RARE DISEASE
Tyrosinemia type 1
Tyrosinemia type 1
Tyrosinemia type 1
Synonyms: FAH deficiency, Fumarylacetoacetase deficiency, Fumarylacetoacetate hydrolase deficiency, Hepatorenal tyrosinemia, Tyrosinemia type I
Synonyms: FAH deficiency, Fumarylacetoacetase deficiency, Fumarylacetoacetate hydrolase deficiency, Hepatorenal tyrosinemia, Tyrosinemia type I
Synonyms: FAH deficiency, Fumarylacetoacetase deficiency, Fumarylacetoacetate hydrolase deficiency, Hepatorenal tyrosinemia, Tyrosinemia type I
Drug discovery
2
drugs
With orphan designations
Overview
Tyrosinemia Type 1 (HT-1) is an autosomal recessive disorder caused by deficient fumarylacetoacetate hydrolase (FAH), leading to toxic accumulation of succinylacetone and tyrosine metabolites. This results in acute/chronic liver failure, renal tubular dysfunction, hypophosphatemic rickets, and porphyria-like neurological crises. Untreated, it carries a high risk of hepatocellular carcinoma. Primary treatment combines nitisinone (NTBC) to inhibit tyrosine catabolism and a tyrosine/phenylalanine-restricted diet. Newborn screening via succinylacetone detection enables early intervention, drastically improving survival [1][2][5].
Therapies
Nitisinone (NTBC): Inhibits 4-hydroxyphenylpyruvate dioxygenase, reducing toxic metabolites [1][3][5].
Dietary management: Protein-restricted diet with medical formulas to limit tyrosine/phenylalanine [5][14][16].
Liver transplantation: Reserved for NTBC non-responders or hepatocellular carcinoma [5][14][17].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare neoplastic diseases, rare neurological diseases, rare renal diseases, rare transplant-related disorders
Research Papers
448 drug discovery papers about Tyrosinemia type 1, with 3 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
448 drug discovery papers about Tyrosinemia type 1, with 3 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-06-02 | An optimized engineered bacterium for tyrosinemia type 1 therapy: A multi-species preclinical study.
Hereditary tyrosinemia type 1 (HT1) is a life-threatening metabolic disorder caused by the toxic accumulation of tyrosine and its metabolites. While treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) combined with a strict dietary regimen has improved outcomes, it imposes a significant lifelong burden and is associated with debilitating side effects and incomplete protection. Here, we developed an engineered probiotic with an optimized design, e-EcN-HT, and demonstrated its comprehensive efficacy and safety in HT1 across multiple animal models, including fumarylacetoacetate hydrolase (FAH)-/- mice, FAH-/- rabbits, and Bama minipigs. Our findings indicate that e-EcN-HT not only mitigates multifaceted acute manifestations of FAH-/- mice, including neonatal death and acute liver injury, but also improves chronic liver lesions when combined with NTBC. The therapeutic effect translated successfully to the FAH-/- rabbit model. Moreover, e-EcN-HT administration led to rapid metabolism of orally administered 13C-tyrosine, confirming robust and active tyrosine consumption in pigs. Comprehensive safety assessments across murine and porcine models showed that e-EcN-HT was well tolerated, with no significant adverse effects, systemic dissemination, or detrimental disruption to the resident gut microbiota. Collectively, our multi-species preclinical data underscore the potential of engineered bacteria as a viable therapeutic strategy for HT1 and possibly other metabolic disorders.
2026-03-07 | Pediatric liver transplantation for inherited metabolic disease-Current challenges.
Liver transplantation (LT) was first introduced in the early 1960s, with early paediatric experience marked by significant technical challenges and high risk. Advances in surgical techniques and immunosuppressive therapy in the late 1970s led to successful paediatric LT outcomes, while continued improvements throughout the 1980s and 1990s have enhanced survival and reduced complications. Current 10-year graft and patient survival rates for elective paediatric indications exceed 90%. Over the past two decades, LT has increasingly been used to treat inherited metabolic diseases (IMDs), which now account for 25-30% of paediatric LT. Initially recommended for tyrosinaemia type 1 in 1978 and later for urea cycle disorders such as ornithine transcarbamylase deficiency, LT can be curative when the metabolic defect is confined to the liver and partially corrective in conditions with extrahepatic involvement. As indications expand and earlier intervention is emphasized, this review examines the role of LT in IMDs, highlighting current concepts, challenges, and controversies.
2025-10-10 | The Evolving Trend of Liver Transplantation in Metabolic Diseases: From Origins to Current Perspectives.
Liver transplantation (LTx) has become, over the years, an increasingly used therapeutic option in patients with inherited metabolic diseases (IMD). Initially performed for Tyrosinemia Type I and ornithine transcarbamylase deficiency, it now accounts as the second indication for pediatric transplants worldwide. The use of LTx has been extended to systemic metabolic disorders, in which a genetically normal liver can correct the defect by providing an enzyme replacement therapy that improves metabolic control and disease burden, reducing the risk of metabolic crises and neurological damage, allowing for the withdrawal, in most diseases, of dietary restrictions and specific medications. The temporal changes, mainly reflecting improved LTx management through a multidisciplinary approach, have provided excellent outcomes and long-term patient survival, shifting the paradigm from a lifesaving procedure to a life-improving treatment. However, challenges still exist, particularly, in systemic IMD due to the persistence of the underlying defect in extra-hepatic tissues. Immunosuppression, especially in organic acidurias, may lead to new, drug-related, neurotoxic risks. The new indications for transplantation should target endpoints that are not exclusively clinical, addressing major attention to the improvement of health-related quality of life issues. Protocols for managing LTx in IMD need to be harmonized, and future joint multicenter actions will fill these gaps and provide a uniform vision of this evolving scenario.
2024-09-10 | Hormonally and chemically defined expansion conditions for organoids of biliary tree Stem Cells
Wholly defined ex vivo expansion conditions for biliary tree stem cell (BTSC) organoids were established, consisting of a defined proliferative medium (DPM) used in combination with soft hyaluronan hydrogels. The DPM consisted of commercially available Kubota's Medium (KM), to which a set of small molecules, particular paracrine signals, and heparan sulfate (HS) were added. The small molecules used were DNA methyltransferase inhibitor (RG108), TGF- β Type I receptor inhibitor (A83-01), adenylate cyclase activator (Forskolin), and L-type Ca2+ channel agonist (Bay K8644). A key paracrine signal proved to be R-spondin 1 (RSPO1), a secreted protein that activates Wnts. Soluble hyaluronans, 0.05 % sodium hyaluronate, were used with DPM to expand monolayer cultures. Expansion of organoids was achieved by using DPM in combination with embedding organoids in Matrigel that was replaced with a defined thiol-hyaluronan triggered with PEGDA to form a hydrogel with a rheology [G*] of less than 100 Pa. The combination is called the BTSC-Expansion-Glycogel-System (BEX-gel system) for expanding BTSCs as a monolayer or as organoids. The BTSC organoids were expanded more than 3000-fold ex vivo in the BEX-gel system within 70 days while maintaining phenotypic traits indicative of stem/progenitors. Stem-cell-patch grafting of expanded BTSC organoids was performed on the livers of Fah-/- mice with tyrosinemia and resulted in the rescue of the mice and restoration of their normal liver functions. The BEX-gel system for BTSC organoid expansion provides a strategy to generate sufficient numbers of organoids for the therapeutic treatments of liver diseases.
2024-06-07 | Revitalizing liver function in mice with liver failure through transplantation of 3D-bioprinted liver with expanded primary hepatocytes.
The utilization of three-dimensional (3D) bioprinting technology to create a transplantable bioartificial liver emerges as a promising remedy for the scarcity of liver donors. This study outlines our strategy for constructing a 3D-bioprinted liver, using in vitro-expanded primary hepatocytes recognized for their safety and enhanced functional robustness as hepatic cell sources for bioartificial liver construction. In addition, we have developed bioink biomaterials with mechanical and rheological properties, as well as printing capabilities, tailored for 3D bioprinting. Upon heterotopic transplantation into the mesentery of tyrosinemia or 90% hepatectomy mice, our 3D-bioprinted liver effectively restored lost liver functions, consequently extending the life span of mice afflicted with liver injuries. Notably, the inclusion of an artificial blood vessel in our 3D-bioprinted liver allowed for biomolecule exchange with host blood vessels, demonstrating, in principle, the rapid integration of the bioartificial liver into the host vascular system. This model underscores the therapeutic potential of transplantation for the treatment of liver failure diseases.
gene therapies
2026-04-03 | Toward Next-Gen Cell Therapy for Pediatric Patients: Neonatal Hepatocytes Tolerate Electroporation-Mediated Gene Editing and Engraft in the Liver.
Hepatocyte transplantation (HTx) offers a safer, less invasive alternative to orthotopic liver transplantation for inherited metabolic liver diseases, especially in high-risk pediatric patients. Combining HTx with ex vivo gene editing is a promising autologous therapeutic strategy using the patient's cells. We investigated the feasibility of this approach by applying CRISPR-Cas9 gene knock-out to neonatal mouse hepatocytes and comparing their engraftment potential with that of mature adult cells in the Fah-/- mouse model of hereditary tyrosinemia type I (HT1). Electroporation-mediated gene editing did not significantly impair the ability of neonatal hepatocytes to engraft in vivo. Quantitative histological analysis revealed comparable liver repopulation levels between recipients of gene-edited neonatal cells and adult cells after hepatoxicity-mediated selection, providing a benchmark for electroporation-mediated gene editing in neonatal hepatocytes, and supporting the development of genetically corrected neonatal hepatocyte products as a crucial long-term or bridge-to-transplant therapeutic strategy for pediatric liver disease.
2025-07-25 | A clinical case of late diagnosis of a chronic type I tyrosinemia
Tyrosinemia type 1 is a genetic disease mainly of the first months and years of life caused by a violation of normal tyrosine catabolism with the formation of final toxic metabolites that have a direct damaging effect on the liver and kidneys with the development of a characteristic clinical picture, represented mainly by functional and morphological disorders on a part of the liver that forms a cirrhosis clinic with a high probability of the latter's degeneration into hepatocellular carcinoma. In the article below, we present a clinical case of the first described late onset of a chronic variant of tyrosinemia type 1 with leading manifestations by type of renal dysfunction with the development of de Toni–Debre–Fanconi syndrome, followed by the formation of phosphopenic osteomalacia and the late appearance of diagnostic criteria corresponding to the initial stage of cirrhosis of the liver.
2025-07-24 | In vivo precision base editing to rescue mouse models of disease.
CRISPR base editing enables precise, irreversible base conversions without inducing double-stranded breaks (DSBs) and has gained significant attention in recent years. By converting cytosine to thymine (C→T) or adenine to guanine (A→G), base editors (BEs) efficiently correct pathogenic single-nucleotide variants (SNVs). This review examines in vivo mouse disease models-assessing editing efficiency, phenotypic rescue, and therapeutic potential across 66 studies. A key challenge in base editing is optimizing delivery. Most studies rely on split-intein dual adeno-associated virus (AAV) vectors due to BEs exceeding AAV packaging limits, though lipid nanoparticle (LNP) delivery is emerging. Editing efficiencies vary widely, influenced by enzyme design, delivery method, and sequence context. Many studies show significant functional gains, including extended survival in severe models such as FAH-deficient tyrosinemia type I and Hutchinson-Gilford progeria, restored dystrophin in Duchenne muscular dystrophy, and cognitive improvement in neurodegenerative models. Despite advantages such as reduced indels and increased precision, base editing is restricted to SNV correction and targets only a limited editing window relative to a protospacer adjacent motif (PAM) site. Advances in enzyme engineering, delivery strategies, and hybrid approaches incorporating prime editing could broaden its applications. As base editing evolves, its success in preclinical models positions it as a key player in next-generation gene therapies.
2025-05-27 | Validation of Clinical-Grade Electroporation Systems for CRISPR-Cas9-Mediated Gene Therapy in Primary Hepatocytes for the Correction of Inherited Metabolic Liver Disease.
Hepatocyte transplantation (HTx) combined with ex vivo gene therapy has garnered significant interest due to its potential for treating many inherited metabolic liver diseases. The biggest obstacle for HTx is achieving sufficient engraftment levels to rescue diseased phenotypes, which becomes more challenging when combined with ex vivo gene editing techniques. However, recent technological advancements have improved electroporation delivery efficiency, cell viability, and scalability for cell therapy. We recently demonstrated the impacts of electroporation for cell-based gene therapy in a mouse model of hereditary tyrosinemia type 1 (HT1). Here, we explore the use of the clinical-grade electroporator, the MaxCyte ExPERT GTx, utilized in the first FDA-approved CRISPR therapy, Casgevy, and evaluate its potential in primary hepatocytes in terms of delivery efficiency and cell viability. We assessed the gene editing efficiency and post-transplantation engraftment of hepatocytes from mTmG mice electroporated with CRISPR-Cas9-ribonucleoproteins (RNPs) targeting 4-hydroxyphenylpyruvate dioxygenase (Hpd) in a fumarylacetoacetate hydrolase (Fah)-deficient mouse model of HT1. After surgery, Fah-/- graft recipients were cycled off and on nitisinone to achieve independence from drug-induced Hpd inhibition, an indicator of HT1 disease correction. Transplanted hepatocytes subjected to electroporation using the GTx system had a cell viability of 89.9% and 100% on-target gene editing efficiency. Recipients transplanted with GTx-electroporated cells showed a smaller weight reduction than controls transplanted with untransfected cells (7.9% and 13.8%, respectively). Further, there were no mortalities in the GTx-recipient mice, whereas there was 25% mortality in the control recipients. Mean donor cell engraftment was significantly higher in GTx-recipient mice compared to untransfected control recipients (97.9% and 81.6%, respectively). Our results indicate that the GTx system does not negatively impact hepatocyte functionality and engraftment potential, thereby demonstrating the promise of GTx electroporation in hepatocytes as a viable cell therapy for treating genetic diseases that affect the liver.
2025-04-11 | CRISPR/Cas9 gene therapy increases the risk of tumorigenesis in the mouse model of hereditary tyrosinemia type I.
The therapeutic potential of CRISPR gene editing has been demonstrated in various animal models; however, little is known about its long-term consequences. This study seeks to bridge this gap by investigating the lasting consequences of CRISPR gene therapy in an animal model of hereditary tyrosinemia type I (HT-I). We compared the standard of care-nitisinone, a small molecule inhibitor of hydroxyphenylpyruvate dioxygenase (HPD)-with the deletion of the Hpd gene by CRISPR gene therapy. Both treatments block flux through tyrosine catabolism and thereby prevent the accumulation of toxic catabolites in HT-I. We assessed the efficacy and safety of CRISPR gene editing in fumarylacetoacetate hydrolase-deficient (Fah-/-) mice, the mouse model of HT-I, 12 months post treatment with either nitisinone or CRISPR deletion of Hpd. We deleted the Hpd gene using an adenovirus containing Cas9 and an adeno-associated virus containing two sgRNA against the Hpd gene. Primary endpoints were survival, urine biochemistry, liver (immuno)histochemistry, and genetic analyses. CRISPR deletion and pharmacological inhibition of HPD both demonstrate efficient metabolic correction and rescue of lethality. Surprisingly, we detected a markedly increased incidence of hepatocellular cancer in the CRISPR gene therapy group (71%, 12/17 mice) compared with four control groups (nitisinone [19%, four of 21 mice], sgRNA only [6%, one of 16 mice], Cas9 only [11%, two of 19 mice], and hydrodynamic tail vein injection of both CRISPR constructs [24%, four of 17 mice]). All analyzed tumors in the CRISPR gene therapy group were deleted for Hpd but showed on-and-off target vector integrations. CRISPR gene therapy increases the risk of hepatocellular cancer in the mouse model of HT-I. Because HT-I is characterized by inherent cancer susceptibility, this severe adverse event exposes the potential limitations of CRISPR gene therapy in cancer-prone disorders. Not much is known about the long-term consequences of somatic gene editing. Our study investigates CRISPR gene therapy in tyrosinemia type I using viral vectors. Although the CRISPR-based therapy effectively treated the metabolic condition, it was associated with a higher incidence of liver cancer than the current standard of care. These findings highlight the potential risks of using CRISPR gene therapy in conditions predisposed to cancer development.
small molecules
2026-05-12 | Rational Design of Small-Molecule Stabilizers of Human Fumarylacetoacetate Hydrolase for the Treatment of Tyrosinemia Type I.
Hereditary tyrosinemia type 1 (HT1) stems from the loss of fumarylacetoacetate hydrolase (FAH) activity, causing severe liver-kidney disease. Nitisinone does not restore FAH function and carries metabolic and dietary burdens. Here, we used an integrated workflow guided by X-ray structures of human FAH to obtain small-molecule pharmacological chaperones that bind with low-μM affinity and stabilize FAH. Hits were validated by NMR and isothermal titration calorimetry. Protein stabilization was assessed by DOSY-NMR and circular dichroism; functional effects were tested in FAH activity assays, a CRISPR-engineered cellular model, and testing in an animal model of HT1. Compounds shifted the G337S pathological variant toward the active dimer and slowed unfolding/aggregation, resulting in dose-dependent enhancement of FAH activity and partial rescue of FAH homeostasis in cells and the liver tissue of a mouse model of HT1. These molecules support a therapeutic approach that could complement nitisinone in HT1.
2025-10-12 | Management of porphyria-like syndrome in tyrosinemia type 1
Abstract Objectives Hereditary tyrosinemia type 1 (HT1) is a rare metabolic disorder that may present with severe hepatic and neurological complications. Acute porphyria-like crises in HT1 are extremely uncommon and may be associated with severe electrolyte disturbances such as hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Case presentation We describe a 9-year-old girl with genetically confirmed HT1 who developed an acute porphyria-like crisis accompanied by severe symptomatic hyponatremia secondary to SIADH. The patient presented with abdominal pain, vomiting, and progressive neurological deterioration culminating in generalized tonic–clonic seizures. Laboratory evaluation revealed profound hyponatremia, elevated urinary succinylacetone, and increased porphyrin precursors. Management included intravenous hemin therapy, fluid restriction, and intensive care support, leading to full neurological recovery without sequelae. Conclusions To our knowledge, this is the first reported case in Türkiye successfully managed with hemin during an acute porphyria-like episode in HT1 and only the second documented case of SIADH in this context. This case underscores the importance of recognizing SIADH and optimizing fluid management in patients with HT1 presenting with acute neurological crises.
2025-10-07 | NTBC dosing and outcomes in hereditary tyrosinemia type 1: insights from a representative human model and 99 patients
Abstract Hereditary tyrosinemia type 1 (HT1) is a rare and severe metabolic liver disorder caused by fumarylacetoacetate hydrolase (FAH) deficiency. The optimal dose and long-term effects of the only available treatment, nitisinone (NTBC), remain unclear due to the absence of clinical trial data. Here, we generated a representative human in vitro model of HT1 using iPSC-derived hepatocytes, which faithfully recapitulated key disease features. We investigated the mechanisms of FAH deficiency-induced hepatocellular injury and evaluated the effects of NTBC treatment. We confirmed treatment efficacy and identified 50 µmol/L as the minimal effective NTBC concentration to prevent cellular damage. This protective dose was subsequently validated in a large cohort of 99 HT1 patients, providing compelling evidence for establishing minimal therapeutic NTBC levels. Notably, approximately 10% of disease-associated genes, many implicated in hepatocellular carcinoma, remained dysregulated despite treatment, raising concerns that NTBC may not fully eliminate long-term oncogenic risk.
2025-08-22 | Unveiling the Unexpected: Refractory Rickets as an Uncommon presentation of Tyrosinemia Type I
Background Tyrosinemia type I is a rare autosomal recessive genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed for the final break down of the amino acid tyrosine, resulting in accumulation of certain metabolic intermediates in tyrosine catabolic pathway primarily causing liver disease, but also affecting kidneys and brain. Tyrosinemia Type I diagnosis is usually made in infancy with acute or chronic liver failure. Refractory Rickets is rarely described as the presenting feature in the literature. Here, we report a case of Tyrosinemia Type I presenting with refractory rickets and hepatosplenomegaly but without liver-dysfunction. Case Presentation A three year old child presented with bilateral limb deformities, for which child had received multiple therapeutic doses of Vitamin D and calcium, but with no response. On detailed history taking child also had floppiness, polyuria and polydipsia. On focused clinical examination child was noted to have hepatomegaly, and hence was evaluated and diagnosed to have hypophosphatemic rickets with Tyrosinemia type I. Child was started on phosphate supplement, specific diet and Nitisinone, and is doing well on follow up. Conclusion We are reporting the case to emphasize the importance of early recognition of hypophosphatemic rickets and to suspect tyrosinemia in children presenting with hypophophatemic rickets with liver involvement as Tyrosinemia Type I is associated with high morbidity and mortality, and early initiation of treatment is imperative to prevent mortality.
2025-07-01 | Tyrosinemia Type 1: A Case Prior to Newborn Screening and the Importance of Early Treatment
Abstract Introduction: Tyrosinemia type 1 (TYR1) is a severe hereditary metabolic disorder caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH), leading to the accumulation of toxic metabolites and hepatorenal damage. Without treatment, it may progress to liver failure or hepatocellular carcinoma. Nitisinone is the treatment of choice, as it blocks the formation of toxic compounds. Early diagnosis is critical, particularly in contexts where newborn screening is not yet implemented. Case report: We present the case of a 2-month-old infant, born to consanguineous parents, who presented with abdominal distension, vomiting, and diarrhea. The patient exhibited severe coagulopathy, metabolic acidosis, and ultrasound findings suggestive of acute abdomen. After transfer to a tertiary care center and completion of metabolic studies, a diagnosis of TYR1 was confirmed. Nitisinone therapy was initiated, with a favorable outcome following a complex stay in the intensive care unit. Discussion: Although the use of nitisinone has significantly reduced the need for liver transplantation, further studies are needed to better understand its potential long-term neurocognitive effects. Continuous clinical and neuropsychological monitoring is recommended for affected individuals. Conclusions: Early diagnosis of TYR1 through newborn screening enables prompt initiation of treatment with nitisinone and dietary management, significantly improving survival and reducing the risk of hepatocellular carcinoma. While treatment has dramatically changed the prognosis, uncertainties remain regarding long-term effects, particularly at the neurocognitive level. Comprehensive follow-up, including clinical, metabolic, and neuropsychological assessments, is essential.
proteins
2024-03-01 | Abstract 1891 Exploring Tyrosine Metabolism: Examining the implications of competition within a microbial community and the health consequences arising from the rivalry between a gut microbial pathway and the human pathway
Tyrosine, a versatile amino acid crucial for protein synthesis, undergoes diverse conversions leading to both beneficial and detrimental metabolites. The modulation of these metabolite levels results from direct competition among different metabolic pathways responsible for tyrosine breakdown, whether it be the competition between distinct microbes or the rivalry between a microbe and its host. This study aims to understand the breakdown of tyrosine through two distinct scenarios: 1) within a microbial community, and 2) during a competition between a microbe and a host. Our objectives include understanding the mechanisms of these competitions, discerning the metabolic outcomes, and identifying the efficiency of different pathways. To achieve this, we constructed a synthetic microbial community comprising various E. coli strains, each differing solely by the presence of a specific enzyme from a distinct tyrosine metabolic pathway. To assess metabolic outcomes in these communities, we developed a tool employing a phenotypic assay. Our findings reveal that breakdown product levels vary based on the type and combination of metabolic pathways within the community, with the metabolic outcome directly proportional to strain ratios. The methodologies employed in this study include SDS-PAGE analysis, genetic manipulation, colorimetric assays, phenotypic assays, and HPLC. Moreover, the inability to metabolize tyrosine resulting from a flawed tyrosine breakdown pathway in humans contributed to diverse metabolic disorders such as tyrosinemias (I, II, III), hawkinsinuria, and alkaptonuria. Utilizing the tool derived from our experiments on tyrosine breakdown within a microbial community, we illustrate a potential metabolic diversion of the human tyrosine breakdown pathway facilitated by a gut microbial enzyme. This approach holds promise as a novel therapeutic intervention for addressing metabolic disorders associated with the human tyrosine breakdown pathway. We thank the New College of Interdisciplinary Arts and Sciences (NCIAS) at Arizona State University for the funding support.
2021-10-28 | Hereditary tyrosinemia type Ⅰ: newborn screening, diagnosis and treatment.
Hereditary tyrosinemia type Ⅰ (HT-1) is a severe autosomal recessive inherited metabolic disease. Due to the deficiency of fumarylacetoacetase hydrolase (FAH), the toxic metabolites are accumulated in the body, resulting in severe liver dysfunction, renal tubular dysfunctions, neurological crises, and the increased risk of hepatocellular carcinoma. Clinical symptoms typically begin at after the birth; the prognosis of patients is poor if they are not treated timely. Succinylacetone is a specific and sensitive marker for HT-1, and the screening in newborns can make early diagnosis of HT-1 at the asymptomatic stage. The diagnosis of HT-1 can be confirmed based on the characteristic biochemical findings and molecular testing of mutations in both alleles of gene. Combined treatment with nitisinone and a low tyrosine diet may significantly improve outcomes for patients. Liver transplantation is an effective treatment in cases where nitisinone is not available. Some novel HT-1 treatments are in clinical trials, including enzyme replacement therapy, hepatocyte transplantation and gene-targeted therapy. Hereditary tyrosinemia type Ⅰ (HT-1) is a severe autosomal recessive inherited metabolic disease. Due to the deficiency of fumarylacetoacetase hydrolase (FAH), the toxic metabolites are accumulated in the body, resulting in severe liver dysfunction, renal tubular dysfunctions, neurological crises, and the increased risk of hepatocellular carcinoma. Clinical symptoms typically begin at 1 year after the birth; the prognosis of patients is poor if they are not treated timely. Succinylacetone is a specific and sensitive marker for HT-1, and the screening in newborns can make early diagnosis of HT-1 at the asymptomatic stage. The diagnosis of HT-1 can be confirmed based on the characteristic biochemical findings and molecular testing of mutations in both alleles of FAHgene. Combined treatment with nitisinone and a low tyrosine diet may significantly improve outcomes for patients. Liver transplantation is an effective treatment in cases where nitisinone is not available. Some novel HT-1 treatments are in clinical trials, including enzyme replacement therapy, hepatocyte transplantation and gene-targeted therapy.
2020-01-28 | Exploring the therapeutic potential of modern and ancestral phenylalanine/tyrosine ammonia-lyases as supplementary treatment of hereditary tyrosinemia
Phenylalanine/tyrosine ammonia-lyases (PAL/TALs) have been approved by the FDA for treatment of phenylketonuria and may harbour potential for complementary treatment of hereditary tyrosinemia Type I. Herein, we explore ancestral sequence reconstruction as an enzyme engineering tool to enhance the therapeutic potential of PAL/TALs. We reconstructed putative ancestors from fungi and compared their catalytic activity and stability to two modern fungal PAL/TALs. Surprisingly, most putative ancestors could be expressed as functional tetramers in Escherichia coli and thus retained their ability to oligomerize. All ancestral enzymes displayed increased thermostability compared to both modern enzymes, however, the increase in thermostability was accompanied by a loss in catalytic turnover. One reconstructed ancestral enzyme in particular could be interesting for further drug development, as its ratio of specific activities is more favourable towards tyrosine and it is more thermostable than both modern enzymes. Moreover, long-term stability assessment showed that this variant retained substantially more activity after prolonged incubation at 25 °C and 37 °C, as well as an increased resistance to incubation at 60 °C. Both of these factors are indicative of an extended shelf-life of biopharmaceuticals. We believe that ancestral sequence reconstruction has potential for enhancing the properties of enzyme therapeutics, especially with respect to stability. This work further illustrates that resurrection of putative ancestral oligomeric proteins is feasible and provides insight into the extent of conservation of a functional oligomerization surface area from ancestor to modern enzyme.
2018-11-01 | Inflammatory Cytokine TNFα Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture
In the healthy adult liver, most hepatocytes proliferate minimally. However, upon physical or chemical injury to the liver, hepatocytes proliferate extensively in vivo under the direction of multiple extracellular cues, including Wnt and pro-inflammatory signals. Currently, liver organoids can be generated readily in vitro from bile-duct epithelial cells, but not hepatocytes. Here, we show that TNFα, an injury-induced inflammatory cytokine, promotes the expansion of hepatocytes in 3D culture and enables serial passaging and long-term culture for more than 6 months. Single-cell RNA sequencing reveals broad expression of hepatocyte markers. Strikingly, in vitro-expanded hepatocytes engrafted, and significantly repopulated, the injured livers of Fah−/− mice. We anticipate that tissue repair signals can be harnessed to promote the expansion of otherwise hard-to-culture cell-types, with broad implications.
2018-01-18 | Insulin-like growth factor 2 is a key mitogen driving liver repopulation in mice
Abstract Hepatocyte transplantation holds great promise as an alternative to orthotopic organ transplantation in the treatment of liver diseases. However, obtaining clinically meaningful levels of liver repopulation has not been achieved because the mechanisms regulating hepatocyte proliferation in recipient livers have not yet been well characterized. In the mouse model of Hereditary Tyrosinemia Type I, the fumarylacetoacetate hydrolase-deficient ( Fah −/− ) mouse, we found gradually increasing expression level of insulin-like growth factor 2 (IGF2) in the hepatocytes of host livers. Similarly, high levels of IGF2 were found in the livers of patients with deficient FAH activity. Recombinant IGF2 directly promotes proliferation of primary hepatocytes in vitro. Inhibition on IGF2 expression through the interruption of PI3K/Akt and MAPK pathways significantly reduced the level of liver repopulation in Fah −/− mice. Interestingly, treatment with IGF2 before hepatocyte transplantation generally improved the amount of liver repopulation seen in various mice models of liver injury. Altogether, these findings underscore the underlying mechanisms of therapeutic liver repopulation in Fah −/− mice, and indicate that IGF2 is a potential hepatocyte mitogen for liver cell transplantation therapies.
other
2026-06-10 | De novo Crohn's Disease Treated with Ustekinumab in a Pediatric Liver Transplant Recipient with Tyrosinemia: A Case Report.
De novo inflammatory bowel disease (IBD) is more frequent in transplant recipients than in the general population and should be considered in the differential diagnosis of chronic diarrhea. In pediatric liver transplant recipients, an incidence of 206 vs. 20 cases per 100,000 patient-years has been reported, suggesting an underrecognized complication of immunosuppression. We report an 11-year-old girl with tyrosinemia type 1 who underwent liver transplantation and later developed de novo Crohn's disease. Despite maintenance therapy with tacrolimus, methylprednisolone, and everolimus, she presented with chronic diarrhea, weight loss, and elevated inflammatory markers after several episodes of Clostridioides difficile infection treated with oral vancomycin and only transient improvement. Initial inflammatory markers were only mildly elevated but showed a progressive rise over 18 months despite antibiotic therapy, alongside positive ASCA IgG and ASCA IgA with negative pANCA at the time of formal evaluation. Colonoscopy showed patchy aphthous and serpiginous ulcers with a cobblestone appearance, and histology revealed cryptitis and a mixed lymphoplasmacytic infiltrate without granulomas. Magnetic resonance enterography demonstrated ileocolic inflammation with wall thickening and mesenteric vessel engorgement. Infectious and drug-induced colitis and Epstein-Barr virus-related disease were excluded, and de novo ileocolic Crohn's disease (Paris A1b L3 B1 G1) was diagnosed. Ustekinumab (260 mg intravenously, then 90 mg subcutaneously every 4 weeks) was added to baseline immunosuppression, inducing clinical remission with normalization of C-reactive protein and a decrease in fecal calprotectin to 10 µg/g by week 20, sustained at 18 months with preserved graft function. This case illustrates the diagnostic challenges of de novo Crohn's disease in pediatric liver transplant recipients with metabolic liver disease and supports ustekinumab as a safe and effective option when other biologics are limited by prior infectious or lymphoproliferative.
2026-02-09 | Optimizing Peptide Ionizable Lipids Enables Efficient and Low-Toxicity mRNA Delivery for In Vivo Prime Editing and Protein Replacement Therapy.
Highly efficient mRNA lipid nanoparticle (LNP) often presents potential safety risks. Here, we establish a structure-activity relationship framework for peptide ionizable lipids (PILs) to facilitate the rational design of safe and effective mRNA-LNPs. The PIL structure comprises three modular components: building block, side-chain length, and hydrophobic tail. Through systematic optimization, a lead compound (Dab4) with four building blocks and a moderate side chain length was identified, demonstrating minimized hepatotoxicity while maintaining superior delivery performance. Leveraging this framework, a series of Dab4-derived PILs with three tail types, including alkyl (a-tail), ester (aat-tail), and hydroxyl (e-tail), were synthesized. This tail chemistry determined organ tropism, with B12-a13Dab4 (a-tail) showing optimal performance in the liver. The B12-a13Dab4 LNP exhibited significantly higher hepatic delivery efficiency and markedly improved biosafety compared with the FDA-approved SM-102 formulation. Moreover, B12-a13Dab4 LNP efficiently triggers in vivo prime editing by co-delivering PE7 mRNA and epegRNA, and achieves significant therapeutic effects in a Hereditary Tyrosinemia Type 1 (HT-1) model through repeated delivery fumarylacetoacetate hydrolase (FAH) mRNA. This study establishes rational design principles for PILs that strike a balance between efficacy and safety, offering a versatile mRNA-LNP platform for the advancement of gene editing and protein replacement therapies.
2025-09-08 | Nebulized LipidNanoparticles Deliver mRNA to theLiver for Treatment of Metabolic Diseases
An optimal administration approach is critical for effective mRNA delivery and treatment. Nebulizer inhalation offers a mild, convenient, and noninvasive strategy with high translational potential but primarily focused on lung delivery. In this study, we found that surface charges influence tissue targeting of mRNA lipid nanoparticle (mRNA-LNP) postnebulization. Charged mRNA-LNPs showed lung tropism, while neutral ones targeted the liver when administered via a microsprayer aerosolizer. Using nebulized liver-targeted LNPs (NebuLi LNPs), we successfully delivered therapeutic mRNAs for the treatment of metabolic diseases. In a Hereditary Tyrosinemia Type 1 model, fumarylacetoacetate hydrolase mRNA was effectively delivered to the liver, which helped to maintain mouse body weight, preserve liver function, and delay liver fibrosis. In a Type 2 diabetes model, dulaglutide mRNA was effectively expressed in the liver and exhibited good hypoglycemic effects. Overall, the NebuLi LNPs delivery platform offers a promising noninvasive strategy for metabolic disease treatment.
2021-01-27 | Murine liver repair via transient activation of regenerative pathways in hepatocytes using lipid nanoparticle-complexed nucleoside-modified mRNA
Induction of intrinsic liver regeneration is an unmet need that can be achieved by temporally activating key hepatocyte regenerative pathways. Here, we establish an efficient, safe, non-integrative method to transiently express hepatocyte-growth-factor (HGF) and epidermal-growth-factor (EGF) in hepatocytes via nucleoside-modified, lipid-nanoparticle-encapsulated mRNA (mRNA-LNP) delivery in mice. We confirm specific hepatotropism of mRNA-LNP via intravenous injection of firefly luciferase encoding mRNA-LNP, with protein expression lasting about 3 days. In the liver, virtually all hepatocytes are transfected along with a subpopulation of endothelial and Kupffer cells. In homeostasis, HGF mRNA-LNP efficiently induce hepatocyte proliferation. In a chronic liver injury mouse model recapitulating non-alcoholic fatty liver disease, injections of both HGF and EGF mRNA-LNP sharply reverse steatosis and accelerate restoration of liver function. Likewise, HGF and EGF mRNA-LNP accelerate liver regeneration after acetaminophen-induced acute liver injury with rapid return to baseline ALT levels. This study introduces mRNA-LNP as a potentially translatable safe therapeutic intervention to harness liver regeneration via controlled expression of endogenous mitogens in vivo.
2019-04-18 | Agonist c-Met Monoclonal Antibody Augments the Proliferation of hiPSC-derived Hepatocyte-Like Cells and Improves Cell Transplantation Therapy for Liver Failure in Mice
Rationale: Hepatocyte-like cells (HLCs) derived from human induced pluripotent stem cells (hiPSCs) have been developed to address the shortage of primary human hepatocytes (PHHs) for therapeutic applications.However, the in vivo repopulation capacity of HLCs remains limited.This study investigated the roles of agonist antibody activating the c-Met receptor in promoting the in vivo proliferation and repopulation of engrafted PHHs and/or HLCs in mice with liver injuries due to different causes.Methods: An agonist c-Met receptor antibody (5D5) was used to treat PHHs and hiPSC-HLCs in both cell culture and hepatocyte-engrafted immunodeficient mice mimicking various inherited and acquired liver diseases.The promoting roles and potential influence on the hepatic phenotype of the 5D5 regimen in cell transplantation-based therapeutic applications were systematically evaluated.Results: In hiPSC-HLC cell cultures, 5D5 treatment significantly stimulated c-Met receptor downstream signalling pathways and accelerated cell proliferation in dose-dependent and reversible manners.In contrast, only slight but nonsignificant promotion was observed in 5D5-treated PHHs.In vivo administration of 5D5 greatly promoted the expansion of implanted hiPSC-HLCs in fumarylacetoacetate hydrolase (Fah) deficient mice, resulting in significantly increased human albumin levels and high human liver chimerism (over 40%) in the transplanted mice at week 8 after transplantation.More importantly, transplantation of hiPSC-HLCs in combination with 5D5 significantly prolonged animal survival and ameliorated liver pathological changes in mice with acute and/or chronic liver injuries caused by Fas agonistic antibody treatment, carbon tetrachloride treatment and/or tyrosinemic stress.Conclusion: Our results demonstrated that the proliferation of hiPSC-HLCs can be enhanced by antibody-mediated modulation of c-Met signalling and facilitate hiPSC-HLC-based therapeutic applications for life-threatening liver diseases.
cell therapies
2026-06-02 | An optimized engineered bacterium for tyrosinemia type 1 therapy: A multi-species preclinical study.
Hereditary tyrosinemia type 1 (HT1) is a life-threatening metabolic disorder caused by the toxic accumulation of tyrosine and its metabolites. While treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) combined with a strict dietary regimen has improved outcomes, it imposes a significant lifelong burden and is associated with debilitating side effects and incomplete protection. Here, we developed an engineered probiotic with an optimized design, e-EcN-HT, and demonstrated its comprehensive efficacy and safety in HT1 across multiple animal models, including fumarylacetoacetate hydrolase (FAH)-/- mice, FAH-/- rabbits, and Bama minipigs. Our findings indicate that e-EcN-HT not only mitigates multifaceted acute manifestations of FAH-/- mice, including neonatal death and acute liver injury, but also improves chronic liver lesions when combined with NTBC. The therapeutic effect translated successfully to the FAH-/- rabbit model. Moreover, e-EcN-HT administration led to rapid metabolism of orally administered 13C-tyrosine, confirming robust and active tyrosine consumption in pigs. Comprehensive safety assessments across murine and porcine models showed that e-EcN-HT was well tolerated, with no significant adverse effects, systemic dissemination, or detrimental disruption to the resident gut microbiota. Collectively, our multi-species preclinical data underscore the potential of engineered bacteria as a viable therapeutic strategy for HT1 and possibly other metabolic disorders.
2026-03-07 | Pediatric liver transplantation for inherited metabolic disease-Current challenges.
Liver transplantation (LT) was first introduced in the early 1960s, with early paediatric experience marked by significant technical challenges and high risk. Advances in surgical techniques and immunosuppressive therapy in the late 1970s led to successful paediatric LT outcomes, while continued improvements throughout the 1980s and 1990s have enhanced survival and reduced complications. Current 10-year graft and patient survival rates for elective paediatric indications exceed 90%. Over the past two decades, LT has increasingly been used to treat inherited metabolic diseases (IMDs), which now account for 25-30% of paediatric LT. Initially recommended for tyrosinaemia type 1 in 1978 and later for urea cycle disorders such as ornithine transcarbamylase deficiency, LT can be curative when the metabolic defect is confined to the liver and partially corrective in conditions with extrahepatic involvement. As indications expand and earlier intervention is emphasized, this review examines the role of LT in IMDs, highlighting current concepts, challenges, and controversies.
2025-10-10 | The Evolving Trend of Liver Transplantation in Metabolic Diseases: From Origins to Current Perspectives.
Liver transplantation (LTx) has become, over the years, an increasingly used therapeutic option in patients with inherited metabolic diseases (IMD). Initially performed for Tyrosinemia Type I and ornithine transcarbamylase deficiency, it now accounts as the second indication for pediatric transplants worldwide. The use of LTx has been extended to systemic metabolic disorders, in which a genetically normal liver can correct the defect by providing an enzyme replacement therapy that improves metabolic control and disease burden, reducing the risk of metabolic crises and neurological damage, allowing for the withdrawal, in most diseases, of dietary restrictions and specific medications. The temporal changes, mainly reflecting improved LTx management through a multidisciplinary approach, have provided excellent outcomes and long-term patient survival, shifting the paradigm from a lifesaving procedure to a life-improving treatment. However, challenges still exist, particularly, in systemic IMD due to the persistence of the underlying defect in extra-hepatic tissues. Immunosuppression, especially in organic acidurias, may lead to new, drug-related, neurotoxic risks. The new indications for transplantation should target endpoints that are not exclusively clinical, addressing major attention to the improvement of health-related quality of life issues. Protocols for managing LTx in IMD need to be harmonized, and future joint multicenter actions will fill these gaps and provide a uniform vision of this evolving scenario.
2024-09-10 | Hormonally and chemically defined expansion conditions for organoids of biliary tree Stem Cells
Wholly defined ex vivo expansion conditions for biliary tree stem cell (BTSC) organoids were established, consisting of a defined proliferative medium (DPM) used in combination with soft hyaluronan hydrogels. The DPM consisted of commercially available Kubota's Medium (KM), to which a set of small molecules, particular paracrine signals, and heparan sulfate (HS) were added. The small molecules used were DNA methyltransferase inhibitor (RG108), TGF- β Type I receptor inhibitor (A83-01), adenylate cyclase activator (Forskolin), and L-type Ca2+ channel agonist (Bay K8644). A key paracrine signal proved to be R-spondin 1 (RSPO1), a secreted protein that activates Wnts. Soluble hyaluronans, 0.05 % sodium hyaluronate, were used with DPM to expand monolayer cultures. Expansion of organoids was achieved by using DPM in combination with embedding organoids in Matrigel that was replaced with a defined thiol-hyaluronan triggered with PEGDA to form a hydrogel with a rheology [G*] of less than 100 Pa. The combination is called the BTSC-Expansion-Glycogel-System (BEX-gel system) for expanding BTSCs as a monolayer or as organoids. The BTSC organoids were expanded more than 3000-fold ex vivo in the BEX-gel system within 70 days while maintaining phenotypic traits indicative of stem/progenitors. Stem-cell-patch grafting of expanded BTSC organoids was performed on the livers of Fah-/- mice with tyrosinemia and resulted in the rescue of the mice and restoration of their normal liver functions. The BEX-gel system for BTSC organoid expansion provides a strategy to generate sufficient numbers of organoids for the therapeutic treatments of liver diseases.
2024-06-07 | Revitalizing liver function in mice with liver failure through transplantation of 3D-bioprinted liver with expanded primary hepatocytes.
The utilization of three-dimensional (3D) bioprinting technology to create a transplantable bioartificial liver emerges as a promising remedy for the scarcity of liver donors. This study outlines our strategy for constructing a 3D-bioprinted liver, using in vitro-expanded primary hepatocytes recognized for their safety and enhanced functional robustness as hepatic cell sources for bioartificial liver construction. In addition, we have developed bioink biomaterials with mechanical and rheological properties, as well as printing capabilities, tailored for 3D bioprinting. Upon heterotopic transplantation into the mesentery of tyrosinemia or 90% hepatectomy mice, our 3D-bioprinted liver effectively restored lost liver functions, consequently extending the life span of mice afflicted with liver injuries. Notably, the inclusion of an artificial blood vessel in our 3D-bioprinted liver allowed for biomolecule exchange with host blood vessels, demonstrating, in principle, the rapid integration of the bioartificial liver into the host vascular system. This model underscores the therapeutic potential of transplantation for the treatment of liver failure diseases.
gene therapies
2026-04-03 | Toward Next-Gen Cell Therapy for Pediatric Patients: Neonatal Hepatocytes Tolerate Electroporation-Mediated Gene Editing and Engraft in the Liver.
Hepatocyte transplantation (HTx) offers a safer, less invasive alternative to orthotopic liver transplantation for inherited metabolic liver diseases, especially in high-risk pediatric patients. Combining HTx with ex vivo gene editing is a promising autologous therapeutic strategy using the patient's cells. We investigated the feasibility of this approach by applying CRISPR-Cas9 gene knock-out to neonatal mouse hepatocytes and comparing their engraftment potential with that of mature adult cells in the Fah-/- mouse model of hereditary tyrosinemia type I (HT1). Electroporation-mediated gene editing did not significantly impair the ability of neonatal hepatocytes to engraft in vivo. Quantitative histological analysis revealed comparable liver repopulation levels between recipients of gene-edited neonatal cells and adult cells after hepatoxicity-mediated selection, providing a benchmark for electroporation-mediated gene editing in neonatal hepatocytes, and supporting the development of genetically corrected neonatal hepatocyte products as a crucial long-term or bridge-to-transplant therapeutic strategy for pediatric liver disease.
2025-07-25 | A clinical case of late diagnosis of a chronic type I tyrosinemia
Tyrosinemia type 1 is a genetic disease mainly of the first months and years of life caused by a violation of normal tyrosine catabolism with the formation of final toxic metabolites that have a direct damaging effect on the liver and kidneys with the development of a characteristic clinical picture, represented mainly by functional and morphological disorders on a part of the liver that forms a cirrhosis clinic with a high probability of the latter's degeneration into hepatocellular carcinoma. In the article below, we present a clinical case of the first described late onset of a chronic variant of tyrosinemia type 1 with leading manifestations by type of renal dysfunction with the development of de Toni–Debre–Fanconi syndrome, followed by the formation of phosphopenic osteomalacia and the late appearance of diagnostic criteria corresponding to the initial stage of cirrhosis of the liver.
2025-07-24 | In vivo precision base editing to rescue mouse models of disease.
CRISPR base editing enables precise, irreversible base conversions without inducing double-stranded breaks (DSBs) and has gained significant attention in recent years. By converting cytosine to thymine (C→T) or adenine to guanine (A→G), base editors (BEs) efficiently correct pathogenic single-nucleotide variants (SNVs). This review examines in vivo mouse disease models-assessing editing efficiency, phenotypic rescue, and therapeutic potential across 66 studies. A key challenge in base editing is optimizing delivery. Most studies rely on split-intein dual adeno-associated virus (AAV) vectors due to BEs exceeding AAV packaging limits, though lipid nanoparticle (LNP) delivery is emerging. Editing efficiencies vary widely, influenced by enzyme design, delivery method, and sequence context. Many studies show significant functional gains, including extended survival in severe models such as FAH-deficient tyrosinemia type I and Hutchinson-Gilford progeria, restored dystrophin in Duchenne muscular dystrophy, and cognitive improvement in neurodegenerative models. Despite advantages such as reduced indels and increased precision, base editing is restricted to SNV correction and targets only a limited editing window relative to a protospacer adjacent motif (PAM) site. Advances in enzyme engineering, delivery strategies, and hybrid approaches incorporating prime editing could broaden its applications. As base editing evolves, its success in preclinical models positions it as a key player in next-generation gene therapies.
2025-05-27 | Validation of Clinical-Grade Electroporation Systems for CRISPR-Cas9-Mediated Gene Therapy in Primary Hepatocytes for the Correction of Inherited Metabolic Liver Disease.
Hepatocyte transplantation (HTx) combined with ex vivo gene therapy has garnered significant interest due to its potential for treating many inherited metabolic liver diseases. The biggest obstacle for HTx is achieving sufficient engraftment levels to rescue diseased phenotypes, which becomes more challenging when combined with ex vivo gene editing techniques. However, recent technological advancements have improved electroporation delivery efficiency, cell viability, and scalability for cell therapy. We recently demonstrated the impacts of electroporation for cell-based gene therapy in a mouse model of hereditary tyrosinemia type 1 (HT1). Here, we explore the use of the clinical-grade electroporator, the MaxCyte ExPERT GTx, utilized in the first FDA-approved CRISPR therapy, Casgevy, and evaluate its potential in primary hepatocytes in terms of delivery efficiency and cell viability. We assessed the gene editing efficiency and post-transplantation engraftment of hepatocytes from mTmG mice electroporated with CRISPR-Cas9-ribonucleoproteins (RNPs) targeting 4-hydroxyphenylpyruvate dioxygenase (Hpd) in a fumarylacetoacetate hydrolase (Fah)-deficient mouse model of HT1. After surgery, Fah-/- graft recipients were cycled off and on nitisinone to achieve independence from drug-induced Hpd inhibition, an indicator of HT1 disease correction. Transplanted hepatocytes subjected to electroporation using the GTx system had a cell viability of 89.9% and 100% on-target gene editing efficiency. Recipients transplanted with GTx-electroporated cells showed a smaller weight reduction than controls transplanted with untransfected cells (7.9% and 13.8%, respectively). Further, there were no mortalities in the GTx-recipient mice, whereas there was 25% mortality in the control recipients. Mean donor cell engraftment was significantly higher in GTx-recipient mice compared to untransfected control recipients (97.9% and 81.6%, respectively). Our results indicate that the GTx system does not negatively impact hepatocyte functionality and engraftment potential, thereby demonstrating the promise of GTx electroporation in hepatocytes as a viable cell therapy for treating genetic diseases that affect the liver.
2025-04-11 | CRISPR/Cas9 gene therapy increases the risk of tumorigenesis in the mouse model of hereditary tyrosinemia type I.
The therapeutic potential of CRISPR gene editing has been demonstrated in various animal models; however, little is known about its long-term consequences. This study seeks to bridge this gap by investigating the lasting consequences of CRISPR gene therapy in an animal model of hereditary tyrosinemia type I (HT-I). We compared the standard of care-nitisinone, a small molecule inhibitor of hydroxyphenylpyruvate dioxygenase (HPD)-with the deletion of the Hpd gene by CRISPR gene therapy. Both treatments block flux through tyrosine catabolism and thereby prevent the accumulation of toxic catabolites in HT-I. We assessed the efficacy and safety of CRISPR gene editing in fumarylacetoacetate hydrolase-deficient (Fah-/-) mice, the mouse model of HT-I, 12 months post treatment with either nitisinone or CRISPR deletion of Hpd. We deleted the Hpd gene using an adenovirus containing Cas9 and an adeno-associated virus containing two sgRNA against the Hpd gene. Primary endpoints were survival, urine biochemistry, liver (immuno)histochemistry, and genetic analyses. CRISPR deletion and pharmacological inhibition of HPD both demonstrate efficient metabolic correction and rescue of lethality. Surprisingly, we detected a markedly increased incidence of hepatocellular cancer in the CRISPR gene therapy group (71%, 12/17 mice) compared with four control groups (nitisinone [19%, four of 21 mice], sgRNA only [6%, one of 16 mice], Cas9 only [11%, two of 19 mice], and hydrodynamic tail vein injection of both CRISPR constructs [24%, four of 17 mice]). All analyzed tumors in the CRISPR gene therapy group were deleted for Hpd but showed on-and-off target vector integrations. CRISPR gene therapy increases the risk of hepatocellular cancer in the mouse model of HT-I. Because HT-I is characterized by inherent cancer susceptibility, this severe adverse event exposes the potential limitations of CRISPR gene therapy in cancer-prone disorders. Not much is known about the long-term consequences of somatic gene editing. Our study investigates CRISPR gene therapy in tyrosinemia type I using viral vectors. Although the CRISPR-based therapy effectively treated the metabolic condition, it was associated with a higher incidence of liver cancer than the current standard of care. These findings highlight the potential risks of using CRISPR gene therapy in conditions predisposed to cancer development.
small molecules
2026-05-12 | Rational Design of Small-Molecule Stabilizers of Human Fumarylacetoacetate Hydrolase for the Treatment of Tyrosinemia Type I.
Hereditary tyrosinemia type 1 (HT1) stems from the loss of fumarylacetoacetate hydrolase (FAH) activity, causing severe liver-kidney disease. Nitisinone does not restore FAH function and carries metabolic and dietary burdens. Here, we used an integrated workflow guided by X-ray structures of human FAH to obtain small-molecule pharmacological chaperones that bind with low-μM affinity and stabilize FAH. Hits were validated by NMR and isothermal titration calorimetry. Protein stabilization was assessed by DOSY-NMR and circular dichroism; functional effects were tested in FAH activity assays, a CRISPR-engineered cellular model, and testing in an animal model of HT1. Compounds shifted the G337S pathological variant toward the active dimer and slowed unfolding/aggregation, resulting in dose-dependent enhancement of FAH activity and partial rescue of FAH homeostasis in cells and the liver tissue of a mouse model of HT1. These molecules support a therapeutic approach that could complement nitisinone in HT1.
2025-10-12 | Management of porphyria-like syndrome in tyrosinemia type 1
Abstract Objectives Hereditary tyrosinemia type 1 (HT1) is a rare metabolic disorder that may present with severe hepatic and neurological complications. Acute porphyria-like crises in HT1 are extremely uncommon and may be associated with severe electrolyte disturbances such as hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Case presentation We describe a 9-year-old girl with genetically confirmed HT1 who developed an acute porphyria-like crisis accompanied by severe symptomatic hyponatremia secondary to SIADH. The patient presented with abdominal pain, vomiting, and progressive neurological deterioration culminating in generalized tonic–clonic seizures. Laboratory evaluation revealed profound hyponatremia, elevated urinary succinylacetone, and increased porphyrin precursors. Management included intravenous hemin therapy, fluid restriction, and intensive care support, leading to full neurological recovery without sequelae. Conclusions To our knowledge, this is the first reported case in Türkiye successfully managed with hemin during an acute porphyria-like episode in HT1 and only the second documented case of SIADH in this context. This case underscores the importance of recognizing SIADH and optimizing fluid management in patients with HT1 presenting with acute neurological crises.
2025-10-07 | NTBC dosing and outcomes in hereditary tyrosinemia type 1: insights from a representative human model and 99 patients
Abstract Hereditary tyrosinemia type 1 (HT1) is a rare and severe metabolic liver disorder caused by fumarylacetoacetate hydrolase (FAH) deficiency. The optimal dose and long-term effects of the only available treatment, nitisinone (NTBC), remain unclear due to the absence of clinical trial data. Here, we generated a representative human in vitro model of HT1 using iPSC-derived hepatocytes, which faithfully recapitulated key disease features. We investigated the mechanisms of FAH deficiency-induced hepatocellular injury and evaluated the effects of NTBC treatment. We confirmed treatment efficacy and identified 50 µmol/L as the minimal effective NTBC concentration to prevent cellular damage. This protective dose was subsequently validated in a large cohort of 99 HT1 patients, providing compelling evidence for establishing minimal therapeutic NTBC levels. Notably, approximately 10% of disease-associated genes, many implicated in hepatocellular carcinoma, remained dysregulated despite treatment, raising concerns that NTBC may not fully eliminate long-term oncogenic risk.
2025-08-22 | Unveiling the Unexpected: Refractory Rickets as an Uncommon presentation of Tyrosinemia Type I
Background Tyrosinemia type I is a rare autosomal recessive genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed for the final break down of the amino acid tyrosine, resulting in accumulation of certain metabolic intermediates in tyrosine catabolic pathway primarily causing liver disease, but also affecting kidneys and brain. Tyrosinemia Type I diagnosis is usually made in infancy with acute or chronic liver failure. Refractory Rickets is rarely described as the presenting feature in the literature. Here, we report a case of Tyrosinemia Type I presenting with refractory rickets and hepatosplenomegaly but without liver-dysfunction. Case Presentation A three year old child presented with bilateral limb deformities, for which child had received multiple therapeutic doses of Vitamin D and calcium, but with no response. On detailed history taking child also had floppiness, polyuria and polydipsia. On focused clinical examination child was noted to have hepatomegaly, and hence was evaluated and diagnosed to have hypophosphatemic rickets with Tyrosinemia type I. Child was started on phosphate supplement, specific diet and Nitisinone, and is doing well on follow up. Conclusion We are reporting the case to emphasize the importance of early recognition of hypophosphatemic rickets and to suspect tyrosinemia in children presenting with hypophophatemic rickets with liver involvement as Tyrosinemia Type I is associated with high morbidity and mortality, and early initiation of treatment is imperative to prevent mortality.
2025-07-01 | Tyrosinemia Type 1: A Case Prior to Newborn Screening and the Importance of Early Treatment
Abstract Introduction: Tyrosinemia type 1 (TYR1) is a severe hereditary metabolic disorder caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH), leading to the accumulation of toxic metabolites and hepatorenal damage. Without treatment, it may progress to liver failure or hepatocellular carcinoma. Nitisinone is the treatment of choice, as it blocks the formation of toxic compounds. Early diagnosis is critical, particularly in contexts where newborn screening is not yet implemented. Case report: We present the case of a 2-month-old infant, born to consanguineous parents, who presented with abdominal distension, vomiting, and diarrhea. The patient exhibited severe coagulopathy, metabolic acidosis, and ultrasound findings suggestive of acute abdomen. After transfer to a tertiary care center and completion of metabolic studies, a diagnosis of TYR1 was confirmed. Nitisinone therapy was initiated, with a favorable outcome following a complex stay in the intensive care unit. Discussion: Although the use of nitisinone has significantly reduced the need for liver transplantation, further studies are needed to better understand its potential long-term neurocognitive effects. Continuous clinical and neuropsychological monitoring is recommended for affected individuals. Conclusions: Early diagnosis of TYR1 through newborn screening enables prompt initiation of treatment with nitisinone and dietary management, significantly improving survival and reducing the risk of hepatocellular carcinoma. While treatment has dramatically changed the prognosis, uncertainties remain regarding long-term effects, particularly at the neurocognitive level. Comprehensive follow-up, including clinical, metabolic, and neuropsychological assessments, is essential.
proteins
2024-03-01 | Abstract 1891 Exploring Tyrosine Metabolism: Examining the implications of competition within a microbial community and the health consequences arising from the rivalry between a gut microbial pathway and the human pathway
Tyrosine, a versatile amino acid crucial for protein synthesis, undergoes diverse conversions leading to both beneficial and detrimental metabolites. The modulation of these metabolite levels results from direct competition among different metabolic pathways responsible for tyrosine breakdown, whether it be the competition between distinct microbes or the rivalry between a microbe and its host. This study aims to understand the breakdown of tyrosine through two distinct scenarios: 1) within a microbial community, and 2) during a competition between a microbe and a host. Our objectives include understanding the mechanisms of these competitions, discerning the metabolic outcomes, and identifying the efficiency of different pathways. To achieve this, we constructed a synthetic microbial community comprising various E. coli strains, each differing solely by the presence of a specific enzyme from a distinct tyrosine metabolic pathway. To assess metabolic outcomes in these communities, we developed a tool employing a phenotypic assay. Our findings reveal that breakdown product levels vary based on the type and combination of metabolic pathways within the community, with the metabolic outcome directly proportional to strain ratios. The methodologies employed in this study include SDS-PAGE analysis, genetic manipulation, colorimetric assays, phenotypic assays, and HPLC. Moreover, the inability to metabolize tyrosine resulting from a flawed tyrosine breakdown pathway in humans contributed to diverse metabolic disorders such as tyrosinemias (I, II, III), hawkinsinuria, and alkaptonuria. Utilizing the tool derived from our experiments on tyrosine breakdown within a microbial community, we illustrate a potential metabolic diversion of the human tyrosine breakdown pathway facilitated by a gut microbial enzyme. This approach holds promise as a novel therapeutic intervention for addressing metabolic disorders associated with the human tyrosine breakdown pathway. We thank the New College of Interdisciplinary Arts and Sciences (NCIAS) at Arizona State University for the funding support.
2021-10-28 | Hereditary tyrosinemia type Ⅰ: newborn screening, diagnosis and treatment.
Hereditary tyrosinemia type Ⅰ (HT-1) is a severe autosomal recessive inherited metabolic disease. Due to the deficiency of fumarylacetoacetase hydrolase (FAH), the toxic metabolites are accumulated in the body, resulting in severe liver dysfunction, renal tubular dysfunctions, neurological crises, and the increased risk of hepatocellular carcinoma. Clinical symptoms typically begin at after the birth; the prognosis of patients is poor if they are not treated timely. Succinylacetone is a specific and sensitive marker for HT-1, and the screening in newborns can make early diagnosis of HT-1 at the asymptomatic stage. The diagnosis of HT-1 can be confirmed based on the characteristic biochemical findings and molecular testing of mutations in both alleles of gene. Combined treatment with nitisinone and a low tyrosine diet may significantly improve outcomes for patients. Liver transplantation is an effective treatment in cases where nitisinone is not available. Some novel HT-1 treatments are in clinical trials, including enzyme replacement therapy, hepatocyte transplantation and gene-targeted therapy. Hereditary tyrosinemia type Ⅰ (HT-1) is a severe autosomal recessive inherited metabolic disease. Due to the deficiency of fumarylacetoacetase hydrolase (FAH), the toxic metabolites are accumulated in the body, resulting in severe liver dysfunction, renal tubular dysfunctions, neurological crises, and the increased risk of hepatocellular carcinoma. Clinical symptoms typically begin at 1 year after the birth; the prognosis of patients is poor if they are not treated timely. Succinylacetone is a specific and sensitive marker for HT-1, and the screening in newborns can make early diagnosis of HT-1 at the asymptomatic stage. The diagnosis of HT-1 can be confirmed based on the characteristic biochemical findings and molecular testing of mutations in both alleles of FAHgene. Combined treatment with nitisinone and a low tyrosine diet may significantly improve outcomes for patients. Liver transplantation is an effective treatment in cases where nitisinone is not available. Some novel HT-1 treatments are in clinical trials, including enzyme replacement therapy, hepatocyte transplantation and gene-targeted therapy.
2020-01-28 | Exploring the therapeutic potential of modern and ancestral phenylalanine/tyrosine ammonia-lyases as supplementary treatment of hereditary tyrosinemia
Phenylalanine/tyrosine ammonia-lyases (PAL/TALs) have been approved by the FDA for treatment of phenylketonuria and may harbour potential for complementary treatment of hereditary tyrosinemia Type I. Herein, we explore ancestral sequence reconstruction as an enzyme engineering tool to enhance the therapeutic potential of PAL/TALs. We reconstructed putative ancestors from fungi and compared their catalytic activity and stability to two modern fungal PAL/TALs. Surprisingly, most putative ancestors could be expressed as functional tetramers in Escherichia coli and thus retained their ability to oligomerize. All ancestral enzymes displayed increased thermostability compared to both modern enzymes, however, the increase in thermostability was accompanied by a loss in catalytic turnover. One reconstructed ancestral enzyme in particular could be interesting for further drug development, as its ratio of specific activities is more favourable towards tyrosine and it is more thermostable than both modern enzymes. Moreover, long-term stability assessment showed that this variant retained substantially more activity after prolonged incubation at 25 °C and 37 °C, as well as an increased resistance to incubation at 60 °C. Both of these factors are indicative of an extended shelf-life of biopharmaceuticals. We believe that ancestral sequence reconstruction has potential for enhancing the properties of enzyme therapeutics, especially with respect to stability. This work further illustrates that resurrection of putative ancestral oligomeric proteins is feasible and provides insight into the extent of conservation of a functional oligomerization surface area from ancestor to modern enzyme.
2018-11-01 | Inflammatory Cytokine TNFα Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture
In the healthy adult liver, most hepatocytes proliferate minimally. However, upon physical or chemical injury to the liver, hepatocytes proliferate extensively in vivo under the direction of multiple extracellular cues, including Wnt and pro-inflammatory signals. Currently, liver organoids can be generated readily in vitro from bile-duct epithelial cells, but not hepatocytes. Here, we show that TNFα, an injury-induced inflammatory cytokine, promotes the expansion of hepatocytes in 3D culture and enables serial passaging and long-term culture for more than 6 months. Single-cell RNA sequencing reveals broad expression of hepatocyte markers. Strikingly, in vitro-expanded hepatocytes engrafted, and significantly repopulated, the injured livers of Fah−/− mice. We anticipate that tissue repair signals can be harnessed to promote the expansion of otherwise hard-to-culture cell-types, with broad implications.
2018-01-18 | Insulin-like growth factor 2 is a key mitogen driving liver repopulation in mice
Abstract Hepatocyte transplantation holds great promise as an alternative to orthotopic organ transplantation in the treatment of liver diseases. However, obtaining clinically meaningful levels of liver repopulation has not been achieved because the mechanisms regulating hepatocyte proliferation in recipient livers have not yet been well characterized. In the mouse model of Hereditary Tyrosinemia Type I, the fumarylacetoacetate hydrolase-deficient ( Fah −/− ) mouse, we found gradually increasing expression level of insulin-like growth factor 2 (IGF2) in the hepatocytes of host livers. Similarly, high levels of IGF2 were found in the livers of patients with deficient FAH activity. Recombinant IGF2 directly promotes proliferation of primary hepatocytes in vitro. Inhibition on IGF2 expression through the interruption of PI3K/Akt and MAPK pathways significantly reduced the level of liver repopulation in Fah −/− mice. Interestingly, treatment with IGF2 before hepatocyte transplantation generally improved the amount of liver repopulation seen in various mice models of liver injury. Altogether, these findings underscore the underlying mechanisms of therapeutic liver repopulation in Fah −/− mice, and indicate that IGF2 is a potential hepatocyte mitogen for liver cell transplantation therapies.
other
2026-06-10 | De novo Crohn's Disease Treated with Ustekinumab in a Pediatric Liver Transplant Recipient with Tyrosinemia: A Case Report.
De novo inflammatory bowel disease (IBD) is more frequent in transplant recipients than in the general population and should be considered in the differential diagnosis of chronic diarrhea. In pediatric liver transplant recipients, an incidence of 206 vs. 20 cases per 100,000 patient-years has been reported, suggesting an underrecognized complication of immunosuppression. We report an 11-year-old girl with tyrosinemia type 1 who underwent liver transplantation and later developed de novo Crohn's disease. Despite maintenance therapy with tacrolimus, methylprednisolone, and everolimus, she presented with chronic diarrhea, weight loss, and elevated inflammatory markers after several episodes of Clostridioides difficile infection treated with oral vancomycin and only transient improvement. Initial inflammatory markers were only mildly elevated but showed a progressive rise over 18 months despite antibiotic therapy, alongside positive ASCA IgG and ASCA IgA with negative pANCA at the time of formal evaluation. Colonoscopy showed patchy aphthous and serpiginous ulcers with a cobblestone appearance, and histology revealed cryptitis and a mixed lymphoplasmacytic infiltrate without granulomas. Magnetic resonance enterography demonstrated ileocolic inflammation with wall thickening and mesenteric vessel engorgement. Infectious and drug-induced colitis and Epstein-Barr virus-related disease were excluded, and de novo ileocolic Crohn's disease (Paris A1b L3 B1 G1) was diagnosed. Ustekinumab (260 mg intravenously, then 90 mg subcutaneously every 4 weeks) was added to baseline immunosuppression, inducing clinical remission with normalization of C-reactive protein and a decrease in fecal calprotectin to 10 µg/g by week 20, sustained at 18 months with preserved graft function. This case illustrates the diagnostic challenges of de novo Crohn's disease in pediatric liver transplant recipients with metabolic liver disease and supports ustekinumab as a safe and effective option when other biologics are limited by prior infectious or lymphoproliferative.
2026-02-09 | Optimizing Peptide Ionizable Lipids Enables Efficient and Low-Toxicity mRNA Delivery for In Vivo Prime Editing and Protein Replacement Therapy.
Highly efficient mRNA lipid nanoparticle (LNP) often presents potential safety risks. Here, we establish a structure-activity relationship framework for peptide ionizable lipids (PILs) to facilitate the rational design of safe and effective mRNA-LNPs. The PIL structure comprises three modular components: building block, side-chain length, and hydrophobic tail. Through systematic optimization, a lead compound (Dab4) with four building blocks and a moderate side chain length was identified, demonstrating minimized hepatotoxicity while maintaining superior delivery performance. Leveraging this framework, a series of Dab4-derived PILs with three tail types, including alkyl (a-tail), ester (aat-tail), and hydroxyl (e-tail), were synthesized. This tail chemistry determined organ tropism, with B12-a13Dab4 (a-tail) showing optimal performance in the liver. The B12-a13Dab4 LNP exhibited significantly higher hepatic delivery efficiency and markedly improved biosafety compared with the FDA-approved SM-102 formulation. Moreover, B12-a13Dab4 LNP efficiently triggers in vivo prime editing by co-delivering PE7 mRNA and epegRNA, and achieves significant therapeutic effects in a Hereditary Tyrosinemia Type 1 (HT-1) model through repeated delivery fumarylacetoacetate hydrolase (FAH) mRNA. This study establishes rational design principles for PILs that strike a balance between efficacy and safety, offering a versatile mRNA-LNP platform for the advancement of gene editing and protein replacement therapies.
2025-09-08 | Nebulized LipidNanoparticles Deliver mRNA to theLiver for Treatment of Metabolic Diseases
An optimal administration approach is critical for effective mRNA delivery and treatment. Nebulizer inhalation offers a mild, convenient, and noninvasive strategy with high translational potential but primarily focused on lung delivery. In this study, we found that surface charges influence tissue targeting of mRNA lipid nanoparticle (mRNA-LNP) postnebulization. Charged mRNA-LNPs showed lung tropism, while neutral ones targeted the liver when administered via a microsprayer aerosolizer. Using nebulized liver-targeted LNPs (NebuLi LNPs), we successfully delivered therapeutic mRNAs for the treatment of metabolic diseases. In a Hereditary Tyrosinemia Type 1 model, fumarylacetoacetate hydrolase mRNA was effectively delivered to the liver, which helped to maintain mouse body weight, preserve liver function, and delay liver fibrosis. In a Type 2 diabetes model, dulaglutide mRNA was effectively expressed in the liver and exhibited good hypoglycemic effects. Overall, the NebuLi LNPs delivery platform offers a promising noninvasive strategy for metabolic disease treatment.
2021-01-27 | Murine liver repair via transient activation of regenerative pathways in hepatocytes using lipid nanoparticle-complexed nucleoside-modified mRNA
Induction of intrinsic liver regeneration is an unmet need that can be achieved by temporally activating key hepatocyte regenerative pathways. Here, we establish an efficient, safe, non-integrative method to transiently express hepatocyte-growth-factor (HGF) and epidermal-growth-factor (EGF) in hepatocytes via nucleoside-modified, lipid-nanoparticle-encapsulated mRNA (mRNA-LNP) delivery in mice. We confirm specific hepatotropism of mRNA-LNP via intravenous injection of firefly luciferase encoding mRNA-LNP, with protein expression lasting about 3 days. In the liver, virtually all hepatocytes are transfected along with a subpopulation of endothelial and Kupffer cells. In homeostasis, HGF mRNA-LNP efficiently induce hepatocyte proliferation. In a chronic liver injury mouse model recapitulating non-alcoholic fatty liver disease, injections of both HGF and EGF mRNA-LNP sharply reverse steatosis and accelerate restoration of liver function. Likewise, HGF and EGF mRNA-LNP accelerate liver regeneration after acetaminophen-induced acute liver injury with rapid return to baseline ALT levels. This study introduces mRNA-LNP as a potentially translatable safe therapeutic intervention to harness liver regeneration via controlled expression of endogenous mitogens in vivo.
2019-04-18 | Agonist c-Met Monoclonal Antibody Augments the Proliferation of hiPSC-derived Hepatocyte-Like Cells and Improves Cell Transplantation Therapy for Liver Failure in Mice
Rationale: Hepatocyte-like cells (HLCs) derived from human induced pluripotent stem cells (hiPSCs) have been developed to address the shortage of primary human hepatocytes (PHHs) for therapeutic applications.However, the in vivo repopulation capacity of HLCs remains limited.This study investigated the roles of agonist antibody activating the c-Met receptor in promoting the in vivo proliferation and repopulation of engrafted PHHs and/or HLCs in mice with liver injuries due to different causes.Methods: An agonist c-Met receptor antibody (5D5) was used to treat PHHs and hiPSC-HLCs in both cell culture and hepatocyte-engrafted immunodeficient mice mimicking various inherited and acquired liver diseases.The promoting roles and potential influence on the hepatic phenotype of the 5D5 regimen in cell transplantation-based therapeutic applications were systematically evaluated.Results: In hiPSC-HLC cell cultures, 5D5 treatment significantly stimulated c-Met receptor downstream signalling pathways and accelerated cell proliferation in dose-dependent and reversible manners.In contrast, only slight but nonsignificant promotion was observed in 5D5-treated PHHs.In vivo administration of 5D5 greatly promoted the expansion of implanted hiPSC-HLCs in fumarylacetoacetate hydrolase (Fah) deficient mice, resulting in significantly increased human albumin levels and high human liver chimerism (over 40%) in the transplanted mice at week 8 after transplantation.More importantly, transplantation of hiPSC-HLCs in combination with 5D5 significantly prolonged animal survival and ameliorated liver pathological changes in mice with acute and/or chronic liver injuries caused by Fas agonistic antibody treatment, carbon tetrachloride treatment and/or tyrosinemic stress.Conclusion: Our results demonstrated that the proliferation of hiPSC-HLCs can be enhanced by antibody-mediated modulation of c-Met signalling and facilitate hiPSC-HLC-based therapeutic applications for life-threatening liver diseases.
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Drug Discovery Landscape
2 orphan drug designations for Tyrosinemia type 1, including 1 approved therapy.
2 orphan drug designations for Tyrosinemia type 1, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Lentiviral vector expressing human fumarylacetoacetate hydrolase | gene therapies | FDA | 2019-08-08 | — | Castle Creek Biosciences, LLC |
Nitisinone [Orfadin] | small molecules | FDA | 1995-05-16 | 2002-01-18 | Swedish Orphan Biovitrum AB (publ) |
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