eRapport

Factor (F) VII deficiency: developing new therapeutic strategies to rescue FVII production and function

Prosjekt
Prosjektnummer
2019071
Ansvarlig person
Per Morten Sandset
Institusjon
Oslo universitetssykehus HF
Prosjektkategori
Åpen prosjektstøtte
Helsekategori
Blood
Forskningsaktivitet
5. Treatment Developement
Rapporter
2024 - sluttrapport
In this project we aimed to develop new therapeutic strategies for the treatment of FVII deficiency. By integrating the newest gene editing technology like nuclease CRISPR-Cas9 and the stem cell and organoids technology we have successfully reprogrammed peripheral blood mononuclear cells from 6 patients carrying the F7 mutation Q160R to induced pluripotent stem cells (iPSCs). These iPSCs were characterized and the pluripotency properties of these cells were demonstrated with the generation of the three germ layers (mesoderm, ectoderm and endoderm). Using a robust differentiation procedure that allows the production of liver organoids that recapitulate all aspects of liver physiology, we have generated liver organoids from the patient-derived iPSCs that reproduce the patient’s phenotype, showing a decreased secretion of FVII protein with undetectable FVII activity. We successfully corrected the F7 mutation Q160R in the patients-derived iPSCs using CRISPR-Cas9 technology with the obtention of a homozygous wild type (WT) F7. The safety of the gene correction was demonstrated by whole exon sequencing with no evidence of the presence of off targets effects in the gene edited patient-derived iPSC. The patient-derived gene corrected iPSCs were differentiated into liver organoids which showed an increased secretion of FVII protein as well as an increase in the activity of the FVII protein. This demonstrated the efficacy of the gene correction. It is important to note that a small increase in FVII activity can improve the bleeding phenotype of the patients. The other approach of the project for the development of new treatments for FVII deficiency consists in the identification of FDA approved small molecules/drugs that can increase the activity of the FVII mutant protein. Using screening of small molecule libraries (Prestwick FDA/EMA approved drugs/Enamine diversity collection) in patients’ plasma we identified two molecules that were able to increase the activity of the FVII mutant protein. We corroborated these results in a cell model using over expression of the mutant FVII protein. The data is supported by comprehensive ex vivo and in vitro studies where we also delve into the mechanistic pathways through which these repurposed drugs exert their effects, providing a thorough scientific foundation for their potential utility. This proof-of concept-study demonstrates that drug repurposing may be feasible for developing novel treatment of FVII deficiency and we aim to inspire further research and clinical trials that could eventually lead to more comprehensive care strategies for patients affected by this and other similar conditions. This project constitutes a proof of principle for the development of autologous cell therapy for FVII deficiency. It gives the first pre-clinical evidence of the use of CRISPR-Cas9 technology together with organoids technology for correcting a F7 mutation and generating liver organoids that produce and secrete a functional FVII protein. The production of these autologous gene-corrected liver organoids can lead to a long-lasting therapy for patients with FVII deficiency through its transplantation back to the patients. A modest increase in the activity of FVII in plasma can ameliorate the bleeding phenotype of the patients decreasing or eliminating the need for the use of recombinant FVII or plasma-derived FVII concentrates for the treatment and/or prophylaxis of the bleeding episodes. This therapy could also be extended to treatment of other coagulation factor deficiencies. This can alleviate the economic burden related to use of recombinant FVII concentrates. More important, it will improve the quality of life of the patients. The identification of FDA approved drugs that can enhance FVII activity in plasma can set the basis for drug repurposing in FVII deficiency. Utilizing approved drugs that have been used for other diseases facilitates their implementation as treatment for FVI deficiency. This study provides the first proof of concept for drug repurposing in FVII deficiency.

No

2023
We have successfully corrected the coagulation factor (F) mutation Q160R, in patient-derived pluripotent stem cells (iPSC). These iPSC have been differentiated into hepatic organoids that shows an increased secretion and activity of the FVII protein . Using drug screening, we have identified two compounds that increase FVII activity in vitro.FVII is a blood coagulation protein that is produced in the liver cells, and it has a critical role in the initiation of the blood coagulation, the system that controls bleeding after vascular injury. Inherited coagulation FVII deficiency is produced by mutations in the F7 gene that cause a reduced plasma levels and activity of the FVII protein. The clinical phenotype consists in bleeding diathesis that can vary from mild to severe including gastrointestinal bleeding and joint bleeding. The only available treatment for the bleeding episodes is the replacement of the deficient factor with recombinant (r) or plasma-derived FVII which has some limitations: it requires frequent bolus injections due to a short half-life of the rFVII, and it also has a high cost. Thus, there is an unmet need for new and improved therapies for patients with FVII deficiency. Gene editing allows for the correction of a specific mutation in a gene with the consequent production of a normal, active protein. In this project we aimed to develop new therapeutic strategies for the treatment of FVII deficiency. Using a combination of the newest gene editing technology like CRISPR-Cas9 and stem cell technology we have successfully reprogrammed peripheral blood mononuclear cells from 6 patients carrying the F7 mutation Q160R to induced pluripotent stem cells (iPSCs). These iPSCs were characterized and the pluripotency properties of these cells were demonstrated with the generation of the three germ layers (mesoderm, ectoderm and endoderm).Using a robust differentiation procedure that allows the production of liver organoids that recapitulate all aspects of liver physiology, we have generated liver organoids from the patient-derived iPSCs that reproduce the patient’s phenotype, showing a decreased secretion of FVII protein with undetectable FVII activity. We have successfully corrected the F7 mutation Q160R in the patients-derived iPSCs using CRISPR-Cas9 technology with the obtention of a homozygous wild type (WT) F7. We have differentiated the gene corrected iPSCs into liver organoids which showed an increased secretion of FVII protein as well as an increase in the activity of the FVII protein. This demonstrated the efficacy of the gene correction. It is important to note that a small increase in FVII activity can improve the bleeding phenotype of the patients. The other approach of the project for the development of new treatments for FVII deficiency consists in the identification of FDA approved small molecules/drugs that can increase the activity of the FVII mutant protein. Using screening of small molecule libraries (Prestwick FDA/EMA approved drugs/Enamine diversity collection) in patients’ plasma we identified two molecules that were able to increase the activity of the FVII mutant protein. We corroborated these results in a cell model using over expression of the mutant FVII protein. Thus, this constitutes a proof of concept for drug repurposing in FVII deficiency.

No

2022
One of the goals of the project is to correct a mutation in the F7 gene (Q160R) that causes reduced coagulant activity of coagulation factor (F) VII and bleeding diathesis in patients. Using the latest technology in gene editing, the CRISPR Cas9 system, we succeeded in correcting the Q160R mutation in pluripotent stem cells from patients.Faktor (F) VII er et protein i blodet vårt som har en kritisk rolle i blodlevringsprosessen. Det produseres i leverceller og sendes derfra ut i sirkulasjonen. Arvelig FVII-mangel er en sjelden blødersykdom forårsaket av mutasjoner i genet som koder for FVII og som fører til at aktiviteten til FVII proteinet i blodet er redusert. Blødningssymptomene kan være spontane eller traume-induserte og varierer i alvorlighetsgrad fra milde og moderate ytre eller indre blødninger som i ledd og fordøyelsessystemet, til potensielt dødelige hjerneblødninger. Den eneste tilgjengelige behandlingen for disse pasientene er symptomatisk ved tilføring av "friskt" FVII protein i forkant av eller under blødningsepisodene. "Friskt" FVII protein blir enten produsert i et rekombinant system eller renset fra blodet til friske givere. Behandlingen har flere begrensninger: den krever hyppige bolusinjeksjoner på grunn av kort halveringstid for FVII, kostnaden er høy og medfører risiko for infeksjoner. Det er derfor behov for nye og forbedrede måter å behandle disse pasientene på. "Drug repurposing" er en relativt ny og rask screening-metode for å finne nye bruksområder til eksisterende legemidler på. I tillegg gjør ny teknologi innen genredigering det nå mulig å korrigere en spesifikk mutasjon i et gen med påfølgende produksjon av et normalt, aktivt protein. I dette prosjektet har vi som mål å utvikle nye terapeutiske strategier for behandling av FVII-mangel ved å benytte slike teknologier. Vi har identifisert to kandidat-legemidler som gir økt aktivitet av mutert FVII protein i blod fra pasienter og vi undersøker nå effekten av disse i detalj i laboratoriet. Dette arbeidet ble presentert som poster på den årlige konferansen til det internasjonale selskapet for trombose og hemostase (ISTH) i London i juli 2022. Videre har vi ved å kombinere CRISPR-Cas9 genredigeringsteknologi med nyeste kunnskap om cellereprogrammering korrigert mutasjonen Q160R i induserte pluripotente stamceller (iPSC) omprogramert fra immunceller isolert fra pasienter med arvelig FVII mangel. Redigeringen har vært effektiv på både ett og to alleler, slik at vi både har korrigert mutasjonen delvis (heterozygot) og fullstendig (homozygot). Videre arbeid innebærer å differensiere de genkorrigerte iPSCene til leverorganoider, ettersom det er i levercellene FVII proteinet lages. Til dette bruker vi en robust differensieringsprotokoll som vi allerede har verifisert gir leverorganoider som rekapitulerer alle aspekter av leverfysiologien, også produksjon av blodlevringsproteiner. Dette arbeidet ble publisert i BioRxiv i 2020 og er under revisjon i Experimental & Molecular Medicine, og ble presentert som poster på den årlig kongressen til det europeiske selskapet for gen- og celleterapi (ESGCT) i Edinburg høsten 2022. Videre arbeid innebærer å verifisere at de genredigerte leverorganoidene produserer et normalt aktivt FVII protein, både in vitro og in vivo i mus. Det er viktig å merke seg at en liten økning i FVII-aktivitet kan forbedre blødningsfenotypen til pasientene.

No

2021
Inherited factor VII deficiency is a rare bleeding disorder with three times higher frequency in Norway compared to other countries. The current treatment, based on replacement therapy, has considerable limitations such as a short half-life and high costs. The aim of this project is to develop new therapeutic strategies for FVII deficiencyFactor (F) VII is a vitamin K dependent coagulation factor, which is synthesized by the hepatocyte cells in the liver and secreted into the plasma. There is a large unmet medical need to develop novel therapies for patients with deficiencies in vitamin K dependent coagulation factors responsible for either bleeding or thrombosis. This project focuses on factor FVII as a model molecule, and may eventually result in simplified, safer and cheaper treatment of severe bleeding as an alternative to the current treatment with FVII concentrates. The aim is to pave the way to the development of new therapeutic strategies directed to stop and prevent the bleeding in patients with FVII deficiency. For this purpose, we are using two different approaches: 1) genome editing by CRISPR/Cas9 to correct the F7 gene mutation in cells derived from patients. 2) pharmacological chaperone therapy to rescue the secretion and activity of the FVII mutant protein. For both approaches, we are using a cell model whereby hepatocyte-like cells (HLCs) are generated from induced pluripotent stem cells (iPSCs), either derived from patient blood or in house available. Main findings and results from the study: 1. We have successfully differentiated a in house iPSCs line to HLCs and to three-dimensional hepatic organoids and have verified that they produce and secrete a functional FVII molecule and other coagulation factors. The levels in the HLCS and the hepatic organoids are comparable to primary liver cells derived from cadavers. 2. We have successfully used CRISPR-Cas9 to introduce the F7 p.Q160R mutation in the iPSCs and we have obtained heterozygous iPSCs clones carrying the mutation. We are now in the process of obtaining homozygous clones. 3. We have successfully recruited 7 FVII-deficient patients carrying the p.Q160R mutation and isolated peripheral blood mononuclear cells from patient blood. We have successfully reprogrammed these cells into iPSCs using viral delivery of pluripotency-inducing transcriptions factors (Yamanaka factors). We have successfully proved the pluripotency of these patient’s derived iPSCs since they were differentiated into endoderm (hepatocytes/liver organoids), mesoderm (cardiomyocytes) and ectoderm (neural epithelium). We are in the process of correcting the mutation by introducing the wild-type FVII using genome editing and then the cells will be differentiated to hepatic organoids and the gene correction will be assessed. This will allow us to generate a cell model derived from the patient’s own cells that will be used for further experiments. 4. We have characterized the clinical phenotype and the molecular mechanisms of the FVII variant p.A354V-p.P464Hfs and found a large variation in clinical phenotypes and defects in the intracellular transport of the mutant protein. 5. We have performed pilot studies on high-throughput screening analyses testing a library of >1500 FDA-approved drugs and identified the orally available histone deacetylase inhibitor abexinostat and the inhaled surfactant tyloxapol as enhancers of FVII p.Q160R variant activity in patient’s plasma ex vivo. In a dose-response study we found that both compounds increased FVII activity about 20% in patient’s plasma ex vivo. We will next test the compounds in patient-derived hepatic cells/organoids.

Nei

2020
Inherited factor VII deficiency is a rare bleeding disorder with three times higher frequency in Norway compared to other countries. The current treatment, based on replacement therapy, has considerable limitations such as a short half-life and high costs. The aim of this project is to develop new therapeutic strategies for FVII deficiencyFactor (F) VII is a vitamin K dependent coagulation factor, which is synthesized by liver cells (hepatocytes) and secreted into the plasma. There is a large unmet medical need to develop novel therapies for patients with deficiencies in vitamin K dependent coagulation factors responsible for either bleeding or thrombosis. This project focuses on factor FVII as a model molecule, and may eventually result in simplified, safer and cheaper treatment of severe bleeding as an alternative to the current treatment with FVII concentrates. The aim is to pave the way to the development of new therapeutic strategies directed to stop and prevent the bleeding in patients with FVII deficiency. For this purpose, we are using two different approaches: 1) genome editing by CRISPR/Cas9 to correct the F7 gene mutation in cells derived from patients. 2) chaperone therapy to rescue the secretion and activity of the FVII mutant protein. For both approaches, we are using a cell model whereby hepatocyte-like cells (HLCs) are generated from induced pluripotent stem cells (iPSCs), either derived from patient blood or commercially available. Main findings and results from the study: 1. We have successfully differentiated an in-house available iPSCs line to HLCs and have verified that these cells produce and secrete a functional FVII molecule. Additionally, we have proved that hepatic organoids (HO), a three-dimensional hepatic tissue culture, can produce and secrete functional FVII. The levels in the HLCS and the HO are comparable to those from primary liver cells derived from cadavers or isolated from patient liver biopsies. We have assessed and confirmed that FVII from HCLs and HO undergoes similar post-translational modifications to plasma FVII. We have also confirmed that these HCLs and HO produce coagulation factors able to activate the extrinsic coagulation pathway. 2. We have successfully use gene editing procedure (CRISPR-Cas9) to introduce a F7 mutation (p.Q160R) in iPSCs (first in a heterozygous state) and have already designed guided RNA sequences to introduce the other two F7 mutations which are part of the study. 3. We have successfully recruited 7 FVII-deficient patients with the p.Q160R mutation and isolated peripheral blood mononuclear cells from patient blood. We are setting the reprogramming of these cells into iPSCs using viral delivery of pluripotency-inducing transcriptions factors (Yamanaka factors). Thereafter, the mutation will be corrected by introducing the wild-type FVII using genome editing and then the cells will be differentiated to HLCs and HO and the gene correction will be assessed. This will allow us to generate a cell model derived from the patient’s own cells that will be used for further experiments. 4. We have successfully performed a screening of small molecules libraries and found around 8 compounds with a positive effect on increasing FVII activity in human mutant FVII p.Q160R overexpressed in CHO-K1 cells. We are at present testing different concentrations of the molecules to determine the concentration with the best effect on FVII activity to further test these compounds in plasma from patients carrying the p.Q160R mutation and in HLCs/HO carrying the FVII mutant proteins object of the study.

No

2019
Inherited factor VII deficiency is a rare bleeding disorder with three times higher frequency in Norway compared to other countries. The current treatment, based on replacement therapy, has considerable limitations such as a short half-life and high costs. The aim of this project is to develop new therapeutic strategies for FVII deficiency.Factor (F) VII is a vitamin K dependent coagulation factor, which is synthesized by the hepatocyte cells in the liver and secreted into the plasma. There is a large unmet medical need to develop novel therapies for patients with deficiencies in vitamin K dependent coagulation factors responsible for either bleeding or thrombosis. This project focuses on factor FVII as a model molecule, and may eventually result in simplified, safer and cheaper treatment of severe bleeding as an alternative to the current treatment with FVII concentrates. The aim is to pave the way for the development of new therapeutic strategies directed to stop and prevent the bleeding in patients with FVII deficiency. For this purpose, we are using two different approaches: 1) genome editing by CRISPR/Cas9 to correct the F7 gene mutation in cells derived from patients. 2) chaperone therapy to rescue the secretion and activity of the FVII mutant protein. For both approaches, we are using a cell model whereby hepatocyte-like cells (HLCs) are generated from induced pluripotent stem cells (iPSCs), either derived from patient blood or commercially available. Main findings and results from the study: 1. We have successfully differentiated a commercially available iPS cell line to HLCs and have verified that these cells produce and secrete a functional FVII molecule. Additionally, we have proved that hepatic organoids, a three-dimensional hepatic tissue culture, can produce and secrete functional FVII. The levels in the HLCS and the hepatic organoids are comparable to primary liver cells derived from cadavers or isolated from patient liver biopsies. We have assessed the intracellular trafficking of FVII in the HLCs and confirmed the localization to compartments involved in processing of secretory proteins. 2. We have successfully designed guide RNA sequences that recognizes the F7 gene sequence and verified that they can direct the Cas9 endonuclease there for editing. We are currently in the process of optimizing the gene editing procedure to ensure successful gene correction. 3. We have successfully recruited 7 FVII-deficient patients with the p.Q160R mutation and isolated peripheral blood mononuclear cells from patient blood. These cells will be reprogrammed into iPSCs using viral delivery of pluripotency-inducing transcriptions factors (Yamanaka factors). Thereafter, the mutation will be corrected by introducing the wild-type FVII using genome editing and then the cells will be differentiated to HLCs or hepatic organoids and the gene correction will be assessed. This will allow us to generate a cell model derived from the patient’s own cells that will be used for further experiments. 4. We have treated Chinese hamster ovary (CHO) cells that overexpress the FVII mutant p.Q160R with the chemical chaperone 4-phenylbutyrate and observed that this increased the secretion of this variant and that it could slightly enhance its specific biological activity. These results are a proof-of-principle that chaperone therapy can be a viable approach to rescue the secretion and activity of the FVII mutant protein. 5. We have performed pilot studies on a fluorogenic substrate to measure FVII activity and verified that the substrate can distinguish between wild type and mutated FVII activity in the cell medium from overexpressing CHO cells. We are at present working to upscale the experimental setup to be suitable for high-throughput screening analyses.

NEI

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Identification and Evaluation of Pharmacological Enhancers of the Factor VII p.Q160R variant

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Autologous gene-corrected stem cell-derived hepatic organoids for the treatment of FVII deficiency

Manuscript in preparation

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Molecular Characterization of Two Homozygous Factor VII Variants Associated With Intracranial Bleeding

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Chollet ME, Andersen E, Skarpen E, Mowinckel MC, Stavik B, Sullivan GJ, Sandset PM

FVII: a human pluripotent stem cell derived hepatocyte model with potential therapeutic applications (Abstract)

XXVII Congress of the International Society on Thrombosis and Haemostasis, 2019

Deltagere
  • Sean Harrison Prosjektdeltaker
  • Saphira Felicitas Baumgarten Forsker (finansiert av denne bevilgning)
  • Bernd Thiede Prosjektdeltaker
  • Ellen Skarpen Prosjektdeltaker
  • Benedicte Stavik Prosjektdeltaker
  • Mirko Pinotti Internasjonal samarbeidspartner
  • Francesco Bernardi Internasjonal samarbeidspartner
  • Vijay Rao Internasjonal samarbeidspartner
  • Pål Andre Holme Prosjektdeltaker
  • Gareth Sullivan Prosjektdeltaker
  • Per Morten Sandset Prosjektleder
  • Elisabeth Andersen Postdoktorstipendiat (finansiert av denne bevilgning)
  • Maria Eugenia Chollet Dugarte Postdoktorstipendiat (finansiert av denne bevilgning)

eRapport er utarbeidet av Sølvi Lerfald og Reidar Thorstensen, Regionalt kompetansesenter for klinisk forskning, Helse Vest RHF, og videreutvikles av de fire RHF-ene i fellesskap, med støtte fra Helse Vest IKT

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