularly those associated with inherited thrombophilia. Early diagnosis and appropriate intervention are essential to prevent complications such as portal hypertension, hepatic ischemia, and liver failure. We describe the case of a 15-year-old female who presented with progressive abdominal distension, right upper quadrant pain, and bilateral lower limb edema. Imaging studies, including ultrasound and contrast-enhanced CT, revealed hepatic venous obstruction with thrombus extension into the portal, superior mesenteric and splenic veins, and gross ascites. Laboratory findings indicated elevated inflammatory markers and impaired liver function. A detailed thrombophilia workup demonstrated deficiencies in protein C and antithrombin III and a Factor V Leiden mutation, confirming a hypercoagulable state as the underlying etiology. The patient was diagnosed with subacute Budd-Chiari Syndrome secondary to inherited thrombophilia. She was initiated on anticoagulation therapy with warfarin, later transitioned to rivaroxaban, and managed with diuretics and dietary modifications. Clinical improvement was achieved, and the patient was referred to a liver transplant center for ongoing evaluation.
2025-07-24 | Long-Term Outcomes of Chenodeoxycholic Acid Therapy for Cerebrotendinous Xanthomatosis: A Nationwide Study on Prognostic Factors and Treatment Response.
Cerebrotendinous xanthomatosis (CTX) is a treatable neurometabolic disorder. Chenodeoxycholic acid (CDCA) is the first-line treatment and can potentially halt disease progression if initiated before neurologic symptoms appear. This nationwide, multicenter study evaluates the long-term effects of treatment in 86 genetically confirmed patients with CTX receiving CDCA for ≥ 6 months, focusing on neurologic and extraneurologic outcomes, prognostic factors, and biochemical response. Clinical and biochemical parameters were recorded at baseline and follow-up, and neurological outcomes were assessed using neurological disability scores. Our results indicate a critical age of 28 years for the start of treatment. Patients diagnosed before 28 years showed 100% neurological stabilization or improvement, whereas patients diagnosed later had a higher rate of disease progression (p < 0.05). CDCA effectively stabilized or improved pyramidal and cerebellar symptoms, although myoclonus and parkinsonism remained less responsive. Psychiatric symptoms showed a lower treatment response, with psychosis being the most refractory finding. CDCA resulted in a strong and sustained reduction in cholestanol levels, although biochemical response did not always correlate with clinical improvement. Longer diagnostic delay and presence of anxiety and pyramidal/cerebellar symptoms were associated with poorer outcomes. Notably, a cholestatic child, for whom liver transplantation had initially been considered, recovered completely under CDCA therapy. Our results show that early diagnosis and initiation of CDCA therapy significantly improve neurological outcomes in CTX. However, even in late-diagnosed patients, treatment continues to be beneficial, demonstrating that it is never too late to start therapy. Biochemical response does not always predict clinical improvement; multidisciplinary follow-up is essential.
antibodies
2026-05-05 | Hepatic Manifestations and Response to Treatment in Deficiency of Adenosine Deaminase 2.
Deficiency of adenosine deaminase 2 (DADA2) is caused by mutations in the ADA2 gene and results in an auto-inflammatory state. Hepatosplenomegaly, with or without abnormalities in liver enzymes, has been reported in DADA2. Anti-tumour necrosis factor (anti-TNF) therapy is the standard of care for the prevention of recurrent ischemic strokes and reduction of inflammatory burden. However, little is known about the extent of hepatic involvement and the utility of non-invasive tools for identifying liver disease and monitoring treatment response. Retrospective analysis was performed on a prospective cohort of 70 patients with DADA2. Patients underwent baseline and annual laboratory testing, abdominal imaging and transient elastography. Hepatomegaly and splenomegaly were assessed on imaging, with splenomegaly defined using the spleen-to-height (SH) ratio. Liver biopsy and esophagogastroduodenoscopy were performed when indicated. At baseline, elevated ALT was uncommon (29%). Hepatomegaly and splenomegaly were present in 36% and 58%, respectively. Liver biopsies were performed in 12 patients, 8 of whom showed porto-sinusoidal vascular disease (PSVD). Over a median follow-up of 4.5 years, 40% demonstrated persistently elevated ALT levels. Clinically evident portal hypertension was present in 14%, and decompensation events, such as ascites and variceal bleeding, occurred in 5%. Anti-TNF therapy resulted in resolution of splenomegaly in 28% and a reduction in mean SH ratio across the entire cohort. Patients who underwent haematopoietic cell transplantation (HCT) appeared to be at risk for complications such as hepatic graft versus host disease and veno-occlusive disease. DADA2 vasculopathy appears to affect intrahepatic portal veins and result in PSVD. SH ratio shows significant promise in identifying liver involvement and monitoring treatment response. The improvement in SH suggests that PSVD may be reversible with treatment in this setting. Hepatic evaluation at baseline is encouraged for all patients, and pre-HCT liver biopsy should be considered, as there can be clinically silent liver disease that could potentially cause transplant-related complications.
2026-01-02 | Nanobodies as therapies for loss-of-function misfolding diseases: the example of Primary Hyperoxaluria Type 1.
Misfolding diseases that result in loss of function represent a considerable burden for both individuals and society. Primary Hyperoxaluria Type 1 (PH1) is a rare genetic disorder caused by the deficit of alanine:glyoxylate aminotransferase (AGT), which leads to excessive endogenous oxalate formation translating into progressive renal damage due to stones formation. The underlying molecular mechanisms causing PH1 are associated with protein misfolding (leading to enhanced degradation, aggregation and/or mitochondrial mistargeting). The main therapeutic approach is a double kidney and liver transplantation, but treatments based on RNA silencing are currently available, although they normalize urinary oxalate excretion only in about 50 % of patients, calling for the need of alternative options. In this work, we developed and characterized a novel biotechnological approach using six single-domain nanobodies (NB-AGT-1 to -6) as potential therapeutics counteracting PH1 misfolding. We show that NB-AGTs are very stable proteins and bind pathogenic and non-pathogenic variants of AGT with high affinities (Kd values from low nM to low pM). Structural studies indicate that NB-AGTs bind to different protein epitopes thus being selective for different variants. Preliminary experiments in a cellular model of PH1 show that internalization of engineered NB-AGT-3 enhances the specific activity of disease-associated variants. Overall, our results provide the basis to consider NBs as a promising approach for PH1 as premise for their application to other loss-of-function misfolding diseases.
2025-11-01 | 26 Post-Transplant Lymphoproliferative Disorder in a Pediatric Liver Transplant Recipient: A Rare but Serious Complication of Chronic Immunosuppression
Abstract Introduction/Objective Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication following solid organ transplantation, including liver transplants. It arises due to chronic immunosuppression, leading to uncontrolled lymphocyte proliferation, often associated with Epstein-Barr virus (EBV) infection. PTLD occurs in 1%–10% of post-solid organ transplant recipients and 1%–5.5% of those who have undergone liver transplantation. These neoplasms are associated with an increased mortality. In pediatric liver transplant recipients, EBV-driven PTLD has a reported incidence ranging from 2% to 8%, with a mortality rate of around 44%. We present a case of a pediatric liver transplant recipient who developed EBV-driven PTLD 3 years after transplant. Methods/Case Report A 6-year-old male, who had undergone orthotopic liver transplantation at the age of 3 due to acute liver failure of unknown etiology, was evaluated during a routine follow-up. His past medical history was significant for mild glucose-6-phosphate dehydrogenase (G6PD) deficiency, along with a history of allograft rejection episodes, which necessitated chronic immunosuppressive therapy. Additionally, he had a documented history of Epstein-Barr virus (EBV) viremia, which is a known risk factor for post-transplant complications. His family history is notable for systemic lupus erythematosus (SLE) in his mother, which may indicate a genetic predisposition to immune dysregulation. A PET-CT scan revealed multiple fluorodeoxyglucose (FDG)-avid hepatic foci, many of which corresponded to hypodense lesions, raising suspicion for PTLD. The patient was admitted for further evaluation, including an EBV DNA quantitative PCR, which revealed significant viremia (>200,000 copies/mL). A liver biopsy confirmed polymorphic PTLD, characterized by lymphoid infiltration with positive EBV-encoded RNA (EBER) in situ hybridization. Management included reduction of immunosuppression and initiation of rituximab therapy for lymphoma treatment. Hematologic parameters remained stable, with no evidence of bone marrow involvement. Results NA Conclusion PTLD is a serious, potentially life-threatening complication of chronic immunosuppression in pediatric liver transplant recipients, with early detection being critical for improving outcomes. This case highlights the importance of routine EBV monitoring and prompt histopathological evaluation in post-transplant patients with suspicious imaging findings. The polymorphous nature of PTLD requires a multimodal diagnostic approach, including immunophenotyping and EBER in situ hybridization, while FDG PET-CT remains a valuable tool for assessing disease burden. Timely intervention with immunosuppression reduction and rituximab therapy can be effective in controlling disease progression. Given the 6% incidence in pediatric liver transplant patients, increased awareness and early intervention strategies are essential to improving survival rates in this vulnerable population.
2025-08-23 | Claudin-1 is a mediator and therapeutic target in primary sclerosing cholangitis.
Primary sclerosing cholangitis (PSC) is a cholangiopathy associated with a high risk of progression to end-stage liver disease and hepatobiliary cancer. Its pathogenesis remains poorly understood, and current clinical management offers limited therapeutic options, primarily liver transplantation. Claudin-1 (CLDN1), a transmembrane protein highly expressed in liver epithelial cells, plays a critical role in cell-cell communication and signaling. We aimed to investigate the functional role of CLDN1 as both a mediator and potential therapeutic target for PSC using patient cohorts alongside murine and patient-derived intervention models. CLDN1 expression patterns and associated cellular phenotypes were analyzed in liver tissues from five PSC patient cohorts using single-cell RNA sequencing, spatial transcriptomics, and multiplex proteomics. Proof-of-concept studies employing CLDN1-specific monoclonal antibodies (mAbs) and genetic loss-of-function approaches were performed in state-of-the-art mouse models of PSC and cholangiopathies. Perturbation studies in human cell-based models were conducted to explore underlying mechanisms. In liver tissues from patients with PSC, CLDN1 expression was markedly upregulated and correlated with disease progression. Spatial transcriptomics and proteomics revealed elevated CLDN1 expression in diseased cholangiocytes and cholestatic periportal hepatocytes, accompanied by activation of pro-inflammatory and pro-fibrotic signaling pathways. Therapeutic administration of CLDN1-specific mAbs or genetic knockout improved liver function in PSC mouse models by reducing hepatobiliary fibrosis and cholestasis. Mechanistic studies indicated that mAb treatment inhibited pro-inflammatory and pro-fibrotic signaling in cholangiocytes and hepatocytes perturbed in PSC liver tissues. These findings demonstrate a functional role for CLDN1 in the pathogenesis of PSC and biliary fibrosis. In vivo proof-of-concept studies, combined with expression analyses in patients with PSC, support the clinical development of CLDN1-specific mAbs as a therapeutic strategy for PSC. Primary sclerosing cholangitis (PSC) is a chronic fibrosing cholangiopathy with limited therapeutic options. We identified the cell surface protein Claudin-1 as a key mediator and potential therapeutic target for PSC. In patients, Claudin-1 expression correlates with disease stage and clinical outcomes. Conditional liver epithelial-specific Claudin-1 knockout in mice reduced liver injury, fibrosis, and cholestasis. Monoclonal antibodies targeting Claudin-1 inhibited fibrosis, cholestasis, and the ductular reaction across advanced PSC mouse models by suppressing pro-inflammatory and fibrogenic signaling. These preclinical findings support the clinical development of Claudin-1-specific antibodies for PSC treatment and have significant implications for physicians, researchers, and drug developers in the field of biliary disease.
2020-07-09 | Clinical Characteristics and Prognostic Factors of Patients with Intrahepatic Cholangiocarcinoma with Fever: A Propensity Score Matching Analysis.
Patients with intrahepatic cholangiocarcinoma (ICC) rarely present fever as the initial symptom. We aimed to identify clinical characteristics and prognostic factors for these feverish patients. This study retrospectively reviewed 31 patients with ICC with fever (≥38.0°C) treated at our hospital between January 2002 and December 2014. A propensity score was used to match patients with and without fever at a ratio of 1:2. Patients with ICC with fever had higher serum γ-glutamyl transferase and carcinoembryonic antigen levels, larger tumors, poorer tumor differentiation, and worse prognosis (all p < .05) than those without fever. This was supported by propensity score matching (PSM) analysis. Univariate and multivariate analyses indicated that microvascular invasion, hilar lymph node metastasis, and temperature ≥ 38.6°C were related to prognosis. Patients with ICC with fever had higher levels of leucocytes, neutrophils, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in peripheral blood before and after PSM analysis. Body temperature positively correlated with leucocytes (r = 0.599, p < .001), neutrophils (r = 0.644, p < .001), NLR (r = 0.681, p < .001), and PLR (r = 0.457, p = .010). Patients with ICC with fever ≥38.0°C and ≥38.6°C had poor and extremely poor prognosis, respectively. Radical surgical treatment may improve the prognosis of patients with ICC with fever <38.6°C. However, systemic therapy (e.g., anti-inflammatory and immune therapy) may be preferable to surgery for these patients with fever ≥38.6°C. Patients with intrahepatic cholangiocarcinoma (ICC) with fever (≥38.0°C) as the initial symptom are extremely rare. Because their symptoms are similar to those of liver abscess, diagnosis is challenging, and most of these patients are already at an advanced stage at the time of diagnosis. Patients with ICC with fever had different clinical characteristics and worse prognosis than those without fever. The prognosis of those with temperature <38.6°C would be improved by timely surgical intervention. Those with fever ≥38.6°C had an extremely dismal outcome, although they all received radical surgical treatment. New therapeutic strategies are needed to improve survival for patients with ICC with temperature ≥38.6°C. 摘要 背景。肝内胆管癌 (ICC) 患者很少将发热作为首诊症状。我们的目的是确定这些发热患者的临床特征和预后因素。 受试者、材料和方法。本研究回顾性地分析了 2002 年 1 月至 2014 年 12 月期间在我院接受治疗的 31 名伴发热 (≥38.0°C) ICC患者。我们采用倾向评分以 1:2 的比例匹配伴发热与未伴发热的患者。 结果。与未伴发热的ICC患者相比，伴发热ICC患者的血清 γ‐谷氨酰转移酶和癌胚抗原水平较高，肿瘤较大，肿瘤分化较差，预后较差(全部的 p < 0.05)。我们通过倾向评分匹配 (PSM) 分析证实了这一点。单变量和多变量分析表明，微血管浸润、肝门淋巴结转移和体温 ≥38.6°C 与预后有关。伴发热ICC患者在PSM分析之前和之后的白细胞水平、中性粒细胞、中性粒细胞与淋巴细胞的比率 (NLR) 以及外周血中血小板与淋巴细胞的比率 (PLR) 均较高。体温与白细胞(r = 0.599，p < 0.001)、中性粒细胞(r = 0.644，p < 0.001)、NLR(r = 0.681，p < 0.001)以及PLR(r = 0.457，p = 0.010)呈正相关。 结论。体温 ≥38.0°C 和 ≥38.6°C 的伴发热ICC患者的预后效果分别为差和极差。根治性手术治疗可改善体温 <38.6°C 的伴发热ICC患者的预后。但是，对于体温 ≥38.6°C 的伴发热ICC患者，全身治疗(例如抗炎和免疫治疗)可能优于手术治疗。 实践意义:以发热 (≥38.0°C) 为首诊症状的肝内胆管癌(ICC)患者极为少见。由于其症状与肝脓肿相似，给诊断带来了很大的挑战，并且大多数患者在诊断时已处于晚期。伴发热ICC患者的临床特征与未伴发热ICC患者不同，并且预后较差。通过及时的手术干预可以改善体温 <38.6°C 的患者的预后。体温 ≥38.6°C 的发热患者虽然接受了根治性手术治疗，但预后极差。需要新的治疗策略来改善体温 ≥38.6°C 的ICC患者的生存期。
gene therapies
2026-08-11 | Liver-directed gene therapy results in amelioration of progressive familial intrahepatic cholestasis type 2 in mice.
Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare disease affecting the ABCB11 gene, encoding the bile salt export pump (BSEP). BSEP dysfunction impairs bile acid (BA) secretion, causing hepatic damage and leading to pruritus, cholestasis, hepatomegaly, and often fibrosis and end-stage hepatic disease. Treatments include ileal BA transporter inhibitors, surgical bile diversion, or ultimately, liver transplantation. Our aim was to develop a PFIC2 gene therapy approach based on the restoration of BSEP hepatocyte expression. We designed several expression cassettes containing the human ABCB11 gene downstream of either a liver-specific constitutive promoter or a BA-inducible promoter. After in vitro screening, the AAV vectors with the best expression cassette for each promoter were tested in a PFIC2 mouse model. The AAV vector containing the constitutive promoter, named VTX-802, showed higher BSEP expression, resulting in better restoration of BA secretion 3 and 7 weeks post-treatment. We then performed a dose-range-finding study of VTX-802 in 5-week-old female PFIC2 mice in which the therapeutic efficacy was monitored until 5 months of age. Treated mice showed a sustained dose-dependent improvement in serum transaminase levels. These mice also exhibited significant, but partial, correction of hepatomegaly, and increased BA levels in bile and small intestine, indicating partial restoration of normal BA secretion. VTX-802 restores hepatic BSEP expression and partially corrects disease phenotype in PFIC2 mice. To our knowledge, VTX-802 is the first gene therapy approach that could potentially benefit PFIC2 patients.
2025-12-09 | Acute severe cholestatic hepatitis and lymphopenia characterize pediatric hepatitis-associated aplastic anemia.
Hepatitis-associated aplastic anemia (HAAA) is described as acute severe hepatitis of unknown origin followed by bone marrow failure (BMF). We aimed to provide a comprehensive picture of pediatric HAAA. Two-center retrospective analysis was performed using data from children diagnosed with acquired BMF, including severe aplastic anemia (SAA) and myelodysplastic syndrome type refractory cytopenia of childhood (RCC). The assessment of the subcohort of HAAA included clinical features indicative of diagnosis and disease progression, with additional data from previously published case series. Cohort comprised 62 children with acquired BMF and 22 children with HAAA. Median age of HAAA patients was 13.5 years. Potentially triggering viral infections were detected in 45%. The median interval from hepatitis onset to cytopenia was 3 weeks. All cases presented with severe hepatitis (median alanine transaminase 2127 U/L) and all but one with hyperbilirubinemia (median bilirubin 15.3 mg/dL). Coagulopathy was variable (median international normalized ratio 1.5). Four patients (18%) developed acute liver failure, two (9%) required liver transplantation. Hepatic parameters normalized within a median of 8.5 weeks. There was no statistically significant difference in the course of hepatitis between patients with SAA and RCC. Early lymphopenia was a key finding in patients with HAAA, progressing from a median of 905/µL at hepatitis onset to 530/µL within 4 weeks. HAAA occurs in both SAA and RCC. Most cases present with severe acute cholestatic hepatitis and variable coagulopathy. Hepatic recovery is common. Lymphopenia at disease onset is frequent and may serve as a diagnostic marker.
2025-07-01 | AAV8 gene therapy for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) in a patient's liver maintained ex situ for 9 days
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare genetic disorder caused by mutations in TYMP . 1 This results in nucleoside accumulation, mitochondrial damage and progressive gastrointestinal and neurological dysfunction leading to cachexia and death before 40 years. No established treatment exists. Liver transplantation restores nucleoside levels, but is not indicated in all patients (eg, severely malnourished patients) and is associated with complications. 1 Adeno-associated virus (AAV) gene therapy offers an attractive therapeutic alternative, which is already clinically approved for other genetic diseases and has been successful in MNGIE animal models. 2 Nevertheless, it has not been tested in human and, because of the rarity of MNGIE (<200 cases described), obtaining sufficient numbers for robust AAV trials is challenging. Ex situ machine perfusion (ESMP) maintains organs in near-physiological conditions before transplantation and is emerging as a new avenue to trial novel therapies in the liver with the potential to address this limitation. 3–7 However, until now only donor livers, not affected by disease, have been used for these studies, preventing testing of treatment efficacy. Our aim was to test AAV gene therapy for MNGIE in the explanted liver of a patient transplanted for this disease, which was maintained on ESMP. A 34-year-old patient with MNGIE underwent liver transplantation as enzyme replacement therapy. The explanted liver was divided into anatomical right and left lobe and perfused ex situ using two XVIVO LiverAssist devices for 9 days. Nucleoside levels in the perfusate were measured with mass spectrometry. An AAV serotype 8 encoding for TYMP was used at a dose of 10 11 viral genomes/kg of liver. PCR, qPCR and immunofluorescence for TYMP were used to assess treatment efficacy. Perfusion parameters (flow and pressure), biochemistry (ALT, pH and glucose) and histology were used to assess treatment toxicity. Within 24 h of perfusion, nucleosides accumulated in the perfusate, recapitulating key features of MNGIE. Subsequently, one lobe received AAV8-TYMP, while the other served as an internal control and received carrier injection. The viral vector was taken up by hepatocytes and TYMP expression was restored in the treated lobe within 3 days. Importantly, AAV8-TYMP treatment resulted in clearance of nucleoside from the perfusate, which recapitulated nucleoside clearance from the patient’s blood following liver transplant. Furthermore, long-term ESMP of the two liver lobes revealed no evidence of hepatotoxicity following AAV8 gene therapy, including normal ALT. Our report provides the first demonstration of the safety and efficacy of AAV gene therapy for MNGIE in a human liver, paving the road for clinical trials. We describe the first UK perfusion of a patient's organ, shifting the paradigm of using ESMP exclusively for donor livers to patient explanted pathological livers as a novel platform for drug testing. Using ESMP to test promising novel therapeutic candidates could offer an intermediate platform bridging the gap between animal studies and clinical trials. Finally, our study provides proof of principle for the efficacy of AAV gene therapy for treating diseased livers on ESMP, which could be applied to various other liver diseases.
other
2025-11-29 | Maladaptive emergency granulopoiesis predicts poor outcomes in patients hospitalized with decompensated cirrhosis.
Whether analysis of whole blood transcriptome assessed on admission of patients with acutely decompensated cirrhosis (ADC) without acute-on-chronic liver failure (ACLF) can provide information on immune cell perturbations characterizing patients who will develop ACLF is unknown. This question was investigated in our study. We analyzed whole-blood RNA-sequencing (RNA-seq) data obtained at admission (baseline) in 1260 patients with ADC without ACLF. The outcome was ACLF development by 28 days. 124 (9.8%) patients developed ACLF and were considered as having pre-ACLF on admission. When compared to patients without pre-ACLF, those with pre-ACLF presented with features of activated emergency granulopoiesis (EG) pathways including neutrophilia, upregulation of STAT3 gene and its target CEBPB (which encodes a master transcription factor driving EG) together with upregulation of genes related to immature and mature neutrophils and elevated blood levels of interleukin-6, a STAT3-CEBPB axis activator. Pre-ACLF patients also had upregulation of genes related to low-density neutrophils and granulocytic-myeloid suppressor cells (known to suppress lymphocyte functions), features indicating maladaptive EG. Baseline maladaptive EG was detected irrespective of the presence and nature of clinically apparent precipitants. Using weighted gene co-expression network analysis, we identified 22 gene modules and their respective eigengenes. In adjusted time-to-event analyses, increases in the eigengenes representative of the module "neutrophil differentiation & immunosuppression" and module "cycling cells", were each independently associated with higher risk of developing ACLF. A higher percentage of patients with pre-ACLF than patients without developed new infections during hospitalization. Using data obtained on admission of patients with ADC without ACLF, this study uncovered that activation of maladaptive EG characterized patients who will develop ACLF by 28 days. This study reveals that among patients who present for acutely decompensated cirrhosis without acute-on-chronic liver failure (ACLF) those who exhibit blood transcriptomic features of maladaptive emergency granulopoiesis are at high risk of developing ACLF by 28 days and dying by 90 days. These results strongly suggest that neutrophil-granulopoietic perturbations play a pathogenic role in the development of poor outcomes. These results should lead to the development of biological therapies targeting neutrophil-granulopoietic perturbations, which is an unmet need. These findings should also give rise to the identification of potential biomarkers for ACLF development, which is also an unmet need, all previous studies having failed to accurately predict this outcome, in particular with the use of clinical blood counts.
2025-07-18 | Novel compound heterozygous variants in NBAS underlying fever-dependent infantile liver failure syndrome type 2: potential implications of protein thermostability.
Infant liver failure syndrome type 2 (ILFS2), a rare autosomal recessive disorder manifesting as recurrent acute liver failure (ALF) triggered by febrile illness, is associated with neuroblastoma amplified sequence (NBAS) mutations. This study employs molecular dynamics simulation (MDS) to investigate how missense variants in the Sec39 domain influence protein conformation and thermostability. We identified novel compound heterozygous variants in the NBAS gene, c.2231 T > C (p.Leu744Pro) and c.2266C > T (p.Arg756Cys), in two Chinese siblings diagnosed with ILFS2. According to ACMG guideline, both variants were initially classified as variants of uncertain significance. To elucidate the potential functional impact, MDS was performed to compare structural dynamics between wild-type (WT) and mutant (MUT) NBASs at physiological temperature (37°C) and under thermal stress (42°C). The results revealed distinct thermal responses. WT demonstrated robust thermotolerance, with comparable trajectory patterns and curve parameters across two temperatures. In contrast, specific variants induced localized conformational perturbations and secondary structural reorganization. Notably, while MUT exhibited kinetic profiles similar to WT at 37°C, it showed pronounced fluctuations in flexible regions under thermal stress, with disrupted hydrogen-bonding networks and significant conformational changes, indicating compromised thermostability. The diagnosis of ILFS2 primarily relies on clinical presentation and genetic confirmation. Although the exact pathogenesis remains unclear, our findings suggest that temperature-sensitive structural destabilization induced by missense mutations within the Sec39 domain of NBAS probably underlies the fever-associated ALF. This provides critical guidance for subsequent protein structural elucidation and mechanism research, and regions exhibiting significantly reduced thermostability represent promising therapeutic targets.
cell therapies
2026-01-10 | Does Gamma-Glutamyl Transpeptidase Serum Level Play a Role as a Prognostic Marker in Biliary Atresia, an Immune-Mediated Cholangiopathy in Children?
Background: Biliary atresia (BA) is a rare, immune-mediated cholangiopathy in children and a leading cause of neonatal cholestasis and pediatric liver transplantation (LT). Gamma-glutamyl transpeptidase (GGT) is commonly elevated in BA and is used as a diagnostic marker; however, recent studies have suggested that a subset of BA patients present with normal or low GGT levels, potentially indicating a more severe disease course. Methods: This retrospective study evaluated the prognostic value of serum GGT levels in 47 children diagnosed with BA at a single center over 15 years. Patients were stratified by GGT levels at diagnosis, and outcomes were compared, including survival with native liver, need for LT, and mortality. GGT thresholds of 200 U/L and 300 U/L were used to define normal and elevated levels. Results: The study found that 12% of patients had normal or low GGT at diagnosis. Still, there were no statistically significant differences in age at diagnosis, severity of liver fibrosis, age at Kasai portoenterostomy (KPE), or overall outcomes between low and high GGT groups. Although patients with lower GGT tended to require LT at a younger age, this difference was not significant. Receiver operating characteristic (ROC) curve analysis showed that GGT levels at diagnosis, before, and after KPE were not reliable predictors of outcome. Conclusions: The findings contrast with some previous reports suggesting that low GGT is associated with a worse prognosis. Low GGT level alone should not delay diagnosis or surgical intervention in suspected BA. Early referral for KPE remains critical, and patients with low GGT may benefit from earlier LT evaluation. Larger, multicenter studies are needed to clarify the prognostic role of GGT in BA.
2025-05-26 | Therapeutic effect of hUC-MSCs from different transplantation routes on acute liver failure in rats.
Acute liver failure (ALF) is a rare yet serious clinical syndrome. Recent studies have indicated that stem cells can effectively treat this condition. However, the optimal route for stem cell transplantation in the treatment of ALF remains unclear. This study aims to investigate the most effective transplantation route for stem cell therapy in ALF. Human umbilical cord mesenchymal stem cells (hUC-MSCs) expressing both luciferase and green fluorescent protein were generated using a lentiviral vector. The hUC-MSCs were transplanted via the tail vein, portal vein, and abdominal cavity. The survival and distribution of the transplanted hUC-MSCs in rats were assessed through in vivo imaging and immunofluorescence. Furthermore, the therapeutic effects of hUC-MSCs transplanted via different routes on ALF were compared. The survival time of hUC-MSCs transplanted via the tail vein and portal vein was shorter compared to those transplanted intraperitoneally. The distribution of hUC-MSCs varied by transplantation route: those injected via the tail vein and portal vein were primarily found in the lungs and liver, respectively, while intraperitoneally transplanted hUC-MSCs predominantly localized in the abdominal cavity. In ALF rats, hUC-MSCs transplanted via the tail vein and portal vein improved survival rates, enhanced liver pathology, and reduced levels of inflammatory cytokines in liver tissue. In contrast, abdominal transplantation of hUC-MSCs showed no significant therapeutic effect. hUC-MSCs transplanted via the tail vein and portal vein exhibited similar therapeutic effects on ALF; however, abdominal transplantation of hUC-MSCs showed no significant effect.
2024-10-25 | Bone marrow transplantation increases sulfatase activity in somatic tissues in a multiple sulfatase deficiency mouse model.
Multiple Sulfatase Deficiency (MSD) is an ultra-rare autosomal recessive disorder characterized by deficient enzymatic activity of all known sulfatases. MSD patients frequently carry two loss of function mutations in the SUMF1 gene, encoding a formylglycine-generating enzyme (FGE) that activates 17 different sulfatases. MSD patients show common features of other lysosomal diseases like mucopolysaccharidosis and metachromatic leukodystrophy, including neurologic impairments, developmental delay, and visceromegaly. There are currently no approved therapies for MSD patients. Hematopoietic stem cell transplant (HSCT) has been applied with success in the treatment of certain lysosomal diseases. In HSCT, donor-derived myeloid cells are a continuous source of active sulfatase enzymes that can be taken up by sulfatase-deficient host cells. Thus, HSCT could be a potential approach for the treatment of MSD. To test this hypothesis, we used a clinically relevant mouse model for MSD, B6-Sumf1(S153P/S153P) mice, engrafted with bone marrow cells, Sumf1+/+, from B6-PtprcK302E mice (CD45.1 immunoreactive). After 10 months post-transplant, flow cytometric analysis shows an average of 90% of circulating leukocytes of donor origin (Sumf1(+/+)). Enzymatic activity for ARSA, ARSB, and SGSH is significantly increased in spleen of B6-Sumf1(S153P/S153P) recipient mice. In non-lymphoid organs, only liver and heart show a significant correction of sulfatase activity and GAG accumulation. Frequency of inflammatory cells and lysosomal pathology is significantly reduced in liver and heart, while no significant improvement is detected in brain. Our results indicate that HSCT could be a suitable approach to treat MSD-pathology affecting peripheral organs, however that benefit to CNS pathology might be limited.
2024-06-16 | Are Current Educational and Therapeutic Programs, Directed at Rare Disease Transplant Candidates and Recipients, Sufficient to Support Them on the Path From Diagnosis to Life After Allogenic Transplantation?-Recommendations for Member State Policymakers.
For many rare disease (RD) patients, allogenic transplantation represents an effective therapy, improving overall survival rates and quality of life (QoL). Globally, ∼1% of liver transplants are performed for RDs and rare indications. However, patients and carers report unmet needs on their pathway toward treatment-in education and therapeutic measures, oftentimes shouldering expertise-building responsibility themselves. These issues are exacerbated in child patients. Estimates indicate that 6% to 8% of Poland's population (2.3-3 million persons) are burdened by RDs and potentially face such issues. This work aims to identify shortcomings of Polish policy in the field of educational and therapeutic measures for RD transplant candidates and recipients. Based on solutions introduced by pioneers, recommendations are formulated regarding priority actions. An analysis of national, transnational, and individual-center programs, directed at patients during their path from diagnosis to life post-transplant, was conducted. The investigation uncovered measure gaps not addressed by the National Plan for Rare Diseases-in fields of patient and stakeholder education (pre- and post-transplant), psychological care provision, specialized center creation, integration of data scattered among registries with the national insurer's database, and artificial intelligence (AI) tool implementation to support both early diagnostic efforts and tailoring of patient treatment. Programs directed at RD transplant candidates and recipients must aim to ensure that a satisfactory psychosomatic condition of the patient is maintained before and following the procedure, therefore lending credence to success. This necessitates early diagnosis schemes, and personalized medicine, multidisciplinary approaches to the individual, achievable only through big data system creation and AI introduction.
2022-09-22 | ATP7B gene therapy of autologous reprogrammed hepatocytes alleviates copper accumulation in a mouse model of Wilson's disease.
Wilson's disease (WD) is a rare hereditary disorder due to ATP7B gene mutation, causing pathologic copper storage mainly in the liver and neurological systems. Hepatocyte transplantation showed therapeutic potential; however, this strategy is often hindered by a shortage of quality donor cells and by allogeneic immune rejection. In this study, we aimed to evaluate the function and efficacy of autologous reprogrammed, ATP7B gene-restored hepatocytes using a mouse model of WD. Sufficient liver progenitor cells (LPCs) were harvested by reprogramming hepatocytes from ATP7B-/- mice with small molecules, which exhibited strong proliferation and hepatic differentiation capacity in vitro. After lentivirus-mediated mini ATP7B gene transfection and redifferentiation, functional LPC-ATP7B-derived hepatocytes (LPC-ATP7B-Heps) were developed. RNA sequencing data showed that, compared with LPC-green fluorescent protein-Heps (LPC-GFP-Heps) with enrichment of genes that were mainly in pathways of oxidative stress and cell apoptosis, in LPC-ATP7B-Heps under high copper stress, copper ion binding and cell proliferation pathways were enriched. LPC-ATP7B-Heps transplantation into ATP7B-/- mice alleviated deposition of excess liver copper with its associated inflammation and fibrosis, comparable with those observed using normal primary hepatocytes at 4 months after transplantation. We established a system of autologous reprogrammed WD hepatocytes and achieved ATP7B gene therapy in vitro. LPC-ATP7B-Heps transplantation demonstrated therapeutic efficacy on copper homeostasis in a mouse model of WD.
small molecules
2026-06-18 | Post-meal loss of consciousness in an adult patient with carbamoyl phosphate synthetase 1 deficiency and two newly identified heterozygous variants: a case report.
Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive disorder characterized by urea cycle dysfunction and secondary hyperammonemia. Although primarily observed in neonates, adult cases are exceedingly rare and warrant reporting due to their novelty and potential for misdiagnosis. We present a case of a 34-year-old male who presented with post-meal loss of consciousness, a symptom atypical of the disease's usual manifestation. A 34-year-old man was admitted with a 2-day history of general fatigue that escalated to unconsciousness over half a day. He also experienced vomiting, bilateral limb convulsions, and a history of epilepsy. Upon admission, he exhibited coma with a Glasgow Coma Scale score of 5/15. Biochemical investigations revealed normal liver and kidney function but a significantly elevated blood ammonia concentration of 597.6 µmol/L. Cranial imaging showed diffuse swelling of the brain parenchyma indicative of encephalopathy. Gene sequencing identified three heterozygous variants in theCPS1 gene, including two novel variants sites. Despite ammonia-lowering treatments, his condition rapidly deteriorated, and he succumbed to hyperammonemia-induced encephalopathy on day 9 of admission. This case highlights the importance of recognizing CPS1D as a potential diagnosis in adults presenting with neurological symptoms, particularly those involving consciousness changes. The rarity and atypical presentation of adult CPS1D underscore the need for early diagnosis through comprehensive evaluation, including blood ammonia measurement and genetic analysis. This case expands the spectrum of clinical manifestations and genetic variants associated with CPS1D and emphasizes the urgency of ammonia-lowering therapy and consideration for liver transplantation in eligible patients.
2026-04-15 | Central nervous system post-transplant lymphoproliferative disorder relapse after pediatric liver transplantation: a case report and literature review.
Post-transplant lymphoproliferative disorder (PTLD) represents a potentially life-threatening and grave complication that can arise following solid organ transplantation (SOT). Clinically, extranodal involvement in PTLD is frequent, whereas involvement of the central nervous system (CNS) is relatively rare and frequently associated with a poor prognosis. Currently, there is no standardized therapeutic approach for CNS-PTLD. We report a pediatric patient who suffered from multiple recurrences of CNS-PTLD after liver transplantation. The patient was Epstein-Barr virus (EBV)-negative before transplantation but developed PTLD involving lymph node, liver, and multiple bones 2 years after liver transplantation, accompanied by elevated EBV-DNA in peripheral blood (PB). As the lesion was systemic and CD20-positive, we chose to use rituximab (RTX) monotherapy and achieved remission. However, after 3 cycles of RTX, the child developed neurological symptoms such as facial nerve palsy and mouth deviation. Brain magnetic resonance imaging (MRI) revealed a mass in the inner ear and thickening of the facial nerve, suggesting that the disease had invaded the CNS. Therefore, we upgraded the treatment plan to R-CHOP chemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), and achieved a complete remission (CR). Following 2 cycles of R-CHOP, the patient experienced facial nerve palsy again, and brain MRI indicated a lesion in the left cerebellopontine angle region, suggesting disease recurrence. Re-treatment with 4 cycles of R-CHOP provided minimal symptomatic relief, and follow-up MRI demonstrated progressive multiple intracranial lesions. Brain biopsy confirmed CNS-PTLD [EBV-positive Burkitt's lymphoma (BL)]. Due to the patient's resistance to standard chemotherapy (R-CHOP) and the limited location of the lesion in the CNS, we switched to a more central-permeable treatment regimen. Then the patient achieved CR following treatment with high-dose methotrexate (HD-MTX) combined with intrathecal methotrexate (IT-MTX), and subsequently underwent timely chimeric antigen receptor T-cell (CAR-T) therapy to consolidate the therapeutic effect and prevent recurrence. The patient currently maintains sustained CR. We observe that the combination of HD-MTX and intrathecal chemotherapy exhibits remarkable efficacy in managing post-transplant CNS-PTLD that is resistant to conventional R-CHOP chemotherapy. CAR-T therapy emerges as a potential option for patients suffering from relapsed or refractory CNS-PTLD.
2026-02-02 | Beyond pruritus in Alagille syndrome: potential effects of maralixibat on fibrosis and portal hypertension-insights from two case studies.
Alagille syndrome (ALGS) is a genetic disorder primarily affecting the liver, often leading to cholestasis and pruritus. Ileal Bile Acid Transporter inhibitors (IBATi), such as maralixibat, have shown promise in controlling pruritus and potentially modifying disease progression. We report two patients with ALGS treated with maralixibat. Case 1 involved a 10-days-old newborn presenting with cholestasis, jaundice, and acholic stools. Genetic testing confirmed a pathogenic JAG1 mutation. Despite preserved liver function, the patient was evaluated for liver transplantation (LT) due to severe pruritus and portal hypertension. Maralixibat initiation led to marked improvement in pruritus, serum bile acids, bilirubin, and cholesterol. Liver biopsies performed 13 months apart demonstrated fibrosis regression from cirrhosis to stage F2. Elastography showed decreased liver stiffness, reduced splenomegaly, and improved platelet counts. Liver enzymes transiently increased, but treatment continued without dose adjustment. Case 2 involved a 15-years-old female with moderate portal hypertension and mild pruritus. After 24 months of maralixibat, pruritus resolved completely, serum bile acids decreased, liver stiffness and splenomegaly improved, and platelet counts increased. Liver enzymes remained mildly elevated without requiring treatment modification. These findings suggest maralixibat may improve portal hypertension and hepatic injury, even in patients with less severe biochemical abnormalities. In ALGS, maralixibat treatment improved pruritus, lowered serum bile acids, and suggested potential benefits on fibrosis and portal hypertension, indicating a possible role beyond symptomatic relief.
2025-12-15 | Unusual Etiology of Budd-Chiari Syndrome in an Adolescent: A Case of Combined Thrombophilic Disorder.
Budd-Chiari syndrome (BCS) is an uncommon but potentially life-threatening hepatic vascular disorder resulting from obstruction of the hepatic venous outflow. While it predominantly affects adults, pediatric and adolescent presentations are rare, particularly those associated with inherited thrombophilia. Early diagnosis and appropriate intervention are essential to prevent complications such as portal hypertension, hepatic ischemia, and liver failure. We describe the case of a 15-year-old female who presented with progressive abdominal distension, right upper quadrant pain, and bilateral lower limb edema. Imaging studies, including ultrasound and contrast-enhanced CT, revealed hepatic venous obstruction with thrombus extension into the portal, superior mesenteric and splenic veins, and gross ascites. Laboratory findings indicated elevated inflammatory markers and impaired liver function. A detailed thrombophilia workup demonstrated deficiencies in protein C and antithrombin III and a Factor V Leiden mutation, confirming a hypercoagulable state as the underlying etiology. The patient was diagnosed with subacute Budd-Chiari Syndrome secondary to inherited thrombophilia. She was initiated on anticoagulation therapy with warfarin, later transitioned to rivaroxaban, and managed with diuretics and dietary modifications. Clinical improvement was achieved, and the patient was referred to a liver transplant center for ongoing evaluation.
2025-07-24 | Long-Term Outcomes of Chenodeoxycholic Acid Therapy for Cerebrotendinous Xanthomatosis: A Nationwide Study on Prognostic Factors and Treatment Response.
Cerebrotendinous xanthomatosis (CTX) is a treatable neurometabolic disorder. Chenodeoxycholic acid (CDCA) is the first-line treatment and can potentially halt disease progression if initiated before neurologic symptoms appear. This nationwide, multicenter study evaluates the long-term effects of treatment in 86 genetically confirmed patients with CTX receiving CDCA for ≥ 6 months, focusing on neurologic and extraneurologic outcomes, prognostic factors, and biochemical response. Clinical and biochemical parameters were recorded at baseline and follow-up, and neurological outcomes were assessed using neurological disability scores. Our results indicate a critical age of 28 years for the start of treatment. Patients diagnosed before 28 years showed 100% neurological stabilization or improvement, whereas patients diagnosed later had a higher rate of disease progression (p < 0.05). CDCA effectively stabilized or improved pyramidal and cerebellar symptoms, although myoclonus and parkinsonism remained less responsive. Psychiatric symptoms showed a lower treatment response, with psychosis being the most refractory finding. CDCA resulted in a strong and sustained reduction in cholestanol levels, although biochemical response did not always correlate with clinical improvement. Longer diagnostic delay and presence of anxiety and pyramidal/cerebellar symptoms were associated with poorer outcomes. Notably, a cholestatic child, for whom liver transplantation had initially been considered, recovered completely under CDCA therapy. Our results show that early diagnosis and initiation of CDCA therapy significantly improve neurological outcomes in CTX. However, even in late-diagnosed patients, treatment continues to be beneficial, demonstrating that it is never too late to start therapy. Biochemical response does not always predict clinical improvement; multidisciplinary follow-up is essential.
antibodies
2026-05-05 | Hepatic Manifestations and Response to Treatment in Deficiency of Adenosine Deaminase 2.
Deficiency of adenosine deaminase 2 (DADA2) is caused by mutations in the ADA2 gene and results in an auto-inflammatory state. Hepatosplenomegaly, with or without abnormalities in liver enzymes, has been reported in DADA2. Anti-tumour necrosis factor (anti-TNF) therapy is the standard of care for the prevention of recurrent ischemic strokes and reduction of inflammatory burden. However, little is known about the extent of hepatic involvement and the utility of non-invasive tools for identifying liver disease and monitoring treatment response. Retrospective analysis was performed on a prospective cohort of 70 patients with DADA2. Patients underwent baseline and annual laboratory testing, abdominal imaging and transient elastography. Hepatomegaly and splenomegaly were assessed on imaging, with splenomegaly defined using the spleen-to-height (SH) ratio. Liver biopsy and esophagogastroduodenoscopy were performed when indicated. At baseline, elevated ALT was uncommon (29%). Hepatomegaly and splenomegaly were present in 36% and 58%, respectively. Liver biopsies were performed in 12 patients, 8 of whom showed porto-sinusoidal vascular disease (PSVD). Over a median follow-up of 4.5 years, 40% demonstrated persistently elevated ALT levels. Clinically evident portal hypertension was present in 14%, and decompensation events, such as ascites and variceal bleeding, occurred in 5%. Anti-TNF therapy resulted in resolution of splenomegaly in 28% and a reduction in mean SH ratio across the entire cohort. Patients who underwent haematopoietic cell transplantation (HCT) appeared to be at risk for complications such as hepatic graft versus host disease and veno-occlusive disease. DADA2 vasculopathy appears to affect intrahepatic portal veins and result in PSVD. SH ratio shows significant promise in identifying liver involvement and monitoring treatment response. The improvement in SH suggests that PSVD may be reversible with treatment in this setting. Hepatic evaluation at baseline is encouraged for all patients, and pre-HCT liver biopsy should be considered, as there can be clinically silent liver disease that could potentially cause transplant-related complications.
2026-01-02 | Nanobodies as therapies for loss-of-function misfolding diseases: the example of Primary Hyperoxaluria Type 1.
Misfolding diseases that result in loss of function represent a considerable burden for both individuals and society. Primary Hyperoxaluria Type 1 (PH1) is a rare genetic disorder caused by the deficit of alanine:glyoxylate aminotransferase (AGT), which leads to excessive endogenous oxalate formation translating into progressive renal damage due to stones formation. The underlying molecular mechanisms causing PH1 are associated with protein misfolding (leading to enhanced degradation, aggregation and/or mitochondrial mistargeting). The main therapeutic approach is a double kidney and liver transplantation, but treatments based on RNA silencing are currently available, although they normalize urinary oxalate excretion only in about 50 % of patients, calling for the need of alternative options. In this work, we developed and characterized a novel biotechnological approach using six single-domain nanobodies (NB-AGT-1 to -6) as potential therapeutics counteracting PH1 misfolding. We show that NB-AGTs are very stable proteins and bind pathogenic and non-pathogenic variants of AGT with high affinities (Kd values from low nM to low pM). Structural studies indicate that NB-AGTs bind to different protein epitopes thus being selective for different variants. Preliminary experiments in a cellular model of PH1 show that internalization of engineered NB-AGT-3 enhances the specific activity of disease-associated variants. Overall, our results provide the basis to consider NBs as a promising approach for PH1 as premise for their application to other loss-of-function misfolding diseases.
2025-11-01 | 26 Post-Transplant Lymphoproliferative Disorder in a Pediatric Liver Transplant Recipient: A Rare but Serious Complication of Chronic Immunosuppression
Abstract Introduction/Objective Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication following solid organ transplantation, including liver transplants. It arises due to chronic immunosuppression, leading to uncontrolled lymphocyte proliferation, often associated with Epstein-Barr virus (EBV) infection. PTLD occurs in 1%–10% of post-solid organ transplant recipients and 1%–5.5% of those who have undergone liver transplantation. These neoplasms are associated with an increased mortality. In pediatric liver transplant recipients, EBV-driven PTLD has a reported incidence ranging from 2% to 8%, with a mortality rate of around 44%. We present a case of a pediatric liver transplant recipient who developed EBV-driven PTLD 3 years after transplant. Methods/Case Report A 6-year-old male, who had undergone orthotopic liver transplantation at the age of 3 due to acute liver failure of unknown etiology, was evaluated during a routine follow-up. His past medical history was significant for mild glucose-6-phosphate dehydrogenase (G6PD) deficiency, along with a history of allograft rejection episodes, which necessitated chronic immunosuppressive therapy. Additionally, he had a documented history of Epstein-Barr virus (EBV) viremia, which is a known risk factor for post-transplant complications. His family history is notable for systemic lupus erythematosus (SLE) in his mother, which may indicate a genetic predisposition to immune dysregulation. A PET-CT scan revealed multiple fluorodeoxyglucose (FDG)-avid hepatic foci, many of which corresponded to hypodense lesions, raising suspicion for PTLD. The patient was admitted for further evaluation, including an EBV DNA quantitative PCR, which revealed significant viremia (>200,000 copies/mL). A liver biopsy confirmed polymorphic PTLD, characterized by lymphoid infiltration with positive EBV-encoded RNA (EBER) in situ hybridization. Management included reduction of immunosuppression and initiation of rituximab therapy for lymphoma treatment. Hematologic parameters remained stable, with no evidence of bone marrow involvement. Results NA Conclusion PTLD is a serious, potentially life-threatening complication of chronic immunosuppression in pediatric liver transplant recipients, with early detection being critical for improving outcomes. This case highlights the importance of routine EBV monitoring and prompt histopathological evaluation in post-transplant patients with suspicious imaging findings. The polymorphous nature of PTLD requires a multimodal diagnostic approach, including immunophenotyping and EBER in situ hybridization, while FDG PET-CT remains a valuable tool for assessing disease burden. Timely intervention with immunosuppression reduction and rituximab therapy can be effective in controlling disease progression. Given the 6% incidence in pediatric liver transplant patients, increased awareness and early intervention strategies are essential to improving survival rates in this vulnerable population.
2025-08-23 | Claudin-1 is a mediator and therapeutic target in primary sclerosing cholangitis.
Primary sclerosing cholangitis (PSC) is a cholangiopathy associated with a high risk of progression to end-stage liver disease and hepatobiliary cancer. Its pathogenesis remains poorly understood, and current clinical management offers limited therapeutic options, primarily liver transplantation. Claudin-1 (CLDN1), a transmembrane protein highly expressed in liver epithelial cells, plays a critical role in cell-cell communication and signaling. We aimed to investigate the functional role of CLDN1 as both a mediator and potential therapeutic target for PSC using patient cohorts alongside murine and patient-derived intervention models. CLDN1 expression patterns and associated cellular phenotypes were analyzed in liver tissues from five PSC patient cohorts using single-cell RNA sequencing, spatial transcriptomics, and multiplex proteomics. Proof-of-concept studies employing CLDN1-specific monoclonal antibodies (mAbs) and genetic loss-of-function approaches were performed in state-of-the-art mouse models of PSC and cholangiopathies. Perturbation studies in human cell-based models were conducted to explore underlying mechanisms. In liver tissues from patients with PSC, CLDN1 expression was markedly upregulated and correlated with disease progression. Spatial transcriptomics and proteomics revealed elevated CLDN1 expression in diseased cholangiocytes and cholestatic periportal hepatocytes, accompanied by activation of pro-inflammatory and pro-fibrotic signaling pathways. Therapeutic administration of CLDN1-specific mAbs or genetic knockout improved liver function in PSC mouse models by reducing hepatobiliary fibrosis and cholestasis. Mechanistic studies indicated that mAb treatment inhibited pro-inflammatory and pro-fibrotic signaling in cholangiocytes and hepatocytes perturbed in PSC liver tissues. These findings demonstrate a functional role for CLDN1 in the pathogenesis of PSC and biliary fibrosis. In vivo proof-of-concept studies, combined with expression analyses in patients with PSC, support the clinical development of CLDN1-specific mAbs as a therapeutic strategy for PSC. Primary sclerosing cholangitis (PSC) is a chronic fibrosing cholangiopathy with limited therapeutic options. We identified the cell surface protein Claudin-1 as a key mediator and potential therapeutic target for PSC. In patients, Claudin-1 expression correlates with disease stage and clinical outcomes. Conditional liver epithelial-specific Claudin-1 knockout in mice reduced liver injury, fibrosis, and cholestasis. Monoclonal antibodies targeting Claudin-1 inhibited fibrosis, cholestasis, and the ductular reaction across advanced PSC mouse models by suppressing pro-inflammatory and fibrogenic signaling. These preclinical findings support the clinical development of Claudin-1-specific antibodies for PSC treatment and have significant implications for physicians, researchers, and drug developers in the field of biliary disease.
2020-07-09 | Clinical Characteristics and Prognostic Factors of Patients with Intrahepatic Cholangiocarcinoma with Fever: A Propensity Score Matching Analysis.
Patients with intrahepatic cholangiocarcinoma (ICC) rarely present fever as the initial symptom. We aimed to identify clinical characteristics and prognostic factors for these feverish patients. This study retrospectively reviewed 31 patients with ICC with fever (≥38.0°C) treated at our hospital between January 2002 and December 2014. A propensity score was used to match patients with and without fever at a ratio of 1:2. Patients with ICC with fever had higher serum γ-glutamyl transferase and carcinoembryonic antigen levels, larger tumors, poorer tumor differentiation, and worse prognosis (all p < .05) than those without fever. This was supported by propensity score matching (PSM) analysis. Univariate and multivariate analyses indicated that microvascular invasion, hilar lymph node metastasis, and temperature ≥ 38.6°C were related to prognosis. Patients with ICC with fever had higher levels of leucocytes, neutrophils, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in peripheral blood before and after PSM analysis. Body temperature positively correlated with leucocytes (r = 0.599, p < .001), neutrophils (r = 0.644, p < .001), NLR (r = 0.681, p < .001), and PLR (r = 0.457, p = .010). Patients with ICC with fever ≥38.0°C and ≥38.6°C had poor and extremely poor prognosis, respectively. Radical surgical treatment may improve the prognosis of patients with ICC with fever <38.6°C. However, systemic therapy (e.g., anti-inflammatory and immune therapy) may be preferable to surgery for these patients with fever ≥38.6°C. Patients with intrahepatic cholangiocarcinoma (ICC) with fever (≥38.0°C) as the initial symptom are extremely rare. Because their symptoms are similar to those of liver abscess, diagnosis is challenging, and most of these patients are already at an advanced stage at the time of diagnosis. Patients with ICC with fever had different clinical characteristics and worse prognosis than those without fever. The prognosis of those with temperature <38.6°C would be improved by timely surgical intervention. Those with fever ≥38.6°C had an extremely dismal outcome, although they all received radical surgical treatment. New therapeutic strategies are needed to improve survival for patients with ICC with temperature ≥38.6°C. 摘要 背景。肝内胆管癌 (ICC) 患者很少将发热作为首诊症状。我们的目的是确定这些发热患者的临床特征和预后因素。 受试者、材料和方法。本研究回顾性地分析了 2002 年 1 月至 2014 年 12 月期间在我院接受治疗的 31 名伴发热 (≥38.0°C) ICC患者。我们采用倾向评分以 1:2 的比例匹配伴发热与未伴发热的患者。 结果。与未伴发热的ICC患者相比，伴发热ICC患者的血清 γ‐谷氨酰转移酶和癌胚抗原水平较高，肿瘤较大，肿瘤分化较差，预后较差(全部的 p < 0.05)。我们通过倾向评分匹配 (PSM) 分析证实了这一点。单变量和多变量分析表明，微血管浸润、肝门淋巴结转移和体温 ≥38.6°C 与预后有关。伴发热ICC患者在PSM分析之前和之后的白细胞水平、中性粒细胞、中性粒细胞与淋巴细胞的比率 (NLR) 以及外周血中血小板与淋巴细胞的比率 (PLR) 均较高。体温与白细胞(r = 0.599，p < 0.001)、中性粒细胞(r = 0.644，p < 0.001)、NLR(r = 0.681，p < 0.001)以及PLR(r = 0.457，p = 0.010)呈正相关。 结论。体温 ≥38.0°C 和 ≥38.6°C 的伴发热ICC患者的预后效果分别为差和极差。根治性手术治疗可改善体温 <38.6°C 的伴发热ICC患者的预后。但是，对于体温 ≥38.6°C 的伴发热ICC患者，全身治疗(例如抗炎和免疫治疗)可能优于手术治疗。 实践意义:以发热 (≥38.0°C) 为首诊症状的肝内胆管癌(ICC)患者极为少见。由于其症状与肝脓肿相似，给诊断带来了很大的挑战，并且大多数患者在诊断时已处于晚期。伴发热ICC患者的临床特征与未伴发热ICC患者不同，并且预后较差。通过及时的手术干预可以改善体温 <38.6°C 的患者的预后。体温 ≥38.6°C 的发热患者虽然接受了根治性手术治疗，但预后极差。需要新的治疗策略来改善体温 ≥38.6°C 的ICC患者的生存期。
gene therapies
2026-08-11 | Liver-directed gene therapy results in amelioration of progressive familial intrahepatic cholestasis type 2 in mice.
Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare disease affecting the ABCB11 gene, encoding the bile salt export pump (BSEP). BSEP dysfunction impairs bile acid (BA) secretion, causing hepatic damage and leading to pruritus, cholestasis, hepatomegaly, and often fibrosis and end-stage hepatic disease. Treatments include ileal BA transporter inhibitors, surgical bile diversion, or ultimately, liver transplantation. Our aim was to develop a PFIC2 gene therapy approach based on the restoration of BSEP hepatocyte expression. We designed several expression cassettes containing the human ABCB11 gene downstream of either a liver-specific constitutive promoter or a BA-inducible promoter. After in vitro screening, the AAV vectors with the best expression cassette for each promoter were tested in a PFIC2 mouse model. The AAV vector containing the constitutive promoter, named VTX-802, showed higher BSEP expression, resulting in better restoration of BA secretion 3 and 7 weeks post-treatment. We then performed a dose-range-finding study of VTX-802 in 5-week-old female PFIC2 mice in which the therapeutic efficacy was monitored until 5 months of age. Treated mice showed a sustained dose-dependent improvement in serum transaminase levels. These mice also exhibited significant, but partial, correction of hepatomegaly, and increased BA levels in bile and small intestine, indicating partial restoration of normal BA secretion. VTX-802 restores hepatic BSEP expression and partially corrects disease phenotype in PFIC2 mice. To our knowledge, VTX-802 is the first gene therapy approach that could potentially benefit PFIC2 patients.
2025-12-09 | Acute severe cholestatic hepatitis and lymphopenia characterize pediatric hepatitis-associated aplastic anemia.
Hepatitis-associated aplastic anemia (HAAA) is described as acute severe hepatitis of unknown origin followed by bone marrow failure (BMF). We aimed to provide a comprehensive picture of pediatric HAAA. Two-center retrospective analysis was performed using data from children diagnosed with acquired BMF, including severe aplastic anemia (SAA) and myelodysplastic syndrome type refractory cytopenia of childhood (RCC). The assessment of the subcohort of HAAA included clinical features indicative of diagnosis and disease progression, with additional data from previously published case series. Cohort comprised 62 children with acquired BMF and 22 children with HAAA. Median age of HAAA patients was 13.5 years. Potentially triggering viral infections were detected in 45%. The median interval from hepatitis onset to cytopenia was 3 weeks. All cases presented with severe hepatitis (median alanine transaminase 2127 U/L) and all but one with hyperbilirubinemia (median bilirubin 15.3 mg/dL). Coagulopathy was variable (median international normalized ratio 1.5). Four patients (18%) developed acute liver failure, two (9%) required liver transplantation. Hepatic parameters normalized within a median of 8.5 weeks. There was no statistically significant difference in the course of hepatitis between patients with SAA and RCC. Early lymphopenia was a key finding in patients with HAAA, progressing from a median of 905/µL at hepatitis onset to 530/µL within 4 weeks. HAAA occurs in both SAA and RCC. Most cases present with severe acute cholestatic hepatitis and variable coagulopathy. Hepatic recovery is common. Lymphopenia at disease onset is frequent and may serve as a diagnostic marker.
2025-07-01 | AAV8 gene therapy for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) in a patient's liver maintained ex situ for 9 days
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare genetic disorder caused by mutations in TYMP . 1 This results in nucleoside accumulation, mitochondrial damage and progressive gastrointestinal and neurological dysfunction leading to cachexia and death before 40 years. No established treatment exists. Liver transplantation restores nucleoside levels, but is not indicated in all patients (eg, severely malnourished patients) and is associated with complications. 1 Adeno-associated virus (AAV) gene therapy offers an attractive therapeutic alternative, which is already clinically approved for other genetic diseases and has been successful in MNGIE animal models. 2 Nevertheless, it has not been tested in human and, because of the rarity of MNGIE (<200 cases described), obtaining sufficient numbers for robust AAV trials is challenging. Ex situ machine perfusion (ESMP) maintains organs in near-physiological conditions before transplantation and is emerging as a new avenue to trial novel therapies in the liver with the potential to address this limitation. 3–7 However, until now only donor livers, not affected by disease, have been used for these studies, preventing testing of treatment efficacy. Our aim was to test AAV gene therapy for MNGIE in the explanted liver of a patient transplanted for this disease, which was maintained on ESMP. A 34-year-old patient with MNGIE underwent liver transplantation as enzyme replacement therapy. The explanted liver was divided into anatomical right and left lobe and perfused ex situ using two XVIVO LiverAssist devices for 9 days. Nucleoside levels in the perfusate were measured with mass spectrometry. An AAV serotype 8 encoding for TYMP was used at a dose of 10 11 viral genomes/kg of liver. PCR, qPCR and immunofluorescence for TYMP were used to assess treatment efficacy. Perfusion parameters (flow and pressure), biochemistry (ALT, pH and glucose) and histology were used to assess treatment toxicity. Within 24 h of perfusion, nucleosides accumulated in the perfusate, recapitulating key features of MNGIE. Subsequently, one lobe received AAV8-TYMP, while the other served as an internal control and received carrier injection. The viral vector was taken up by hepatocytes and TYMP expression was restored in the treated lobe within 3 days. Importantly, AAV8-TYMP treatment resulted in clearance of nucleoside from the perfusate, which recapitulated nucleoside clearance from the patient’s blood following liver transplant. Furthermore, long-term ESMP of the two liver lobes revealed no evidence of hepatotoxicity following AAV8 gene therapy, including normal ALT. Our report provides the first demonstration of the safety and efficacy of AAV gene therapy for MNGIE in a human liver, paving the road for clinical trials. We describe the first UK perfusion of a patient's organ, shifting the paradigm of using ESMP exclusively for donor livers to patient explanted pathological livers as a novel platform for drug testing. Using ESMP to test promising novel therapeutic candidates could offer an intermediate platform bridging the gap between animal studies and clinical trials. Finally, our study provides proof of principle for the efficacy of AAV gene therapy for treating diseased livers on ESMP, which could be applied to various other liver diseases.
other
2025-11-29 | Maladaptive emergency granulopoiesis predicts poor outcomes in patients hospitalized with decompensated cirrhosis.
Whether analysis of whole blood transcriptome assessed on admission of patients with acutely decompensated cirrhosis (ADC) without acute-on-chronic liver failure (ACLF) can provide information on immune cell perturbations characterizing patients who will develop ACLF is unknown. This question was investigated in our study. We analyzed whole-blood RNA-sequencing (RNA-seq) data obtained at admission (baseline) in 1260 patients with ADC without ACLF. The outcome was ACLF development by 28 days. 124 (9.8%) patients developed ACLF and were considered as having pre-ACLF on admission. When compared to patients without pre-ACLF, those with pre-ACLF presented with features of activated emergency granulopoiesis (EG) pathways including neutrophilia, upregulation of STAT3 gene and its target CEBPB (which encodes a master transcription factor driving EG) together with upregulation of genes related to immature and mature neutrophils and elevated blood levels of interleukin-6, a STAT3-CEBPB axis activator. Pre-ACLF patients also had upregulation of genes related to low-density neutrophils and granulocytic-myeloid suppressor cells (known to suppress lymphocyte functions), features indicating maladaptive EG. Baseline maladaptive EG was detected irrespective of the presence and nature of clinically apparent precipitants. Using weighted gene co-expression network analysis, we identified 22 gene modules and their respective eigengenes. In adjusted time-to-event analyses, increases in the eigengenes representative of the module "neutrophil differentiation & immunosuppression" and module "cycling cells", were each independently associated with higher risk of developing ACLF. A higher percentage of patients with pre-ACLF than patients without developed new infections during hospitalization. Using data obtained on admission of patients with ADC without ACLF, this study uncovered that activation of maladaptive EG characterized patients who will develop ACLF by 28 days. This study reveals that among patients who present for acutely decompensated cirrhosis without acute-on-chronic liver failure (ACLF) those who exhibit blood transcriptomic features of maladaptive emergency granulopoiesis are at high risk of developing ACLF by 28 days and dying by 90 days. These results strongly suggest that neutrophil-granulopoietic perturbations play a pathogenic role in the development of poor outcomes. These results should lead to the development of biological therapies targeting neutrophil-granulopoietic perturbations, which is an unmet need. These findings should also give rise to the identification of potential biomarkers for ACLF development, which is also an unmet need, all previous studies having failed to accurately predict this outcome, in particular with the use of clinical blood counts.
2025-07-18 | Novel compound heterozygous variants in NBAS underlying fever-dependent infantile liver failure syndrome type 2: potential implications of protein thermostability.
Infant liver failure syndrome type 2 (ILFS2), a rare autosomal recessive disorder manifesting as recurrent acute liver failure (ALF) triggered by febrile illness, is associated with neuroblastoma amplified sequence (NBAS) mutations. This study employs molecular dynamics simulation (MDS) to investigate how missense variants in the Sec39 domain influence protein conformation and thermostability. We identified novel compound heterozygous variants in the NBAS gene, c.2231 T > C (p.Leu744Pro) and c.2266C > T (p.Arg756Cys), in two Chinese siblings diagnosed with ILFS2. According to ACMG guideline, both variants were initially classified as variants of uncertain significance. To elucidate the potential functional impact, MDS was performed to compare structural dynamics between wild-type (WT) and mutant (MUT) NBASs at physiological temperature (37°C) and under thermal stress (42°C). The results revealed distinct thermal responses. WT demonstrated robust thermotolerance, with comparable trajectory patterns and curve parameters across two temperatures. In contrast, specific variants induced localized conformational perturbations and secondary structural reorganization. Notably, while MUT exhibited kinetic profiles similar to WT at 37°C, it showed pronounced fluctuations in flexible regions under thermal stress, with disrupted hydrogen-bonding networks and significant conformational changes, indicating compromised thermostability. The diagnosis of ILFS2 primarily relies on clinical presentation and genetic confirmation. Although the exact pathogenesis remains unclear, our findings suggest that temperature-sensitive structural destabilization induced by missense mutations within the Sec39 domain of NBAS probably underlies the fever-associated ALF. This provides critical guidance for subsequent protein structural elucidation and mechanism research, and regions exhibiting significantly reduced thermostability represent promising therapeutic targets.
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Drug Discovery Landscape
1 orphan drug designation for Rare disorder potentially indicated for liver transplant.
1 orphan drug designation for Rare disorder potentially indicated for liver transplant.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
4-[[[4-(4-Chlorophenoxy)phenyl]sulfonyl]-methyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide | small molecules | FDA | — | Conatus Pharmaceuticals, Inc. |
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