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Strategy developed to improve symptoms of acute intermittent porphyria in animal models

Researchers at Cima University of Navarra achieve a more effective restoration of the liver deficiency present in this rare disease.

/Researchers from the University of Navarra and CNB-CSIC who participated in the study

24 | 02 | 2022

Six percent of the Spanish population (more than 3 million people) are born with small changes in their genes that cause one of the 7,000 rare diseases recognised by the World Health Organisation. The study of drugs for these patients is a challenge as their leave incidence limits their knowledge and makes it difficult to obtain economic funding to improve their diagnosis and treatment.

Researchers at Cima University of Navarra have developed a strategy that more effectively reduces the symptoms of acute intermittent porphyria in animal models. The results have been published in the scientific journal Science Translational Medicine.

Acute intermittent porphyria is a disease that causes acute attacks of severe fatigue, abdominal pain, nausea and sometimes mobility problems. It is known to be caused by a liver deficiency. "Our work has been to fuse a normal version of the defective protein in this disease (PBGD) with a very common molecule in our blood, apolipoprotein (ApoAI), which is responsible for transporting it to the liver and brain. By administering this combination in mouse models of porphyria, we confirmed that it restores its deficit in the liver and protects against the accumulation of toxic metabolites. As a consequence, it reduces pain and neuropathy, characteristic symptoms of this disease," say Karol Córdoba and Daniel Jericó, pre-doctoral researchers in the Hepatology Programme at Cima and two of the first authors of the study.

This therapy has the advantage that it is easily administered subcutaneously (similar to insulin injection), acts within a few hours and maintains efficacy after repeated administrations in experimental models. "In addition, the fusion of the two molecules prolongs the therapeutic protein in the blood and increases its expression in the liver and brain for more than a month. These characteristics are very attractive for reducing the symptoms of both porphyria and other diseases affecting the liver and central nervous system," says Dr Antonio Fontanellas, director of laboratory of Acute Porphyrias of Cima and researcher of the CIBER in Liver and Digestive Diseases (CIBEREHD).

partnership with Moderna Therapeutics

To develop this strategy, researchers at Cima designed, at partnership with business Moderna Therapeutics, RNA messengers that are transported to the liver in small water-soluble fat droplets (nanolipids) where they produce the therapeutic protein. As Dr Fontanellas explains, 'this technology is famous today thanks to the mRNA-based vaccines against the COVID-19 pandemic, but it is also being tested for cancer and rare disease treatments. At our laboratory we have demonstrated the efficacy and safety of these mRNAs in several models of acute porphyria in mice and large animals".

In subsequent trials, they found that ApoAI-conjugated protein is more stable than unconjugated protein in the liver and can prolong the time of protection against acute seizures in the porphyric mouse. These results open the door to a new line of research to increase the therapeutic effects of drugs by fusing them to ApoAI.

The approach of this work, co-directed by Dr. Pedro Berraondo and Dr. Antonio Fontanellas, has been carried out by a team multidisciplinary of Cima, the University of Navarra, the Clínica Universidad de Navarra and the Proteomics Unit of the National Biotechnology Centre (CNB-CSIC).

→ Recombinant porphobilinogen deaminase targeted to the liver corrects enzymopenia in a mouse model of acute intermittent porphyria. Science Translational Medicine. 2022 Jan 12;14(627):eabc0700. doi: 10.1126/scitranslmed.abc0700. PMID: 35020410.