Porphyrias: Animal models and prospects for cellular and gene therapy

The development over the past decade of methods for delivering genes to mammalian cells has stimulated great interest in the possibility of treating human disease by gene-based therapies. However, despite substantial progress, a number of key technical issues need to be resolved before gene therapy can be safely and effectively applied in the clinic. Future technological developments, particularly in the areas of gene delivery and cell transplantation, will be critical for the successful practice of gene therapy.

The molecular basis of an inherited defect of ferrochelatase in mouse (Fechm1Pas/Fechm1Pas, described by Tutois et al., 1991, J. Clin. Invest. 88:1730-1736) was investigated. cDNA clones encoding ferrochelatase, isolated by amplification of the mRNA from the liver of a mutant mouse using the polymerase chain reaction, were sequenced by the dideoxynucleotide chain-termination method. All the clones carried a T to A transversion at nucleotide 293, leading to a methionine to lysine substitution at position 98 in the protein (mutation M98K). Hybridization with allele-specific oligonucleotides (ASOs) confirmed the mutation at the cDNA and genomic levels. Finally, expression of the mutant ferrochelatase protein in E. coli demonstrated a marked deficiency in activity in agreement with the activity of the deficient enzyme in vivo. This Fechm1Pas/Fechm1Pas mutant mouse represents a useful model for studying the pathophysiological feature of the human disease and the first accessible model for gene therapy in the field of porphyrias.

The case of a woman with protoporphyria who developed liver failure and underwent liver transplantation is described. During the pretransplant episode of liver failure she developed quadriparesis that rapidly progressed after transplantation to a severe polyneuropathy. Following transplantation she also developed a second-degree burn of the light-exposed abdominal wall. The neuropathy resembled that observed in other forms of porphyria, and it is proposed that the extreme disturbance of protoporphyrin levels associated with protoporphyrin-induced liver failure caused this neuropathy. Such a neuropathy has not previously been described in protoporphyria. Erythrocyte protoporphyrin levels remain high and fecal levels normal, although results of liver tests are normal. She remains photosensitive, which emphasizes that although liver transplantation may be lifesaving in this disorder, it is not curative, and care must be taken to prevent photosensitive damage to skin and light-exposed internal organs.