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An experimental study in zebrafish has suggested the decades-old, first-generation antihistamine chlorcyclizine and/or other antihistamines may be a strategy for treating erythropoietic protoporphyria (EPP)-associated liver disease by decreasing hepatic protoporphorin IX (PP-IX) accumulation.
Currently, liver transplantation is the primary treatment for this rare, painful, and life-threatening genetic disease, which is caused by excessive PP-IX accumulation and affects about 4000 people in the United States.
The findings could eventually lead to a simpler treatment that prevent shepatic damage at a much earlier stage, according to researchers led by M. Bishr Omary, MD, PhD, a professor in the Center for Advanced Biotechnology and Medicine and Robert Wood Johnson Medical School at Rutgers University in Piscataway, New Jersey.
Reporting in Cellular and Molecular Gastroenterology and Hepatology, the investigators found that chlorcyclizine reduced PP-IX levels. EPP is caused by mutations leading to deficiency of the enzyme ferrochelatase, which inserts iron into PP-IX to generate heme. The resulting condition is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. “Despite available drugs that address photosensitivity, the treatment of EPP-related liver disease remains an unmet need,” Omary and colleagues wrote.
The Study
In order to trigger PP-IX overproduction and accumulation, the investigators administered delta-aminolevulinic acid and deferoxamine to zebrafish. These freshwater tropical fish share many physiological characteristics with humans and have been used to model human disease and develop drugs. Furthermore, these fish are transparent at the larval stage, allowing quantification and visualization of porphyrin, which is fluorescent.
The researchers had screened some 2500 approved and bioactive compounds and identified chlorcyclizine as a potent PP-IX–lowering agent.
High-throughput compound screening of ALA + DFO-treated zebrafish found that the HH-1 blocker reduced zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes, transgenic mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine.
Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and quantitative polymerase chain reaction.
Chlorcyclizine-treated zebrafish larvae as well as the two types of mice all showed reduced hepatic PP-IX levels compared with controls. While the neurotransmitter played an important role in PP-IX accumulation in porphyrin-stressed hepatocytes, blockading notably decreased PP-IX levels.
Detailed analysis showed that chlorcyclizine appeared to work through multiple mechanisms, helping the liver clear toxic porphyrin buildup and reducing inflammation. It also decreased the presence of histamine-producing mast cells. The result was less liver injury, decreased porphyrin-triggered protein aggregation and oxidation, and increased clearance of s PP-I in stool.
Interestingly, in both mouse models, chlorcyclizine lowered PP-IX levels in female but not male mice in liver, erythrocytes, and bone marrow. This sex-specific effect appeared to be related to the greater speed at which male murines metabolize the drug, the authors explained in a news release. In rats, for example, the metabolism of chlorcyclizine is 8 times higher in male than in female livers.
The investigators plan to launch a clinical trial in EPP patients to evaluate the effectiveness of chlorcyclizine for both liver and skin involvement. And a phase 2 trial is already underway testing the antacid cimetidine for treating EPP skin manifestations. It is possible that the different antihistamines may act additively or synergistically.
This work was supported by National Institutes of Health (NIH) grants and the Henry and Mala Dorfman Family Professorship of Pediatric Hematology/Oncology.
Omary is a member of the NIH/National Institute of Diabetes and Digestive and Kidney Diseases Data and Safety Monitoring Board of the Porphyrias Consortium.
A provisional patent application has been submitted for the use of H1-receptor blockers with or without receptor blockers to treat protoporphyrias associated with PP-IX accumulation.
Mutations in the ferrochelatase (FECH) gene cause erythropoietic porphyria. EPP is characterized biochemically by liver and bone marrow accumulation of protoporphyrin-IX (PP-IX), and is characterized clinically by hepatic dysfunction with progression in 1-4% to advanced liver disease.
A recent study by Kuo and colleagues exemplifies a bench-to-bedside evolution comprising pharmacological screening, mechanistic dissection, and ultimately translation of this mechanism to human subjects to treat EPP. They utilized high-throughput compound screening in a zebrafish model to identify the anti-histamine, chlorcyclizine (CCZ), as a candidate EPP therapy. Chlorciclizine lowered hepatocyte PP-IX in multiple EPP models by blocking peripheral histamine production, and by inducing hepatocyte PP-IX efflux. The data represent advances in the realms of both clinical therapeutics and molecular pathophysiological discovery.
From a discovery standpoint, strategic compound screening that utilizes the LOPAC (library of pharmaceutically active compounds) and Prestwick libraries offers at least two key characteristics. First, these compounds have largely known targets. The known pharmacology of chlorcyclizine provided immediate clues to validate mechanism rapidly in hepatic HPP, a relatively poorly understood disease. Moreover, screening libraries comprising FDA-approved drugs can minimize lag time between discovery and translation to interventional trials in human subjects.
Beyond such strategic discovery considerations, perhaps more exciting is the therapeutic potential for anti-histaminergic therapy to mitigate hepatic manifestations in EPP. Specifically, other porphyrias with hepatic complications have FDA-approved treatments, such as anti-ALAS1 siRNAs to treat acute hepatic porphyria (AHP). No such treatment currently exists for liver dysfunction in EPP, yet CCZ and other histamine-1 receptor blockers hold such promise. Indeed, the H1 inhibitor, cimetidine, is currently in an active phase 2 trial to treat EPP (NCT05020184).
Given the already widespread use of antihistamines to symptomatically treat cutaneous EPP, we may not be too distant from pivoting and deploying readily available H1Bs like cimetidine to treat EPP liver manifestations as well. Given recent data by Kuo and colleagues, such an outcome should not be too far-FECHed.
Brian DeBosch, MD, PhD, is Center Director of the nutrition & molecular metabolism research program, in the Division of Gastroenterology, Hepatology & Nutrition at Indiana University School of Medicine, Indianapolis. He declares no conflicts of interest.
Mutations in the ferrochelatase (FECH) gene cause erythropoietic porphyria. EPP is characterized biochemically by liver and bone marrow accumulation of protoporphyrin-IX (PP-IX), and is characterized clinically by hepatic dysfunction with progression in 1-4% to advanced liver disease.
A recent study by Kuo and colleagues exemplifies a bench-to-bedside evolution comprising pharmacological screening, mechanistic dissection, and ultimately translation of this mechanism to human subjects to treat EPP. They utilized high-throughput compound screening in a zebrafish model to identify the anti-histamine, chlorcyclizine (CCZ), as a candidate EPP therapy. Chlorciclizine lowered hepatocyte PP-IX in multiple EPP models by blocking peripheral histamine production, and by inducing hepatocyte PP-IX efflux. The data represent advances in the realms of both clinical therapeutics and molecular pathophysiological discovery.
From a discovery standpoint, strategic compound screening that utilizes the LOPAC (library of pharmaceutically active compounds) and Prestwick libraries offers at least two key characteristics. First, these compounds have largely known targets. The known pharmacology of chlorcyclizine provided immediate clues to validate mechanism rapidly in hepatic HPP, a relatively poorly understood disease. Moreover, screening libraries comprising FDA-approved drugs can minimize lag time between discovery and translation to interventional trials in human subjects.
Beyond such strategic discovery considerations, perhaps more exciting is the therapeutic potential for anti-histaminergic therapy to mitigate hepatic manifestations in EPP. Specifically, other porphyrias with hepatic complications have FDA-approved treatments, such as anti-ALAS1 siRNAs to treat acute hepatic porphyria (AHP). No such treatment currently exists for liver dysfunction in EPP, yet CCZ and other histamine-1 receptor blockers hold such promise. Indeed, the H1 inhibitor, cimetidine, is currently in an active phase 2 trial to treat EPP (NCT05020184).
Given the already widespread use of antihistamines to symptomatically treat cutaneous EPP, we may not be too distant from pivoting and deploying readily available H1Bs like cimetidine to treat EPP liver manifestations as well. Given recent data by Kuo and colleagues, such an outcome should not be too far-FECHed.
Brian DeBosch, MD, PhD, is Center Director of the nutrition & molecular metabolism research program, in the Division of Gastroenterology, Hepatology & Nutrition at Indiana University School of Medicine, Indianapolis. He declares no conflicts of interest.
Mutations in the ferrochelatase (FECH) gene cause erythropoietic porphyria. EPP is characterized biochemically by liver and bone marrow accumulation of protoporphyrin-IX (PP-IX), and is characterized clinically by hepatic dysfunction with progression in 1-4% to advanced liver disease.
A recent study by Kuo and colleagues exemplifies a bench-to-bedside evolution comprising pharmacological screening, mechanistic dissection, and ultimately translation of this mechanism to human subjects to treat EPP. They utilized high-throughput compound screening in a zebrafish model to identify the anti-histamine, chlorcyclizine (CCZ), as a candidate EPP therapy. Chlorciclizine lowered hepatocyte PP-IX in multiple EPP models by blocking peripheral histamine production, and by inducing hepatocyte PP-IX efflux. The data represent advances in the realms of both clinical therapeutics and molecular pathophysiological discovery.
From a discovery standpoint, strategic compound screening that utilizes the LOPAC (library of pharmaceutically active compounds) and Prestwick libraries offers at least two key characteristics. First, these compounds have largely known targets. The known pharmacology of chlorcyclizine provided immediate clues to validate mechanism rapidly in hepatic HPP, a relatively poorly understood disease. Moreover, screening libraries comprising FDA-approved drugs can minimize lag time between discovery and translation to interventional trials in human subjects.
Beyond such strategic discovery considerations, perhaps more exciting is the therapeutic potential for anti-histaminergic therapy to mitigate hepatic manifestations in EPP. Specifically, other porphyrias with hepatic complications have FDA-approved treatments, such as anti-ALAS1 siRNAs to treat acute hepatic porphyria (AHP). No such treatment currently exists for liver dysfunction in EPP, yet CCZ and other histamine-1 receptor blockers hold such promise. Indeed, the H1 inhibitor, cimetidine, is currently in an active phase 2 trial to treat EPP (NCT05020184).
Given the already widespread use of antihistamines to symptomatically treat cutaneous EPP, we may not be too distant from pivoting and deploying readily available H1Bs like cimetidine to treat EPP liver manifestations as well. Given recent data by Kuo and colleagues, such an outcome should not be too far-FECHed.
Brian DeBosch, MD, PhD, is Center Director of the nutrition & molecular metabolism research program, in the Division of Gastroenterology, Hepatology & Nutrition at Indiana University School of Medicine, Indianapolis. He declares no conflicts of interest.
An experimental study in zebrafish has suggested the decades-old, first-generation antihistamine chlorcyclizine and/or other antihistamines may be a strategy for treating erythropoietic protoporphyria (EPP)-associated liver disease by decreasing hepatic protoporphorin IX (PP-IX) accumulation.
Currently, liver transplantation is the primary treatment for this rare, painful, and life-threatening genetic disease, which is caused by excessive PP-IX accumulation and affects about 4000 people in the United States.
The findings could eventually lead to a simpler treatment that prevent shepatic damage at a much earlier stage, according to researchers led by M. Bishr Omary, MD, PhD, a professor in the Center for Advanced Biotechnology and Medicine and Robert Wood Johnson Medical School at Rutgers University in Piscataway, New Jersey.
Reporting in Cellular and Molecular Gastroenterology and Hepatology, the investigators found that chlorcyclizine reduced PP-IX levels. EPP is caused by mutations leading to deficiency of the enzyme ferrochelatase, which inserts iron into PP-IX to generate heme. The resulting condition is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. “Despite available drugs that address photosensitivity, the treatment of EPP-related liver disease remains an unmet need,” Omary and colleagues wrote.
The Study
In order to trigger PP-IX overproduction and accumulation, the investigators administered delta-aminolevulinic acid and deferoxamine to zebrafish. These freshwater tropical fish share many physiological characteristics with humans and have been used to model human disease and develop drugs. Furthermore, these fish are transparent at the larval stage, allowing quantification and visualization of porphyrin, which is fluorescent.
The researchers had screened some 2500 approved and bioactive compounds and identified chlorcyclizine as a potent PP-IX–lowering agent.
High-throughput compound screening of ALA + DFO-treated zebrafish found that the HH-1 blocker reduced zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes, transgenic mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine.
Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and quantitative polymerase chain reaction.
Chlorcyclizine-treated zebrafish larvae as well as the two types of mice all showed reduced hepatic PP-IX levels compared with controls. While the neurotransmitter played an important role in PP-IX accumulation in porphyrin-stressed hepatocytes, blockading notably decreased PP-IX levels.
Detailed analysis showed that chlorcyclizine appeared to work through multiple mechanisms, helping the liver clear toxic porphyrin buildup and reducing inflammation. It also decreased the presence of histamine-producing mast cells. The result was less liver injury, decreased porphyrin-triggered protein aggregation and oxidation, and increased clearance of s PP-I in stool.
Interestingly, in both mouse models, chlorcyclizine lowered PP-IX levels in female but not male mice in liver, erythrocytes, and bone marrow. This sex-specific effect appeared to be related to the greater speed at which male murines metabolize the drug, the authors explained in a news release. In rats, for example, the metabolism of chlorcyclizine is 8 times higher in male than in female livers.
The investigators plan to launch a clinical trial in EPP patients to evaluate the effectiveness of chlorcyclizine for both liver and skin involvement. And a phase 2 trial is already underway testing the antacid cimetidine for treating EPP skin manifestations. It is possible that the different antihistamines may act additively or synergistically.
This work was supported by National Institutes of Health (NIH) grants and the Henry and Mala Dorfman Family Professorship of Pediatric Hematology/Oncology.
Omary is a member of the NIH/National Institute of Diabetes and Digestive and Kidney Diseases Data and Safety Monitoring Board of the Porphyrias Consortium.
A provisional patent application has been submitted for the use of H1-receptor blockers with or without receptor blockers to treat protoporphyrias associated with PP-IX accumulation.
An experimental study in zebrafish has suggested the decades-old, first-generation antihistamine chlorcyclizine and/or other antihistamines may be a strategy for treating erythropoietic protoporphyria (EPP)-associated liver disease by decreasing hepatic protoporphorin IX (PP-IX) accumulation.
Currently, liver transplantation is the primary treatment for this rare, painful, and life-threatening genetic disease, which is caused by excessive PP-IX accumulation and affects about 4000 people in the United States.
The findings could eventually lead to a simpler treatment that prevent shepatic damage at a much earlier stage, according to researchers led by M. Bishr Omary, MD, PhD, a professor in the Center for Advanced Biotechnology and Medicine and Robert Wood Johnson Medical School at Rutgers University in Piscataway, New Jersey.
Reporting in Cellular and Molecular Gastroenterology and Hepatology, the investigators found that chlorcyclizine reduced PP-IX levels. EPP is caused by mutations leading to deficiency of the enzyme ferrochelatase, which inserts iron into PP-IX to generate heme. The resulting condition is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. “Despite available drugs that address photosensitivity, the treatment of EPP-related liver disease remains an unmet need,” Omary and colleagues wrote.
The Study
In order to trigger PP-IX overproduction and accumulation, the investigators administered delta-aminolevulinic acid and deferoxamine to zebrafish. These freshwater tropical fish share many physiological characteristics with humans and have been used to model human disease and develop drugs. Furthermore, these fish are transparent at the larval stage, allowing quantification and visualization of porphyrin, which is fluorescent.
The researchers had screened some 2500 approved and bioactive compounds and identified chlorcyclizine as a potent PP-IX–lowering agent.
High-throughput compound screening of ALA + DFO-treated zebrafish found that the HH-1 blocker reduced zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes, transgenic mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine.
Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and quantitative polymerase chain reaction.
Chlorcyclizine-treated zebrafish larvae as well as the two types of mice all showed reduced hepatic PP-IX levels compared with controls. While the neurotransmitter played an important role in PP-IX accumulation in porphyrin-stressed hepatocytes, blockading notably decreased PP-IX levels.
Detailed analysis showed that chlorcyclizine appeared to work through multiple mechanisms, helping the liver clear toxic porphyrin buildup and reducing inflammation. It also decreased the presence of histamine-producing mast cells. The result was less liver injury, decreased porphyrin-triggered protein aggregation and oxidation, and increased clearance of s PP-I in stool.
Interestingly, in both mouse models, chlorcyclizine lowered PP-IX levels in female but not male mice in liver, erythrocytes, and bone marrow. This sex-specific effect appeared to be related to the greater speed at which male murines metabolize the drug, the authors explained in a news release. In rats, for example, the metabolism of chlorcyclizine is 8 times higher in male than in female livers.
The investigators plan to launch a clinical trial in EPP patients to evaluate the effectiveness of chlorcyclizine for both liver and skin involvement. And a phase 2 trial is already underway testing the antacid cimetidine for treating EPP skin manifestations. It is possible that the different antihistamines may act additively or synergistically.
This work was supported by National Institutes of Health (NIH) grants and the Henry and Mala Dorfman Family Professorship of Pediatric Hematology/Oncology.
Omary is a member of the NIH/National Institute of Diabetes and Digestive and Kidney Diseases Data and Safety Monitoring Board of the Porphyrias Consortium.
A provisional patent application has been submitted for the use of H1-receptor blockers with or without receptor blockers to treat protoporphyrias associated with PP-IX accumulation.
From Cellular and Molecular Gastroenterology and Hepatology