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Introduction
Inborn errors of metabolism (IEMs) often result from single-gene mutations and collectively cause liver dysfunction in neonates leading to chronic liver and systemic disease. Current treatments for many IEMs are limited to maintenance therapies that may still require orthotropic liver transplantation. Gene therapies offer a potentially...
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Context 1
... with HTI lack the intracellular enzyme fumarylacetoacetate hydrolase (FAH) responsible for the downstream metabolism of tyrosine [9,10]. This prevents proper metabolism of this essential amino acid and results in the buildup of maleylacetoacetic acid and fumarylacetoacetic acid, two hepatotoxic metabolic intermediates of tyrosine metabolism that can severely injure hepatocytes ( Figure 1). These metabolites are primarily responsible for the progression of disease, leading to inflammation, fibrosis, cirrhosis, liver failure, and often hepatocellular carcinoma (HCC) [9,11]. ...
Context 2
... alternative approach designed to disrupt the HPD gene (the target of NTBC therapy) by using similar gene editing methods showed efficacy in treating test animals, but this results in subjects with a second homozygous or compound heterozygous genetic mutation, which results in sustained HT1 and HT3 phenotypes [43]. Notably, in this approach the genomic copy of the mutant FAH gene remains unchanged, and these subjects would require more than correction of the mutant FAH if/when a gene therapy is available due to this additional upstream mutation in HPD (Figure 1). ...
Citations
... 6 However, as NTBC is expensive and needs to be combined with a low-protein diet, additional treatment options against HT-1, such as gene-targeted therapy, are an urgent clinical need. 7 In this issue of the Journal of Hepatology, Gu et al. describe the development of a genetically modified bacterial strain that metabolizes tyrosine as a further potential targeted therapy for HT-1. They used a modified bacterial stain to ameliorate the disease in a mouse model of HT-1 (Fig. 1C). ...
Tyrosinemia type 1 (HT-1) is a rare autosomal recessive disease caused by a deficiency of fumarylacetoacetate hydrolase (FAH) [1] ,[2] and occurs in approximately 1 in 100,000 newborns [3] . The lack of FAH leads to an increase of intermediary products when degrading the amino acids phenylalanine and tyrosine to fumarate and acetoacetate [2] (Figure 1a). Next to the name-giving increase of tyrosine levels in the sera of patients suffering from this disease, an elevation of fumarylacetoacetate (FAA), the direct substrate of FAH, can be detected [2] (Figure 1b). Elevated levels of FAA and its increased metabolization into succinylacetone (SA) are thought to be mainly responsible for HT-1´s most common symptoms, which are renal dysfunction, neurological complications, and hepatic failure including a high risk of developing hepatocellular carcinoma [2] .
... HT1 is an inborn error in amino acid metabolism caused by a deficiency in functional fumarylacetoacetate hydrolase (FAH), which results in the accumulation of toxic and carcinogenic metabolites [52][53][54]. HT1 patients are at an increased risk of developing neurologic symptoms, renal failure, and early-onset HCC. The standard of patient care consists of a strict life-long diet low in tyrosine and phenylalanine that is supplemented with nitisinone, 2-(2-nitro-4-trifluoromethyl benzoyl) cyclohexane-1, 3-dione (NTBC), taken orally twice daily [53]. ...
Diseases that affect the liver account for approximately 2 million deaths worldwide each year. The increasing prevalence of these diseases and the limited efficacy of current treatments are expected to stimulate substantial growth in the global market for therapeutics that target the liver. Currently, liver transplantation is the only curative option available for many liver diseases. Gene therapy represents a valuable approach to treatment. The liver plays a central role in a myriad of essential metabolic functions, making it an attractive organ for gene therapy; hepatocytes comprise the most relevant target. To date, viral vectors constitute the preferred approach to targeting hepatocytes with genes of therapeutic interest. Alternatively, mRNA-based therapy offers a number of comparative advantages. Clinical and preclinical studies undertaken to treat inherited metabolic diseases affecting the liver, cirrhosis and fibrosis, hepatocellular carcinoma, hepatitis B, and cytomegalovirus using lipid nanoparticle-encapsulated mRNAs that encode the therapeutic or antigenic protein of interest are discussed.
... For example, studies have used adenoviral vectors encoding human interleukin-10 during ex-situ preservation of donor lungs in both discarded human and porcine models to inhibit pro-inflammatory cytokine secretion and promote improvement in lung function prior to transplantation 35,36 . Gene therapy strategies in allotransplantation can be potentially used to correct genetic deficiencies, inborn errors of metabolism, or clotting disorders that are associated with an increased risk of graft loss 37 . Gene silencing strategies have also been implemented in organ transplantation to modulate gene expression at the messenger RNA (mRNA) and protein level. ...
Machine perfusion has transformed the field of organ preservation permitting longer preservation and open a new avenue for graft treatment. As we are entering an era of “precision medicine”, the organ transplant field is becoming equipped with the tools necessary to personalize and optimize organs designed specifically to withstand injurious pathways that occur during transplantation. Here we highlight recent progress using different treatment strategies during ex-situ perfusion. In the future, customized graft therapy will create a reality where organs will be optimized, personalized, and likely be available on demand.
... [1] In order to enable these patients to develop normally and to be nourished adequately, nutritional therapy has always been an irreplaceable adjunct to medication and surgery because of its safety and efficiency. [2][3][4][5][6][7][8] Dietary therapy of the patients with metabolic disorder of AAA is mostly defined as the three parts: ...
Aromatic amino acids (AAA), including phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp), are essential building blocks of proteins, however, they have been implicated in multiple amino acid metabolism diseases, such as phenylketonuria, tyrosinemia, and glutaric acidemia type I. Dietary therapy is indispensable for patients with AAA metabolism disorder. This review briefly describes the pathogenesis and nutritional treatment guidelines of several AAA metabolic diseases. The techniques of protein hydrolysis and AAA removal from raw protein materials are very important in the development of special medical foods (SMFs) for above diseases. Therefore, existing protein hydrolysis techniques including enzymatic and microbial hydrolysis are reviewed, and the widely applied AAA removing methods including ultrafiltration and adsorption by active carbon and resin are also discussed. In addition, the application of several promising materials to remove AAA with better selectivity, such as molecular imprinting polymer, cyclodextrin, TiO2 and carbohydrate-based reverse micelle are prospected. This review may promote the development of SMFs for AAA metabolic diseases, and provide potential directions for processing technology improvement.
... Since 1992, NTBC/nitisinone, a selective drug working as an inhibitor of 4-Hydroxyphenylpyruvate dioxygenase, has been offered as a successful treatment in combination with a restricted diet, poor in tyrosine and phenylalanine amino acids [118,119]. Recently, it was demonstrated that a generic and bioequivalent version of NTBC, NITYR, and another brand of nitisinone (Orfadin) could offset the high costs of HT1 treatment [120]. Unfortunately, such pharmacological treatments do not protect patients from developing hepatocellular carcinoma, supporting new and improved cell and gene therapeutic approaches. ...
The majority of monogenic liver diseases are autosomal recessive disorders, with few being sex-related or co-dominant. Although orthotopic liver transplantation (LT) is currently the sole therapeutic option for end-stage patients, such an invasive surgical approach is severely restricted by the lack of donors and post-transplant complications, mainly associated with life-long immunosuppressive regimens. Therefore, the last decade has witnessed efforts for innovative cellular or gene-based therapeutic strategies. Gene therapy is a promising approach for treatment of many hereditary disorders, such as monogenic inborn errors. The liver is an organ characterized by unique features, making it an attractive target for in vivo and ex vivo gene transfer. The current genetic approaches for hereditary liver diseases are mediated by viral or non-viral vectors, with promising results generated by gene-editing tools, such as CRISPR-Cas9 technology. Despite massive progress in experimental gene-correction technologies, limitations in validated approaches for monogenic liver disorders have encouraged researchers to refine promising gene therapy protocols. Herein, we highlighted the most common monogenetic liver disorders, followed by proposed genetic engineering approaches, offered as promising therapeutic modalities.
... Given that nitisinone has availability problems and liver transplantation carries risks of surgical complications, there is a need for new, effective, and less expensive treatments, especially for developing countries. Other therapeutic options are currently being explored for this disease, such as the use of molecular chaperones (35) and gene therapy (36). ...
Background:
Hereditary tyrosinemia type 1 is a rare genetic disorder leading to liver cirrhosis and hepatocellular carcinoma. Few decades ago, dietary measures and ultimately liver transplant constituted the only treatment modalities. Nowadays, early diagnosis and therapy with nitisinone can reverse the clinical picture. In developing countries, diagnostic and therapeutic challenges may affect the outcome of this disease. The choice of the treatment modality may depend on the economic status of each country. Few reports on the long-term outcome of hereditary tyrosinemia type 1 are available from developing and Arab countries.
Methods:
A retrospective study of charts of Lebanese patients diagnosed with tyrosinemia type 1 and followed, at the American University of Beirut, during a 12-year period was performed. Clinical presentation and liver biochemical profile at diagnosis were analyzed, along with therapeutic modalities and long-term outcome.
Results:
Twenty-two children were diagnosed and followed during the study period. Median age at diagnosis was 7 months (range: one day to 35 months). Most of the patients presented with hepatomegaly and jaundice. Four patients were referred for atypical presentations with developmental delay and seizures, secondary to undiagnosed hypoglycemia episodes. Around half of the patients presented with failure to thrive. Transaminitis, cholestasis and increased α-fetoprotein level were variably present at diagnosis (36% to 50%). All patients had elevated plasma tyrosine and urinary succinylacetone levels. Genetic testing was performed in 9%. Only one third could be treated with nitisinone. Liver transplant was electively performed in 9% of cases, to overcome the long-term cost of nitisinone. One third of the patients died between the age of 1 month and 11 years. Surviving patients are still candidates for liver transplant.
Conclusion:
Our experience reflects the challenges of diagnosis and treatment of hereditary tyrosinemia type 1 in a developing country. In the absence of specific neonatal screening, early diagnosis relies mostly on the clinical awareness of the physician. Long-term nitisinone use may be deterred by its high cost and liver transplantation carries risks of surgical complications.
New, effective, and less expensive treatments are needed, especially for developing countries.
Liver transplantation is the most effective treatment for end-stage liver disease. Transplant indications have been progressively increasing, with a huge discrepancy between the supply and demand of optimal organs. In this context, the use of extended criteria donor grafts has gained importance, even though these grafts are more susceptible to ischemic reperfusion injury (IRI). Hepatic IRI is an inherent and inevitable consequence of all liver transplants; it involves ischemia-mediated cellular damage exacerbated upon reperfusion and its severity directly affects graft function and post-transplant complications. Strategies for organ preservation have been constantly improving since they first emerged. The current gold standard for preservation is perfusion solutions and static cold storage. However, novel approaches that allow extended preservation times, organ evaluation, and their treatment, which could increase the number of viable organs for transplantation, are currently under investigation. This review discusses the mechanisms associated with IRI, describes existing strategies for liver preservation, and emphasizes novel developments and challenges for effective organ preservation and optimization.
Purpose of review:
This review aims to highlight current advances in gene therapy methods, describing advances in CRISPR-Cas9 gene editing and RNA interference in relevance to liver transplantation, and machine perfusion.
Recent findings:
In order to minimize rejection, increase the donor pool of available organs, and minimize the effects of ischemia-reperfusion injury, gene therapy and gene modification strategies are, thus, required in the context of liver transplantation.
Summary:
Gene therapy has been used successfully in a diverse array of diseases, and, more recently, this technique has gained interest in the field of organ transplantation. Biological and logistical challenges reduce the rate of successful procedures, increasing the waiting list even more. We explore the exciting future implications of customized gene therapy in livers using machine perfusion, including its potential to create a future in which organs destined for transplant are individualized to maximize both graft and recipient longevity.
Hereditary tyrosinemia type 1 is an inborn error of amino acid metabolism characterized by deficiency of fumarylacetoacetate hydrolase (FAH). Only limited treatment options, e.g., oral nitisinone, are available. Patients must adhere to a strict diet and face a life-long risk of complications including liver cancer and progressive neurocognitive decline. There is a tremendous need for innovative therapies that standardize metabolite levels and promise normal development. Here, we describe an mRNA-based therapeutic approach that rescues Fah-deficient mice, a well-established tyrosinemia model. Repeated intravenous or intramuscular administration of lipid nanoparticle-formulated human FAH mRNA resulted in FAH protein synthesis in deficient mouse livers, stabilized body weight, normalized pathologic increases in metabolites after nitisinone withdrawal, and prevented early death. Dose reduction and extended injection intervals proved therapeutically effective. These results provide proof-of-concept for an mRNA-based therapeutic approach to treating hereditary tyrosinemia type 1 that is superior to the standard-of-care.
Organ transplantation is the definitive treatment for end-stage solid organ diseases, yet biological and logistical barriers reduce the rate of successful organ transplants. As such, there is a need for gene therapy and gene modulation strategies in the organ transplantation setting to prevent rejection, expand the donor pool of available organs, and attenuate ischemia-reperfusion damage. As we are entering an era of “precision medicine,” the organ transplant field is becoming equipped with the tools necessary to personalize and optimize organs designed specifically to withstand injurious pathways that occur during transplantation, such that the concept of “designer organs” will be a reality in the near future. In this review, we highlight the recent progress using gene knockout and knock-in strategies used mainly in the context of xenotransplantation. We also discuss advancements in CRISPR-Cas9 gene editing and RNA interference in relation to organ transplantation. Lastly, we discuss the exciting future implications of customized gene therapy in the transplantation setting, and its ability to potentially create a future where organs intended for transplant are personalized to maximize both graft and patient survival.
