Story of discovery: porphyrias research
Decades of scientific research discoveries have advanced understanding of and care for a group of potentially severe and debilitating disorders called porphyrias. These advances include the identification of genetic factors underlying many of its forms, development of animal models for exploring these genetic factors and other contributors, and continuing findings from collaborative, large-scale clinical research on these rare disorders. In recent years, this research progress has led to new treatments, meaning that some forms of these disorders—recognized since ancient times—are now treatable. One major driver of this progress has been the NIDDK and its support of research on liver and hematologic (blood) diseases, particularly the Porphyrias Consortium, as well as many additional research studies conducted by investigators across the United States.
A Rare and Varied Set of Disorders
Derived from the Greek word for purple, porphyrias were so named for the unusual reddish-purple color of urine when exposed to sunlight in samples from people with this condition. Some have speculated that major historical figures such as King George III may have had a form of this disorder. Porphyrias result from an overabundance of heme precursors originating in the liver or bone marrow, where red blood cells are produced. Heme is the red, iron-rich component of the hemoglobin proteins used by red blood cells to deliver oxygen to cells throughout the body, and heme is also found in liver proteins called cytochromes that break down hormones, medications, and other chemicals. The heme precursors, called porphyrins, are essential for heme production, but they can also be toxic to tissue in high concentrations.
Porphyrias are typically inherited, due to a genetic variant in any one of several enzymes within the multi-step pathway that transforms biochemicals into heme. The altered enzymatic function causes buildup of in the liver or bone marrow. This results in the various forms of porphyria, which can be divided into two broad categories: “acute” and “cutaneous.” The acute forms include acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and aminolevulinic acid dehydratase deficiency porphyria (ADP). These are marked mainly by sudden attacks of stomach pain that can be severe and persist for many days, as well as pain in the chest, limbs, or back; nausea, vomiting, or constipation; urinary retention; confusion, hallucinations, or seizures; and muscle weakness. Some acute forms disproportionately affect certain groups of people; for example, AIP is more common in women of reproductive age, with severe abdominal pain attacks related to hormonal changes during the menstrual cycle. The cutaneous forms of porphyria, which include hepatoerythropoietic porphyria (HEP), congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLP), and porphyria cutanea tarda (PCT), are associated with skin issues, such as blistering, itching, swelling, scarring, pain, or redness upon exposure to sunlight. Each of these disorders can profoundly compromise quality of life, often beginning in early childhood, due to pain or the need to avoid the sun or wear sun-protective clothing over the entire body and face, to avoid potentially disfiguring tissue damage. PCT is the most common form of the disorder found in the United States, and can be triggered by factors such as excessive iron accumulation from the diet, heavy alcohol use, taking certain drugs containing estrogen, smoking, and as a complication of infection with the hepatitis C or HIV viruses.
Diagnosing porphyrias is based on clinical symptoms and high levels of porphyrins in the blood, stool, or urine, but can be challenging because these disorders are rare and the symptoms overlap with other conditions, which often results in missed or incorrect diagnoses. Treatment depends on the specific form of porphyria, but may involve use of heme-based or glucose treatments that reduce porphyrin production in the liver; liver transplantation; avoiding sunlight as much as possible; removal of some blood (therapeutic phlebotomy); and medications, including pain relievers. Genetic testing may also be used to confirm a particular inherited form of porphyria and determine appropriate care, for individuals and their potentially affected family members.
Research Advances in Understanding and Managing Porphyrias
NIDDK-sponsored efforts helped lay the groundwork for understanding the underlying mechanisms and clinical symptoms of porphyrias and developing diagnostic tests and treatments. In the 1980s, researchers capitalized on the unique fluorescent properties of porphyrins to identify diagnostic plasma markers for forms of porphyria such as VP. Also during this time, researchers documented responses in individual patients to treatments for CEP, such as oral activated charcoal to lower porphyrin levels or continuous blood transfusions to suppress red cell production. Building on findings supported by others to develop a form of heme called hematin as a therapy for acute porphyrias, and its U.S. Food and Drug Administration (FDA) approval in 1983, the NIDDK sponsored continuing research in the 1990s to further develop this treatment.
NIDDK research in the 1980s to 1990s helped to test the use of liver transplantation to treat people with some forms of porphyria, sometimes in combination with a pre-treatment to lower blood porphyrin levels, such as hematin or plasmapheresis (a procedure involving removal, treatment, and reinfusion of blood plasma). Research at this time also aimed to understand the burden of porphyrias in the population, such as studies in the 1990s documenting mortality in people with AIP and characterizing PCT and its risk factors, including hereditary hemochromatosis gene mutations and hepatitis C infection. Advances in recent decades demonstrated the influence of factors, such as nutrition, alcohol use, and smoking, on heme biosynthesis and their impacts on different forms of porphyria.
In parallel with, and supportive of, these advancing clinical efforts, NIDDK-supported researchers helped map out the intricate pathway of heme biosynthesis, identifying the key enzymes that catalyze reactions at multiple steps to convert porphyrins into heme. Scientists supported by the Institute also identified and sequenced some of the genes that encode enzymes of the heme synthetic pathway, and helped to define numerous genetic mutations associated with different forms of porphyria. For example, in the 1980s, scientists purified the enzyme that is impaired in CEP and isolated the gene encoding it. A study in 1990 identified the gene coding for the enzyme at the first step in the heme biosynthetic pathway, delta-aminolevulinic acid synthase 1 (ALAS1)—mutations in which are responsible for some of the acute hepatic porphyrias—from human liver samples. Studies in the 1980s and 1990s also characterized and purified the enzyme underlying PCT and HEP, including multi-generational family genetic studies that shed light on relationships between genetic traits, enzyme activity, and clinical symptoms. In the 1990s to 2000s, through several studies in animal models and people, researchers identified the genetic mutations responsible for the symptoms of EPP in the final enzyme within the heme biosynthetic pathway that result in reduced enzymatic activity. Throughout the 1990s, researchers continued to identify mutated forms of genes coding for enzymes responsible for other forms of porphyria, such as ADP and HCP. Later studies provided additional insights into these enzymes, including their structures—key information for understanding their functioning and role in disease processes. In 2005, the NIDDK initiated support for a Center for Excellence in Molecular Hematology that enabled additional discoveries about the molecular mechanisms in the porphyrias, including clues to the underlying pathways involved in PCT. Further genetic discoveries, related to EPP and XLP, were made by the Porphyrias Consortium, described below.
Scientists have utilized this explosion of new knowledge about the genetic factors underlying each of the porphyrias to develop unique animal models in which to study disease pathways and processes, as well as to test new treatments. For example, in 1998, researchers developed a zebrafish model with a mutated form of the gene associated with HEP in humans, followed soon after by mouse models with the genetic mutations and symptoms present in PCT, VP, and CEP. In 2010, a research group used a mouse model with a genetic mutation causing AIP to successfully test a corrective gene therapy approach using a viral vector to target cells in the liver. A more recent mouse model of an AIP subtype that causes early-onset neurological impairment revealed mechanisms behind this severe form of the disorder. Researchers developed mouse models with distinct genetic mutations associated with different severities of human CEP to further understanding of these disorder subtypes.
The Porphyrias Consortium
In 2009, building upon these decades of basic and clinical research, the NIH’s Rare Diseases Clinical Research Network announced the establishment of the Porphyrias Consortium. The Consortium is supported by the NIDDK and the NIH’s National Center for Advancing Translational Sciences, in collaboration with the American Porphyria Foundation. The present-day Consortium includes six centers in the United States and other satellite sites, which bring together scientists, patient advocates, and industry to address the current challenges in porphyria research by conducting collaborative, large-scale clinical studies on these rare disorders. The Consortium’s multiple centers, covering several geographical areas, help researchers recruit enough participants with these rare disorders for robust studies. The Consortium also focuses on training the next generation of clinicians and investigators in porphyria care and research, and provides information on porphyrias for patients and their families, health care professionals, and the public.
The Consortium has conducted several studies aimed at understanding the mechanisms and disease course of the multiple forms of porphyria and developing new approaches to their diagnosis, treatment, and prevention. In 2014, the Consortium reported on early observational findings in their U.S.-based study cohort, describing the key clinical and genetic features and current approaches to clinical care for acute porphyrias—including AIP, HCP, and VP—and documenting an average delayed diagnosis of more than a decade. In 2015, researchers reported variability in how different clinical laboratories were measuring red blood cell protoporphyrin, a molecule derived from porphyrin during heme production, that can lead to missed diagnoses, particularly for the EPP and XLP forms of porphyria. Results of a Consortium study in 2017 helped to identify the genetic mutations present in people with EPP and XLP and showed that higher levels of red blood cell protoporphyrin were associated with increased disease severity and risk of liver dysfunction. In addition to these original studies, the Consortium has also issued recommendations for the diagnosis, treatment, and counseling of patients with acute porphyrias that originate in the liver, to ensure optimal health outcomes.
Progress Toward New Treatments
The decades of research advances on the porphyrias and the ongoing efforts of investigators involved in the Porphyrias Consortium have helped develop breakthrough treatments for two forms of porphyria—AIP and EPP. NIDDK-supported studies mapping out the biological pathways involved in these disorders provided the foundation for this work.
In the case of AIP, a disease marked by severe abdominal pain attacks and fatigue, the main treatment since the 1970s has been intravenous infusions with hematin, containing heme extracted from red blood cells. However, this treatment proved relatively slow-acting and came with side effects such as inflammation in the veins and iron overload. In recent years, the NIDDK and other NIH Institutes supported research on a cutting-edge approach to therapeutics called RNA interference (RNAi) using small interfering RNAs (siRNAs)—short strings of genetic material that effectively turn off genes that produce disease-causing proteins. Research in a mouse model supported through the Porphyrias Consortium showed that this approach could be used to target ALAS1, an overactive enzyme in AIP: an infusion of the siRNA inhibiting this enzyme effectively prevented and treated the attacks associated with AIP. The NIDDK also supported early pre-clinical research to develop an injection-based form of the treatment and assays that monitored response. This important work paved the way for testing this therapeutic in humans as part of clinical trials sponsored by a pharmaceutical company, with the participation of many scientists and centers within the Porphyrias Consortium. In November 2019, the FDA approved this new therapeutic for AIP in the form of a drug called givosiran (Givlaari®), which is already improving quality of life for people with AIP.
The Porphyrias Consortium also worked closely with another pharmaceutical company on a clinical trial to evaluate a treatment for EPP, called afamelanotide (Scenesse®). Afamelanotide binds to a receptor in skin cells, stimulating them to produce a pigment that protects against sunlight. In clinical trials conducted by the pharmaceutical company in the United States and Europe, with additional support from the NIDDK and the NIH’s National Heart, Lung, and Blood Institute, Consortium investigators worked closely with the company to evaluate the safety and efficacy of an implant under the skin containing afamelanotide for treating EPP. These trials found afamelanotide increased the amount of pain-free time people with EPP could spend in sunlight, as well as their overall quality of life. The treatment was approved by the FDA in October 2019—the first agent available to help people with EPP experience pain-free sun exposure.
Building on the past progress made possible by the Porphyrias Consortium and other NIDDK-supported investigators, the Institute is committed to continuing support for research to advance understanding of the porphyrias and discover better ways to manage these disorders. The Consortium is conducting ongoing clinical studies on natural history, diagnosis, and treatments for all forms of porphyria. The Consortium’s active studies include a longitudinal study to characterize the long-term course and outcomes of several forms of porphyria. Ongoing clinical trials will determine the safety and efficacy of new therapies. Recent efforts by the Consortium include characterizing the natural history and clinical management of acute hepatic porphyrias in people with recurrent attacks, evaluating methods for measuring quality of life in people with AIP, and joining together with the European Porphyria Network to establish an international database with diagnostic information on genetic variants linked to all forms of porphyria. In addition to these Consortium-based activities, the NIDDK also continues to support investigator-initiated porphyria research, such as studies in cell and animal models to decipher specific mechanisms of cell injury caused by an overabundance of porphyrins. Together, these research efforts will continue to advance our understanding of porphyrias, and help lead the way to new treatments, with the overarching goal of improving the lives of people with these disorders.
For more information on the Porphyrias Consortium, please visit: www.rarediseasesnetwork.org/cms/porphyrias.