Combined transgene immortalized urothelial cells capable of reprogramming and hepatic differentiation.

Human primary cells, including urine-derived cells (UCs), are an excellent source for generation of pluripotent stem cells (iPSCs) to model disease. However, replicative senescence starts early and shortens the time window for generation of iPSCs. We addressed the question whether combinations of transgenes allows efficient immortalization of UCs, iPSC generation, and differentiation into hepatocyte-like cells (HLCs).

SERPINA1 modulates expression of amyloidogenic transthyretin.

Hereditary transthyretin amyloidosis (ATTR) is caused by amyloid deposition of misfolded transthyretin (TTR) in various tissues. Recently, reduction of circulating serum TTR, achieved via silencing oligonucleotides, was introduced as therapy of ATTR amyloidosis. We explored the impact of Serpin Family A Member 1 (SERPINA1) on TTR mRNA and protein expression.

APOE polymorphism in ATTR amyloidosis patients treated with lipid nanoparticle siRNA.

The novel class of compounds represented by lipid nanoparticle (LNP)-encapsulated siRNA formulations has an enormous potential to target disease, notably of the liver. Endocytosis of LNPs is believed to be mediated by APOE, an important serum protein of lipoprotein homeostasis. APOE polymorphisms affect binding to hepatic receptors and have been associated with development of specific disease.

Mutation-specific Fabry disease patient-derived cell model to evaluate the amenability to chaperone therapy.

Background: Patients with Fabry disease (FD) and amenable mutations can be treated with the chaperone migalastat to restore endogenous α-galactosidase A (AGAL) activity. However, certain amenable mutations do not respond biochemically in vivo as expected. Here, we aimed to establish a patient-specific and mutation-specific cell model to evaluate the amenability to chaperone therapy in FD.

Hepatocyte-like cells reveal novel role of SERPINA1 in transthyretin amyloidosis.

Transthyretin (TTR)-related familial amyloid polyneuropathy (ATTR) results from aggregation and extracellular disposition of misfolded TTR mutants. Growing evidence suggests the importance of hepatic chaperones for the modulation of pathogenesis. We took advantage of induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) from ATTR patients (ATTR-HLCs) to compare chaperone gene expression to that in HLCs from healthy individuals (H-HLCs).

[Transthyretin Familial Amyloid Polyneuropathy - Disease Profile of a Multisystem Disorder].

Transthyretin-related Familial Amyloid Polyneuropathy (ATTR Amyloidosis, former FAP, here called TTR-FAP) is a rare, progressive autosomal dominant inherited amyloid disease ending fatal within 5 - 15 years after final diagnosis. TTR-FAP is caused by mutations of transthyretin (TTR), which forms amyloid fibrils affecting peripheral and autonomic nerves, the heart and other organs. Due to the phenotypic heterogeneity and partly not specific enough clinical symptoms, diagnosis of TTR-FAP can be complicated.

Organic cation transporter 3 mediates cisplatin and copper cross-resistance in hepatoma cells.

Platinum-based drugs are first-line compounds in the treatment of many solid cancers. Major obstacles are tumors that become resistant and toxic side effects, both largely due to the expression of transporters that mediate the cellular processing of platinum. In this study, we addressed the establishment of cisplatin resistance in the absence of copper transporter ATP7B that has been previously found to be overexpressed in various resistant cells.

Downregulation of hepatic multi-drug resistance protein 1 (MDR1) after copper exposure.

Copper homeostasis is strictly regulated in mammalian cells. We investigated the adaptation of hepatocytes after long-term copper exposure. Copper-resistant hepatoma HepG2 cell lines lacking ATP7B were generated.

Evaluation of Therapeutic Oligonucleotides for Familial Amyloid Polyneuropathy in Patient-Derived Hepatocyte-Like Cells.

Familial amyloid polyneuropathy (FAP) is caused by mutations of the transthyretin (TTR) gene, predominantly expressed in the liver. Two compounds that knockdown TTR, comprising a small interfering RNA (siRNA; ALN-TTR-02) and an antisense oligonucleotide (ASO; IONIS-TTRRx), are currently being evaluated in clinical trials. Since primary hepatocytes from FAP patients are rarely available for molecular analysis and commercial tissue culture cells or animal models lack the patient-specific genetic background, this study uses primary cells derived from urine of FAP patients.

Methanobactin reverses acute liver failure in a rat model of Wilson disease.

In Wilson disease (WD), functional loss of ATPase copper-transporting β (ATP7B) impairs biliary copper excretion, leading to excessive copper accumulation in the liver and fulminant hepatitis. Current US Food and Drug Administration- and European Medicines Agency-approved pharmacological treatments usually fail to restore copper homeostasis in patients with WD who have progressed to acute liver failure, leaving liver transplantation as the only viable treatment option. Here, we investigated the therapeutic utility of methanobactin (MB), a peptide produced by Methylosinus trichosporium OB3b, which has an exceptionally high affinity for copper.

Therapeutic Oligonucleotides Targeting Liver Disease: TTR Amyloidosis.

The liver has become an increasingly interesting target for oligonucleotide therapy. Mutations of the gene encoding transthyretin (TTR), expressed in vast amounts by the liver, result in a complex degenerative disease, termed familial amyloid polyneuropathy (FAP). Misfolded variants of TTR are linked to the establishment of extracellular protein deposition in various tissues, including the heart and the peripheral nervous system.