Heterozygous carriage of the alpha1-antitrypsin PiZ variant increases the risk to develop liver fibrosis

Strnad, Pavel; Buch, Stephan; Hamesch, Karim; Fischer, Janett; Heimes, CV; Gutberlet, Manuela; Janciauskiene, Sabina; Mandorfer, Mattias; Trauner, Michael; Reichert, M; Krawczyk, Marcin; Deltenre, Pierre; Schafmayer, Clemens; Nothnagel, Michael; Aigner, Elmar; Datz, Christian; Stickel, Felix; Morgan, Marsha Y.; Berg, Thomas

doi:10.1055/s-0037-1612696

Cited by 3 publications

(4 citation statements)

References 37 publications

(62 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Future studies are required to increase our understanding of how LRRK2 works in this context and could therefore help drive new treatment approaches for ATZ. Notably, this may also increase our understanding of the pathological mechanisms in other liver diseases such as NAFLD in which protein aggregates and ER stress are postulated to represent fundamental components of a multi-factorial pathology 8,[38][39][40][41] .…”

Section: Discussionmentioning

confidence: 98%

Small molecule screen employing patient-derived iPSC hepatocytes identifies LRRK2 as a novel therapeutic target for Alpha1 Antitrypsin Deficiency

Kent

Khoshkenar

et al. 2022

Preprint

View full text Add to dashboard Cite

Alpha-1 antitrypsin deficiency (A1ATD) is a life-threatening condition caused by inheritance of the SERPINA1-Z genetic variant (PiZ) leading to protein misfolding and liver toxicity. There remain no approved medicines for this disease. Here we report the results of a small molecule screen performed in patient-derived iPSC hepatocytes that identified Leucine-rich repeat kinase-2 (LRRK2), as a potentially new therapeutic target. Genetic deletion of LRRK2 in PiZ mice reduced both intrahepatic misfolded polymers and fibrosis leading us to test a library of commercially available LRRK2 inhibitors across several cell models. One of these molecules, CZC-25146, a candidate with favourable pharmacokinetic properties, reduced polymer load, increased normal AAT secretion and reduced inflammatory cytokines in both cells and the PiZ mouse. Mechanistically, this effect was achieved via inhibition of LRRK2 kinase activity and autophagy induction. These findings support the use of CZC-25146 (and potentially LRRK2 inhibitors more broadly) in hepatic proteinopathy disease research and as potential new therapies.

show abstract

Section: Discussionmentioning

confidence: 98%

Small molecule screen employing patient-derived iPSC hepatocytes identifies LRRK2 as a novel therapeutic target for Alpha1 Antitrypsin Deficiency

Kent

Khoshkenar

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…We do not as yet know however what the specific molecular players interacting with LRRK2 to regulate those observations are. Future studies to increase our understanding of how LRRK2 works in this context could therefore help drive new treatment approaches for ATZ as well as other liver diseases such as NAFLD in which protein aggregates and ER stress are postulated to represent fundamental components of a multifactorial pathology (6,(40)(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Small molecule screen employing patient-derived iPS hepatocytes identifies LRRK2 as a novel therapeutic target for Alpha1 Antitrypsin Deficiency

Kent

Khoshkenar³

et al. 2021

Preprint

View full text Add to dashboard Cite

Alpha-1 antitrypsin deficiency is a life-threatening condition caused by inheritance of the SERPINA1 gene Z variant. This single base pair mutation leads to protein misfolding, ER entrapment and gain of toxic function. Despite the significant unmet medical need presented by this disorder, there remain no approved medicines and the only curative option is liver transplantation. We hypothesized that an unbiased screen of human hepatocytes harbouring the Z mutation (ATZ) using small molecules targeted against protein degradation pathways would uncover novel biological insights of therapeutic relevance. Here we report the results of that screen performed in a patient-derived iPSC model of ATZ. Starting from 1,041 compounds we identified 14 targets capable of reducing polymer burden, including Leucine-rich repeat kinase-2 (LRRK2), a well-studied target in Parkinsons. Genetic deletion of LRRK2 in ATZ mice reduced polymers and associated fibrotic liver disease leading us to test a library of commercially available LRRK2 kinase inhibitors in both patient iPSC and CHO cell models. One of the molecules tested, CZC-25146, reduced polymer load, increased normal AAT secretion and reduced inflammatory cytokines with pharmacokinetic properties supporting its potential use for treating liver diseases. We therefore tested CZC-25146 in the ATZ mouse model and confirmed its efficacy for polymer reduction without signs of toxicity. Mechanistically, in both human and mouse models, our data show CZC-25146 inhibits LRRK2 kinase activity and induces autophagy. Cumulatively, these findings support the use of CZC-25146 and LRRK2 inhibitors in general in hepatic proteopathy disease research and as potential new treatment approaches for patients.

show abstract

“…Subjects with alcoholic and nonalcoholic fatty liver disease are particularly prone to liver fibrosis when simultaneously carrying a heterozygous Pi*Z variant. 4 67 Along the same lines, metabolic cofactors, such as obesity, diabetes, or the presence of metabolic syndrome increased the likelihood of Pi*MZ subjects to harbor significant liver fibrosis. 45 63 The relevance of Pi*MZ genotype for the progression of other liver diseases is less well studied and the available evidence is based only on small studies.…”

Section: Liver Disease In Adulthoodmentioning

confidence: 95%

“…Subjects with alcoholic and non-alcoholic fatty liver disease are particularly prone to liver fibrosis when simultaneously carrying a heterozygous Pi*Z variant [4,67]. Along the same lines, metabolic cofactors, such as obesity, diabetes or presence of metabolic syndrome increased the likelihood of Pi*MZ subjects to harbor significant liver fibrosis [45,63].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Pediatric and Adult Liver Disease in Alpha-1 Antitrypsin Deficiency

Ruiz

Lacaille²,

Schrader

et al. 2023

Semin Liver Dis

View full text Add to dashboard Cite

Alpha1-antitrypsin (AAT) deficiency (AATD) arises due to inherited variants in SERPINA1, the AAT gene that impair the production or secretion of this hepatocellular protein and lead to a gain-of-function liver proteotoxicity. Homozygous Pi*Z pathogenic variant (Pi*ZZ genotype) is the leading cause of severe AATD. It manifests in 2-10% of carriers as neonatal cholestasis and 20-35% of adults as significant liver fibrosis. Both children and adults may develop an end-stage liver disease requiring liver transplantation. Heterozygous Pi*Z pathogenic variant (Pi*MZ genotype) constitutes an established disease modifier. Our review summarizes the natural history and management of subjects with both pediatric and adult AATD-associated liver disease. Current findings from a phase 2 clinical trial indicate that RNA silencing may constitute a viable therapeutic approach for adult AATD. In conclusion, AATD is an increasingly appreciated pediatric and adult liver disorder that is becoming an attractive target for modern pharmacologic strategies.

show abstract

Heterozygous carriage of the alpha1-antitrypsin PiZ variant increases the risk to develop liver fibrosis

Cited by 3 publications

References 37 publications

Small molecule screen employing patient-derived iPSC hepatocytes identifies LRRK2 as a novel therapeutic target for Alpha1 Antitrypsin Deficiency

Small molecule screen employing patient-derived iPSC hepatocytes identifies LRRK2 as a novel therapeutic target for Alpha1 Antitrypsin Deficiency

Small molecule screen employing patient-derived iPS hepatocytes identifies LRRK2 as a novel therapeutic target for Alpha1 Antitrypsin Deficiency

Pediatric and Adult Liver Disease in Alpha-1 Antitrypsin Deficiency

Contact Info

Product

Resources

About