Treatment of the underlying cause of erythropoietic protoporphyria (EPP) made a big leap forward, as reported by two groups of Swiss scientists based in Zurich. In over 97 % of ferrochelatase-deficient EPP patients, misregulation of the “healthy” copy of the gene for ferrochelatase reduces the overall enzyme activity below a threshold that causes the phototoxic heme precursor protoporphyrin IX to accumulate in the body (Gouya et al. 2002). Earlier results by a French group of scientists from Paris demonstrated that the misregulation can be reversed by treating cells of EPP patients grown in culture with short, specific DNA strands, so called “splice switching oligonucleotides”, which favorably modulate the splicing process of the genetic intermediary, called “messenger RNA”, responsible for the production of ferrochelatase (Oustric et al. 2014). However, the main obstacle in treating EPP patients with these kinds of therapeutics was to deliver the compounds into the main site of protoporphyrin IX production, the developing red blood cells located in the bone marrow. By changing the chemical composition of the splice switching oligonucleotide and coupling it to molecules that facilitate uptake by the bone marrow, the Swiss research groups could demonstrate delivery of the compounds to the bone marrow in an EPP mouse model. The mouse had been previously developed by the two groups and carries the same misregulation in the ferrochelatase gene as found in human EPP patients (Barman-Aksözen et al. 2017). Importantly, highly efficient correction of the misregulation of the ferrochelatase gene could also be demonstrated in the red blood cells of the mouse model. The study is therefore a proof-of-concept for a new, causative treatment option for EPP, which one day could broaden the available therapeutic alternatives to address this life-limiting condition.
The project is a collaboration between the municipal hospital Zurich (Swiss center for expertise for porphyrias) and the Swiss Federal Institute of Technology in Zurich and funded by the Swiss National Science Foundation as part of a National Centre of Competence in Research (NCCR) grant.
Delivery of oligonucleotides to bone marrow to modulate ferrochelatase splicing in a mouse model of Erythropoietic Protoporphyria: Halloy, F., Iyer, P. S., Ćwiek, P., Ghidini, A., Barman-Aksözen, J., Wildner-Verhey van Wijk, N., … & Hall, J. (2020). Nucleic Acids Research.