Autologous Gene and Cell Therapy Provides Safe and Long-Term Curative Therapy in A Large Pig Model of Hereditary Tyrosinemia Type 1

Orthotopic liver transplantation remains the only curative therapy for inborn errors of metabolism. Given the tremendous success for primary immunodeficiencies using ex-vivo gene therapy with lentiviral vectors, there is great interest in developing similar curative therapies for metabolic liver diseases. We have previously generated a pig model of hereditary tyrosinemia type 1 (HT1), an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH). Using this model, we have demonstrated curative ex-vivo gene and cell therapy using a lentiviral vector to express FAH in autologous hepatocytes. To further evaluate the long-term clinical outcomes of this therapeutic approach, we continued to monitor one of these pigs over the course of three years. The animal continued to thrive off the protective drug NTBC, gaining weight appropriately, and maintaining sexual fecundity for the course of his life. The animal was euthanized 31 months after transplantation to perform a thorough biochemical and histological analysis. Biochemically, liver enzymes and alpha-fetoprotein levels remained normal and abhorrent metabolites specific to HT1 remained corrected. Liver histology showed no evidence of tumorigenicity and Masson’s trichrome staining revealed minimal fibrosis and no evidence of cirrhosis. FAH-immunohistochemistry revealed complete repopulation of the liver by transplanted FAH-positive cells. A complete histopathological report on other organs, including kidney, revealed no abnormalities. This study is the first to demonstrate long-term safety and efficacy of hepatocyte-directed gene therapy in a large animal model. We conclude that hepatocyte-directed ex-vivo gene therapy is a rational choice for further exploration as an alternative therapeutic approach to whole organ transplantation for metabolic liver disease, including HT1.

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Curative ex vivo liver-directed gene therapy in a pig model of hereditary tyrosinemia type 1

Science Translational Medicine ◽

10.1126/scitranslmed.aaf3838 ◽

2016 ◽

Vol 8 (349) ◽

pp. 349ra99-349ra99 ◽

Cited By ~ 30

Author(s):

Raymond D. Hickey ◽

Shennen A. Mao ◽

Jaime Glorioso ◽

Faysal Elgilani ◽

Bruce Amiot ◽

...

Keyword(s):

Gene Therapy ◽

Ex Vivo ◽

Pig Model ◽

Tyrosinemia Type 1 ◽

Hereditary Tyrosinemia

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Understanding and Prevention of “Therapy-” Induced Dyskinesias

Parkinson s Disease ◽

10.1155/2012/640815 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Iciar Aviles-Olmos ◽

Zinovia Kefalopoulou ◽

Thomas Foltynie

Keyword(s):

Gene Therapy ◽

Synaptic Plasticity ◽

Basal Ganglia ◽

Cell Therapy ◽

Dopamine Release ◽

The Subject ◽

Cell And Gene Therapy ◽

Further Development ◽

Gene And Cell Therapy

L-dopa is the most effective, currently available treatment for Parkinson’s disease (PD), but it leads to the development of involuntary movements known as L-dopa-induced dyskinesia (LID) in the majority of patients after long-term use. Both gene and cell therapy approaches are the subject of multiple ongoing studies as potential ways of relieving symptoms of PD without the complication of dyskinesia. However, the spectre of dyskinesia in the absence of L-dopa, the so-called “off-phase” or graft-induced dyskinesia (GID), remains a major obstacle particularly in the further development of cell therapy in PD, but it is also a concern for proponents of gene therapy approaches. LID results from nonphysiological dopamine release, supersensitivity of dopamine receptors, and consequent abnormal signalling through mechanisms of synaptic plasticity. Restoration of physiological circuitry within the basal ganglia loops is ultimately the aim of all cell and gene therapy approaches but each using distinctive strategies and accompanied by risks of exacerbation of LID or development of “off-phase”/GID. In this paper we discuss the details of what is understood regarding the development of dyskinesias with relevance to cell and gene therapy and potential strategies to minimize their occurrence.

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Ex vivo Gene Therapy and Cell Therapy for Stroke

Progress in Neurological Surgery - Principles of Molecular Neurosurgery ◽

10.1159/000084474 ◽

2005 ◽

pp. 439-457

Author(s):

Douglas Kondziolka ◽

Jason Sheehan ◽

Ajay Niranjan

Keyword(s):

Gene Therapy ◽

Cell Therapy ◽

Ex Vivo ◽

Ex Vivo Gene Therapy

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Long-term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbits

Science ◽

10.1126/science.1722351 ◽

1991 ◽

Vol 254 (5039) ◽

pp. 1802-1805 ◽

Cited By ~ 270

Author(s):

Chowdhury ◽

M Grossman ◽

S Gupta ◽

N. Chowdhury ◽

J. Baker ◽

...

Keyword(s):

Gene Therapy ◽

Ex Vivo ◽

Ex Vivo Gene Therapy

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Diagnostic and Therapeutic Challenges of Hereditary Tyrosinemia Type 1 in Lebanon: A 12-Year Retrospective Review

Frontiers in Pediatrics ◽

10.3389/fped.2021.698577 ◽

2021 ◽

Vol 9 ◽

Author(s):

Karim N. Daou ◽

Abir Barhoumi ◽

Amina Bassyouni ◽

Pascale E. Karam

Keyword(s):

Developing Countries ◽

Early Diagnosis ◽

Liver Transplant ◽

Term Outcome ◽

Long Term Outcome ◽

Tyrosinemia Type 1 ◽

Hereditary Tyrosinemia ◽

Clinical Awareness

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.

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385. Tol2 Transposon as a Gene Therapy Vector: Characterization, Optimization and Correction of Hereditary Tyrosinemia Type 1 in Mouse

Molecular Therapy ◽

10.1016/j.ymthe.2006.08.446 ◽

2006 ◽

Vol 13 ◽

pp. S147

Author(s):

Darius Balciunas ◽

Andrew Wilber ◽

Kirk Wangensteen ◽

Jason Bell ◽

Aron Geurts ◽

...

Keyword(s):

Gene Therapy ◽

Gene Therapy Vector ◽

Tyrosinemia Type 1 ◽

Hereditary Tyrosinemia ◽

Tol2 Transposon

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Directed protein evolution as a tool to innovate gene therapy for hereditary tyrosinemia type 1

Journal of Hepatology ◽

10.1016/s0168-8278(20)31559-2 ◽

2020 ◽

Vol 73 ◽

pp. S543

Author(s):

Jessie Neuckermans ◽

Haaike Colemonts-Vroninks ◽

Marcelis Lionel ◽

Alan Mertens ◽

Ulrich Schwaneberg ◽

...

Keyword(s):

Gene Therapy ◽

Protein Evolution ◽

Tyrosinemia Type 1 ◽

Hereditary Tyrosinemia

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In vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions

10.1101/2021.01.02.425079 ◽

2021 ◽

Author(s):

Clara T Nicolas ◽

Caitlin J VanLith ◽

Kari L Allen ◽

Raymond D Hickey ◽

Zeji Du ◽

...

Keyword(s):

Lentiviral Vector ◽

Ex Vivo ◽

Expression Patterns ◽

Tyrosinemia Type 1 ◽

Vector Targeting ◽

Fumarylacetoacetate Hydrolase ◽

Hereditary Tyrosinemia ◽

First Time

AbstractConventional therapy for hereditary tyrosinemia type-1 (HT1) with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) delays but in some cases fails to prevent disease progression to liver fibrosis, liver failure, and activation of tumorigenic pathways. Here we demonstrate for the first time a complete cure of HT1 by direct, in vivo administration of a therapeutic lentiviral vector targeting the expression of a human fumarylacetoacetate hydrolase (FAH) transgene in the porcine model of HT1. This therapy was well tolerated and provided stable long-term expression of FAH in pigs with HT1. Genomic integration displayed a benign profile, with subsequent fibrosis and tumorigenicity gene expression patterns similar to wild-type animals as compared to NTBC-treated or diseased untreated animals. Indeed, the phenotypic and genomic data following in vivo lentiviral vector administration demonstrate comparative superiority over other therapies including ex vivo cell therapy and therefore support clinical application of this approach.

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