Research Studies

The porphyrias are a group of rare metabolic diseases that may present in childhood or adult life and are due to deficiencies of enzymes in the heme biosynthetic pathway. Porphyrias have various symptoms depending on the type, but these can range from neurological symptoms to sun sensitivity. See the descriptions of each type to get more information. The natural history of these disorders is not well described and it is not known why some patients are more severe than others. Therefore, the purpose of this long-term follow-up study is to collect a large group of patients with the different types of porphyria and to provide a better understanding of the natural history of these disorders. The hope is that this information will help in developing new forms of treatment. The research aims are: 1. To study the prevalence of specific indicators of disease severity. To study the effects on quality of life and health of various porphyrias. 2. To determine the relationships between disease severity and various biological characteristics, genetic information, and environmental factors.

The purpose of this study is to collect information on acute porphyria attacks that may have been caused by a medication. Individuals who have tested positive for an acute porphyria, or have been told by a doctor that they may have the disease may join this study. We are particularly interested in the following: (1) Attacks that appeared to be due to a specific medication; (2) Use of a medication that is considered risky in porphyria but caused no problems; and (3) Use of medications for which the safety profile in porphyria is unknown.

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) result from genetic defects of heme biosynthesis that cause life-long, painful cutaneous sensitivity to light. The objective of this study is to determine the efficacy and safety of oral cimetidine administration for treatment of the protoporphyrias. Efficacy will be based on protoporphyrin levels, photosensitivity, and quality of life questionnaires.

AIP is rare a genetic disorder caused by mutations in the hydroxymethylbilane synthase gene (HMBS) that reduce the function of an enzyme (a type of protein) in the body that is necessary for the production of heme. Heme is important for your body to use oxygen and for your liver to work properly. When a person does not produce enough of this enzyme, substances called ALA and PBG can accumulate, and this can cause symptoms of AIP. These symptoms may include abdominal pain; pain in the arms, legs and back; muscle weakness; nausea and vomiting; and confusion, hallucinations, and seizures. A small portion of AIP patients have recurrent attacks, while many others who have a mutation in the HMBS gene never develop symptoms. The purpose of this research study is to learn more about genetic factors (specific patterns in a gene) that predispose or protect an individual with a change (or mutation) in the gene that causes Acute Intermittent Porphyria (AIP) to develop symptoms.

This study examines the possibility that abnormal expression of the gene mitoferrin-1, which codes for the protein that transports iron in the mitochondria of cells, is a contributing factor to the phenotype in individuals with EPP. Erythropoietic protoporphyria (EPP) is a human genetic/metabolic disorder in which accumulation of the compound protoporphyrin causes skin sensitivity to sunlight. Some individuals with the disorder also have mild anemia, and a few have hepatobiliary disease. Iron is joined to protoporphyrin to form heme in the mitochondria of cells, under control of the enzyme ferrochelatase. Defects in this process cause the accumulation of protoporphyrin, leading to the biochemical and clinical features of EPP. Abnormalities in the ferrochelatase gene are the major cause of the defect, but do not satisfactorily explain the severity of the phenotype in all subjects. Mitoferrin-1 transports iron to ferrochelatase in the mitochondria of cells for heme formation, and also transports iron for the formation of a compound that keeps ferrochelatase active and stable. Thus, a deficiency of this iron transporter could reduce ferrochelatase activity and contribute to the phenotype in EPP.

This study aims to provide high quality evidence for the effectiveness and safety of hemin (PanhematinTM , Recordati) for treatment of acute attacks of porphyria. These types of studies have not been done before with either PanhematinTM or the hemin preparation available in Europe (NormosangTM, Orphan Europe). There are two treatment groups in this study. One group will be treated with PanhematinTM plus glucose, and the other group will be treated with glucose plus an inactive salt solution (called a "placebo"). To avoid prejudice, the treatment given to each participant will be blinded (meaning the participants and most of the hospital staff will not know which treatment the participant will receive) and randomized (meaning participants will have an equal chance of receiving either treatment, like the flip of a coin). A placebo-controlled, randomized study is the standard method used to prove treatments are effective and safe. PanhematinTM and glucose will be given in the same manner as is usual for treating an attack of porphyria. For participants who are chosen to receive the placebo, their treatment will be switched to real PanhematinTM at any time if their symptoms do not improve. This is called "rescue" treatment, and assures that they study is safe and patients who need hemin will receive it. Treatment with hemin will be for 4 days, or longer if needed. Since the study treatment is started as soon as possible after symptoms appear, there will be very little delay in providing hemin to those who need it.

This study will determine if the activity of aminolevulinic acid synthase (ALAS), the first and rate limiting step in heme biosynthesis, can be down-regulated by limiting the available plasma supply of, pyridoxal-5’-phosphate (PLP), an obligate cofactor required for synthesis of ALA by ALAS. Isoniazid, a drug commonly used to treat tuberculosis, binds PLP (a derivative of vitamin B6) forming a hydrazone that is excreted in the urine. The reaction between isoniazid and PLP and the subsequent excretion of the newly formed hydrazone limits the availability of PLP for binding to enzymes including ALAS that require it as a cofactor. We hypothesize that by dampening the activity of ALAS by restricting availability of PLP, isoniazid can be used to ameliorate the symptoms of erythropoietic protoporphyria (EPP) that are a consequence of accumulation of toxic metabolites of the heme biosynthetic pathway. The primary outcome measured in this pilot study will be plasma protoporphyrin, the toxic metabolite that causes the photosensitivity that is the clinical hallmark of EPP. This study will be conducted in patients who have EPP due to inherited genetic mutations either in the ferrochelatase gene or in the gene that encodes the red blood cell form of ALA (ALAS2). EPP is characterized by photosensitivity that is due to excess accumulation of protoporphyrin IX (PPIX), the last intermediate in the heme biosynthetic pathway that is formed prior to incorporation by ferrochelatase (FECH) of iron into the tetrapyrrole ring that results in formation of the heme molecule. Subjects will be given a standard dose of isoniazid (INH), 5 mg/kg up to 300 mg daily in a single dose, to be taken daily for eight weeks, and the effect of this treatment on the concentration of plasma PPIX will be monitored every two weeks for 12 weeks.

Porphyria cutanea tarda (PCT) is the most common human porphyria and the most responsive to treatment. Two very different approaches to therapy are considered effective. Repeated phlebotomy is most widely used, but has disadvantages that include discomfort, inconvenience and expense. A low-dose regimen of the 4-aminoquinoline antimalarial drugs, either hydroxychloroquine or chloroquine, is more convenient and cost-effective but is not widely used as first line therapy. A randomized study with frequent and detailed assessment of efficacy is proposed to compare these treatments. Up to 120 patients with well-documented PCT will be enrolled in this prospective, randomized, unblinded phase 2 noninferiority study comparing treatment by phlebotomy with treatment by low-dose hydroxychloroquine. Sixty will be randomized and those who do not qualify for randomization will be assigned the most appropriate treatment and be followed in a substudy. The study will be conducted under an active IND with the PI as sponsor (IND 66,042). Patients will be characterized in terms of known risk factors for PCT, including ethanol use, smoking, hepatitis C, HIV infection, estrogen use, HFE mutations and autosomal dominant inheritance of a partial deficiency of uroporphyrinogen decarboxylase (UROD) due to UROD mutations (as in familial PCT). Plasma and urine porphyrin concentrations will be measured at 2-week intervals for 6 months. The main measure of efficacy to be compared will be time to achieving a normal plasma porphyrin concentration. Skin manifestations, tolerability of treatment and safety measures will also be followed. It is likely that this study will justify more general use of low-dose hydroxychloroquine and eventually lead to treatment of PCT as an approved indication. Greater acceptance of this approach will lower health care costs and increase the convenience of treating PCT.

The initial objective of this protocol is to assemble a well-documented group of patients with confirmed diagnoses of the erythropoietic protoporphyrias, including autosomal recessive Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP) for clinical, biochemical, and genetic studies. The long-term objectives are (1) to conduct a longitudinal investigation of the natural history, complications, and therapeutic outcomes in people with erythropoietic protoporphyria, (2) to systematically investigate the psychological effects of the erythropoietic protoporphyrias on children and adults, and (3) to investigate the correlation between the identified genotypes and the resulting clinical presentation, also determining the possible interaction of other genetic markers.

This is a clinical trial, which means its purpose is to study an intervention or treatment. In this study all patients with EPP or XLP will be given a standard dose of iron pills and monitored for one year. There is currently no effective Food and Drug Administration (FDA) approved treatment for EPP or XLP in the US. Giving iron to patients with low ferritin (a measure of body iron stores) levels may help improve their EPP symptoms by decreasing erythrocyte protoporphyrin levels. Patients will be asked come to the study site once every three months over the course of a year for a total of five visits. At these visits the study doctors will check in with participants and some blood and urine samples will be taken. Participants will not be charged for any of the lab tests that are being done for part of this study alone. In between these study visits there will be phone call to check in and see how participants are doing. All patients in this study will receive iron pills at no cost to them.

The purpose of this study is to learn if treating patients who have porphyria cutanea tarda (PCT) and hepatitis C (HCV) with Harvoni, a treatment for HCV, will also treat PCT symptoms. This is a clinical trial, which means its purpose is to study an intervention or treatment. In this study all patients with PCT will be given a standard dose of Harvoni and monitored for two years. Currently there are two standard therapies for PCT, phlebotomies (removing certain amounts of blood at specific intervals), or low dose hydroxychloroquine (an oral pill). These treatments are used for patients with PCT whether or not they also have HCV. For patients with HCV however, we do not know whether treating the HCV first will also resolve the PCT symptoms. There will be an initial visit to determine whether participants are eligible to be in the study. If a participant is found to be eligible, he/she will be asked come to the study site once every month over the course of one year, and then once every 3 months for an additional year. There will be approximately 17 visits over the course of the whole study. At these visits the study doctors will check in with the participant and some blood and urine samples will be taken. Participants will not be charged for any of the lab tests that are being done as a part of this study alone. All participants in this study will receive the Harvoni pills at no cost to them.