PORPHYRIAS - ANIMAL-MODELS AND PROSPECTS FOR CELLULAR AND GENE-THERAPY

The rapid progress in the development of molecular technology has resu lted in the identification of most of the genes of the heme biosynthes is pathway. Important problems in the pathogenesis and treatment of po rphyrias now seem likely to be solved by the possibility of creating a nimal models and by the transfer of normal genes or cDNAs to target ce lls. Animal models of porphyrias naturally occur for erythropoietic pr otoporphyria and congenital erythropoietic porphyria, and different mu rine models have been or are being created for erythropoietic and hepa tic porphyrias. The PBGD knock-out mouse will be useful for the unders tanding of nervous system dysfunction in acute porphyrias. Murine mode ls of erythropoietic porphyrias are being used for bone-marrow transpl antation experiments to study the features of erythropoietic and hepat ic abnormalities. Gene transfer experiments have been started in vitro to look at the feasibility of somatic gene therapy in erythropoietic porphyrias. In particular, we have documented sufficient gene transfer rate and metabolic correction in different CEP disease cells to indic ate that this porphyria is a good candidate for treatment by gene ther apy in hematopoietic stem cells. With the rapid advancement of methods that may allow more precise and/or efficient gene targeting, gene the rapy will become a new therapeutic option for porphyrias.