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Hepatorenal tyrosinemia/fumarylacetoacetate hydrolase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Hepatorenal tyrosinemia, which has been referred to as tyrosinemia type 1, tyrosinosis, or hereditary tyrosinemia, was first reported by Sakai and Kitagawa in 1957 [1–3]. The patient reported was the product of a consanguineous mating, who developed progressive liver disease, which led to death following hematemesis and hepatic coma at three years of age. In addition, the patient had rickets, which was resistant to vitamin D. The major metabolic products in the urine were p-hydroxyphenyllactic acid, p-hydroxyphenylpyruvic acid, and p-hydroxyphenylacetic acid, as well as tyrosine. Gentz and colleagues [4], in a report of seven patients with the disease, first characterized the renal component as Fanconi syndrome. It was noted that patients had neurologic crises reminiscent of porphyria [5, 6], and this led to the recognition that δ-aminolevulinic acid was excreted in large amounts [6–9]. Lindblad and colleagues [10] reported that succinylacetone, which they found in the urine of these patients, is an inhibitor of the synthesis of porphobilinogen from δ-aminolevulinic acid. They reasoned that the fundamental defect was in the activity of fumarylacetoacetate hydrolase (Figure 22.1). This was confirmed enzymatically by these investigators [11] and others [12–14].
Adult Stem Cell Plasticity
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
An important discovery that highlights the therapeutic potential of HSC was made by Lagasse and colleagues in a study in which they used both whole bone marrow and purified BM sub-populations enriched for HSC to rescue mice with a fatal error in liver metabolism.25 The fumarylacetoacetate hydrolase (FAH-/-) mouse suffers progressive renal tubule damage and liver failure unless treated with the drug 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC).26 Up to 50% of hepatocytes (defined by morphology and expression of albumin, FAH, CD26, or E-cadherin) are BM-derived when FAH mice are transplanted with either whole BM or c-kithighThyloLin-Sca-1+ BM cells. The putative BM-derived hepatocytes did not express hematopoietic markers, and were often found in clusters, or nodules. This engraftment of BMSC as FAH+/+ cells was sufficient to rescue the recipient FAH-/- animals. Lagasse also determined that, separately, c-kit+, Sca-1+, and Lin- BM fractions, but not c-kit-, Sca-1-, or Lin+ fractions could reconstitute the BM and livers of irradiated recipients. This study thus showed that a highly selected population of BMSC can produce sufficient numbers of healthy hepatocytes to rescue animals with a fatal metabolic liver disease. In addition, only the BM subpopulations that can engraft the hematopoietic system show the ability to become functional hepatocytes.
Amino acid disorders and urea cycle disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
Tyrosinaemia type 1 is a rare metabolic disorder characterised by raised levels of the amino acid tyrosine in the blood. The disorder occurs when there is an absence or deiciency of an enzyme known as fumarylacetoacetate hydrolase, which is needed to break down tyrosine. If this amino acid is not broken down, it accumulates in the body, especially in the liver, kidneys and brain. Individuals may present with either an acute or a chronic form of this condition. The two forms are based on the age of the child and the severity of their symptoms.
Delivery approaches for CRISPR/Cas9 therapeutics in vivo: advances and challenges
Published in Expert Opinion on Drug Delivery, 2018
D.C. Luther, Y.W. Lee, H. Nagaraj, F. Scaletti, V.M. Rotello
In 2014, the Anderson lab was the first to report systemic delivery of the CRISPR/Cas9 system to adult mammalian organs [52]. The researchers selected a mouse model of hereditary tyrosinemia that included a point mutation (G->A) of fumarylacetoacetate hydrolase (Fah), an essential enzyme in the tyrosine catabolic pathway, to show the potential for correction of human genetic disease. The components of the CRISPR-Cas9 system were designed and delivered in plasmid format by hydrodynamic injection. However, the correction rate was insufficient for clinical translation due to the low expression of the wt-Fah protein (∼1/250 hepatocytes), with concurrent weight gain which was hypothesized to be a result of this correction. Additionally, the authors of this paper acknowledged the impracticality of hydrodynamic injection for clinical application and took different approaches in subsequent studies [44,53]. Regardless, this work illustrated the applicability of plasmid-based CRISPR/Cas9 in vivo.
Humanized mouse models infected with human Plasmodium species for antimalarial drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Alicia Moreno-Sabater, Jean Louis Pérignon, Dominique Mazier, Catherine Lavazec, Valerie Soulard
The HmHPf-LS, long time forgotten, has also benefited from the generation of broader immunodeficient mice [35] (Figure 1). Efficient liver humanization relies simultaneously on the host immunodeficiency that facilitates xenotransplantation and on the selective elimination of endogenous murine hepatocytes in order to make room for the transplanted HH to repopulate the liver, prior to inoculation of human malaria sporozoites. Hence, P. falciparum LS development was first observed in homozygous Alb-UpA SCID mice [36,37] which express the hepatotoxic Urokinase Plasminogen Activator (UpA) transgene under the albumin (Alb) promoter leading to a constitutive loss of endogenous hepatocytes. Alb-UpASCID mice are best engrafted at very young age (3–4 weeks) but given their low level of immunodeficiency, additional treatment to deplete NK cells and macrophages is required. Mice deficient for fumarylacetoacetate hydrolase (FAH−/−) with the broader immunodeficient Rag2−/−, IL2R gamma null−/− background (FRG) has been also used in malaria studies [38]. The FAH−/− mice suffer from an acute liver failure that can be rescued by providing NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione) at regular intervals pre- and post-HH transplantation. The FRG mice backcrossed onto the NOD background (FRG NOD) allowed full maturation of the P. falciparum LS up to the generation of infectious hepatic merozoites [38]. Although this HmHPf-LS supported reproducible transition from LS to ES, the graft of HRBC was ephemeral and the ES were only observed when infected HRBC were cultured ex vivo. More recently, the TK-NOG mouse strain, a model of inducible liver injury, has also proved to be valuable as a HmHPf-LS [39]. TK-NOG mice harbor the herpes simplex virus type 1 thymidine kinase (HSVtk) transgene under the albumin promoter onto the NSG background and upon a brief exposure to a nontoxic dose of gancyclovir, endogenous hepatocytes are depleted [40]. Numerous studies have then provided the proof of concept that HmHPf-LS are robust new experimental models to evaluate passive transfer therapies [41,42], to study the identification of genetic determinants of parasite traits and adaptations [43], and to evaluate prophylaxis therapies [44]. Furthermore, LS development of other human Plasmodium species has been obtained with the FRG and TK-NOG mouse strains grafted with HH and infected with P. vivax and P. ovale (HmHPv-LS and HmHPo-LS), including the generation, persistence, and activation of hypnozoites [39,45].