Optimalisering: A corrective therapy for acute intermittent porphyria

Acute intermittent porphyria (AIP) is an inherited metabolic disease that causes symptoms related to the gastrointestinal and nervous systems and where the symptoms usually require hospitalization. The disease can also cause serious long-term complications such as liver cancer and kidney failure. AIP is caused by a defect in the gene that encodes an enzyme, i.e. a biological catalyst, called hydroxymethylbilan synthase (HMBS). HMBS is essential for the formation of heme - a molecule that is vital for humans because, among other things, it transports oxygen in the blood and is involved in detoxification reactions in the liver. In AIP, HMBS has impaired function in the liver, which leads to the precursors of heme accumulating and giving the symptoms we see in AIP. There are currently few good treatment options for AIP, and preventive treatment that prevents the disease from ever developing does not exist. We therefore want to develop a preventive and simple treatment for AIP using small molecules called pharmacological chaperones that work by stabilizing and correcting enzymes such as HMBS. Our research team is recognized for our expertise in the discovery and commercial development of pharmacological chaperones for congenital metabolic diseases. In the project, we have developed methods to look at the effect of such small molecules and have tested the activity and effect of these in cells and mice that have impaired HMBS function. Using this, we have identified and patented molecules that increase the amount of HMBS in cells and in mice that have AIP. Our results provide important knowledge in the way of developing candidates for preventive treatment at AIP. The research team from the University of Bergen, the National Competence Center for Porphyria Diseases (NAPOS) and the French Porphyria Center have also contributed to a greater understanding of the normal pathways affected by the disease, and the project is further strengthened through direct patient involvement. A preventive treatment against AIP could help to avoid the development of symptoms and long-term complications and thus provide better health and increased quality of life for AIP patients and their families.

Behandling av AIP med farmakologiske chaperoner har et stort markedspotensial og fordeler sammenliknet med nåværende standardbehandling. I dette prosjektet har vi forbedret molekylene som stabiliserer HMBS, og fått bedre kunnskap om mutanters effekt på enzymet og muligheten til å kategorisere mutantene bedre. Dette bidrar til forståelsen av genotype-fenotyperelasjonen i AIP, og vil være med på å danne grunnlaget for analyse av sykdomsmekanismer på molekylært nivå i PredPor-studiet og til bedre klassifisering av pasientene i den Norsk Porfyriregister Biobank (ved Haukelandsuniversitets sykehus). Til sammen vil dette gi en bedre klassifisering av pasienter og muligheten for bedre tilpasset behandling. Ved å identifisere subklasser av AIP-pasienter, kan nåværende og framtidig behandling tilpasses bedre, og det vil ha stor betydning for enkeltindivider og med hensyn til bruk av helseressurser.

Acute intermittent porphyria (AIP) is a dominantly inherited genetic disease caused by mutations in the gene coding for the enzyme hydroxymethylbilane synthase (HMBS), which is involved in the synthesis of heme. In AIP the mutated gene results in a defective protein with incorrect folding. As heme has many functions in human, such as essential oxygen transport in blood, AIP is a serious disease. Defective HMBS causes an accumulation of the heme building blocks (ALA and PBG), which are toxic to the nervous system and triggers acute life-threatening neuropsychiatric attacks. There are currently limited treatment options for AIP patients with recurrent attacks, as well as a strong unmet need for new therapeutic alternatives. Pharmacological chaperones (PCs) represent a novel therapeutic approach to correct the enzyme defect. Our team will develop a PC-based therapy for AIP, and initiate an expert hit-to-lead expansion and optimization leading to potent and optimal lead molecule candidates. A new prophylactic drug in the AIP market will considerably lower the burden of the disease for patients and patient families, which we hope to futher develop through the course of the project.