7205: Measuring the Effects of Isoniazid Treatment on Erythrocyte and Plasma Protoporphyrin IX Concentration in Patients with Erythropoietic Protoporphyria

Study Summary

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.