Results of a pilot study of isoniazid in patients with erythropoietic protoporphyria

Publication date: Available online 31 July 2019Source: Molecular Genetics and MetabolismAuthor(s): Charles J. Parker, Robert J. Desnick, Montgomery D. Bissel, Joseph R. Bloomer, Ashwani Singal, Laurent Gouya, Herve Puy, Karl E. Anderson, Manisha Balwani, John D. PhillipsAbstractErythropoietic protoporphyria (EPP), the most common porphyria of childhood and the third most common porphyria of adulthood, is characterized clinically by painful, non-blistering cutaneous photosensitivity. Two distinct inheritance patterns involving mutations affecting genes that encode enzymes of the heme biosynthetic pathway underlie the clinical phenotype. Aminolevulinic acid synthase 2 (ALAS2), the rate limiting enzyme of the heme pathway in the erythron, is a therapeutic target in EPP because inhibiting enzyme function would reduce downstream production of protoporphyrin IX (PPIX), preventing accumulation of the toxic molecule and thereby ameliorating symptoms. Isoniazid (INH) is widely used for treatment of latent and active M. tuberculosis (TB). Sideroblastic anemia is observed in some patients taking INH, and studies have shown that this process is a consequence of inhibition of ALAS2 by INH. Based on these observations, we postulated that INH might have therapeutic activity in patients with EPP. We challenged this hypothesis in a murine model of EPP and showed that, after 4 weeks of treatment with INH, both plasma PPIX and hepatic PPIX were significantly reduced. Next, we tested the effec...
Source: Molecular Genetics and Metabolism - Category: Genetics & Stem Cells Source Type: research