Liver-directed gene therapy results in long-term correction of progressive familial intrahepatic cholestasis type 3 in mice

Progressive Familial Intrahepatic Cholestasis (PFIC) are inherited severe liver disorders presenting early in life, with high serum bile salt and bilirubin levels. Six types have been reported, two of these are caused by deficiency of an ABC transporter; ABCB11 (bile salt export pump) in type 2; ABCB4 (phosphatidylcholine floppase) in type 3. In addition, ABCB11 function is affected in 3 other types of PFIC. A lack of effective treatment makes a liver transplantation necessary in most patients. In view of long-term adverse effects, for instance due to life-long immune suppression needed to prevent organ rejection, gene therapy could be a preferable approach, as supported by proof of concept in animal models for PFIC3. This review discusses the feasibility of gene therapy as an alternative for liver transplantation for all forms of PFIC based on their pathological mechanism. Conclusion: Using presently available gene therapy vectors, major hurdles need to be overcome to make gene therapy for all types of PFIC a reality.

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Gene therapy for progressive familial intrahepatic cholestasis type 3 in a clinically relevant mouse model

Nature Communications ◽

10.1038/s41467-019-13614-3 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Nicholas D. Weber ◽

Leticia Odriozola ◽

Javier Martínez-García ◽

Veronica Ferrer ◽

Anne Douar ◽

...

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Therapeutic Effect ◽

Intrahepatic Cholestasis ◽

Bile Salts ◽

Monogenic Disease ◽

Progressive Familial Intrahepatic Cholestasis ◽

Disease Biomarkers ◽

Type 3 ◽

Old Females

AbstractProgressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare monogenic disease caused by mutations in the ABCB4 gene, resulting in a reduction in biliary phosphatidylcholine. Reduced biliary phosphatidylcholine cannot counteract the detergent effects of bile salts, leading to cholestasis, cholangitis, cirrhosis and ultimately liver failure. Here, we report results from treating two- or five-week-old Abcb4−/− mice with an AAV vector expressing human ABCB4, resulting in significant decreases of PFIC3 disease biomarkers. All male mice achieved a sustained therapeutic effect up through 12 weeks, but the effect was achieved in only 50% of females. However, two-week-old females receiving a second inoculation three weeks later maintained the therapeutic effect. Upon sacrifice, markers of PFIC3 disease such as, hepatosplenomegaly, biliary phosphatidylcholine and liver histology were significantly improved. Thus, AAV-mediated gene therapy successfully prevented PFIC3 symptoms in a clinically relevant mouse model, representing a step forward in improving potential therapy options for PFIC3 patients.

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Progressive familial intrahepatic cholestasis type 3: report of four clinical cases, novel ABCB4 variants, and long-term follow-up

Annals of Hepatology ◽

10.1016/j.aohep.2021.100342 ◽

2021 ◽

pp. 100342

Author(s):

Patryk Lipiński ◽

Elżbieta Ciara ◽

Dorota Jurkiewicz ◽

Rafał Płoski ◽

Marta Wawrzynowicz-Syczewska ◽

...

Keyword(s):

Intrahepatic Cholestasis ◽

Progressive Familial Intrahepatic Cholestasis ◽

Long Term Follow Up ◽

Type 3 ◽

Clinical Cases

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A novel etiologic factor of highly elevated cholestanol levels: progressive familial intrahepatic cholestasis

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0314 ◽

2020 ◽

Vol 33 (5) ◽

pp. 665-669

Author(s):

Aynur Küçükçongar Yavaş ◽

Büşra Çavdarlı ◽

Özlem Ünal Uzun ◽

Ayşen Uncuoğlu ◽

Mehmet Gündüz

Keyword(s):

Primary Biliary Cirrhosis ◽

Intrahepatic Cholestasis ◽

Density Lipoprotein ◽

Etiologic Factor ◽

Compound Heterozygous ◽

Cholestatic Liver Disease ◽

Biliary Cirrhosis ◽

Progressive Familial Intrahepatic Cholestasis ◽

Turkish Patient ◽

Type 3

AbstractBackgroundProgressive familial intrahepatic cholestasis type 3 (PFIC3) is an uncommon cholestatic liver disease caused by mutations in the ATP binding cassette subfamily B member 4 (ABCB4) gene. Although PFIC3 is frequently identified in childhood, ABCB4 disease-causing alleles have been described in adults affected by intrahepatic cholestasis of pregnancy, hormone-induced cholestasis, low-phospholipid-associated cholelithiasis syndrome or juvenile cholelithiasis, cholangiocarcinoma and in sporadic forms of primary biliary cirrhosis. Cholestanol is a biomarker which is elevated especially in cerebrotendinous xanthomatosis and rarely in primary biliary cirrhosis (PBC) and Niemann Pick type C.Case presentationHere we report a Turkish patient with compound heterozygous mutations in the ABCB4 gene, who has hepatosplenomegaly, low level of high-density lipoprotein, cholestasis and high level of cholestanol.ConclusionThis is the first PFIC3 case with a high cholestanol level described in the literature. There are very few diseases linked to increased cholestanol levels, two of which are CTX and PBC. From this case, we can conclude that a high cholestanol level might be another indicator of PFIC type 3.

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A Novel Compound Heterozygous Mutation in ABCB4 Gene Leading to Cholelithiasis, Progressive Familial Intrahepatic Cholestasis (Type 3), and Cirrhosis in a Child

Journal of Child Science ◽

10.1055/s-0040-1717106 ◽

2020 ◽

Vol 10 (01) ◽

pp. e134-e136

Author(s):

Nida Mirza ◽

Smita Malhotra ◽

Anupam Sibal

Keyword(s):

Intrahepatic Cholestasis ◽

Gall Stone ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Initial Symptom ◽

Progressive Familial Intrahepatic Cholestasis ◽

Presenting Symptoms ◽

Abcb4 Gene ◽

Type 3

AbstractProgressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive disorders of childhood which presents with intermittent or progressive episodes of cholestasis, with jaundice and pruritus as most common presenting symptoms. PFIC type 3 occurs due to mutations in the ABCB4 gene, mutation in this gene has wide spectrum of features which include intrahepatic stones, cholelithiasis, PFIC type 3, and intrahepatic cholestasis of pregnancy. Here, we are reporting a peculiar case of young male adolescent with novel variant compound heterozygote missense mutation in ABCB4 gene who had gall stone as initial symptom, followed by symptoms of PFIC and eventually decompensated chronic liver disease.

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