Systemic messenger RNA as an etiological treatment for acute intermittent porphyria复制标题

系统性信使RNA作为急性间歇性卟啉病的病因学治疗

The dominant clinical feature of AIP is acute neurovisceral attacks associated with high production of potentially neurotoxic porphyrin precursors. Symptoms of AIP are heterogeneous and include severe fatigue, abdominal pain, loss of appetite, nausea, vomiting and constipation. Patients may also have trouble sleeping, anxiety, depression, confused states, hypertension and tachycardia. Severe neurological complications also occur, and death may result from respiratory and bulbar paralysis . Current treatments include infusions of hemin (panhematin in the United States and normosang in the European Union, Recordati) and carbohydrate loading. Hemin replacement therapy, which restores the regulatory heme pool in the liver and suppresses ALAS1 induction, is more effective than glucose therapy, which antagonizes hepatic ALAS1 induction , in reducing ALA and PBG accumulation5,8 . Reductions in the levels of ALA and PBG occur 3d after intravenous (i.v.) hemin infusion (3–4mg kg−1day−1 ), and pain and nausea typically resolve on day four . Hemin treatment should therefore be started as soon as the diagnosis is established and monitored through assessments of urinary ALA and/or PBG levels, pain scoring and clinical improvement10. Approximately 5% of patients suffer recurrent attacks, which persist for many years. Recurrent attacks have a marked impact on the quality of life of these patients. Patients usually require hospitalization and strong analgesic treatment, and opiates are often necessary for pain control. Prophylactic hemin is increasingly used for treating chronic symptoms, as an off-label indication of the drug. Of note, repeated courses of this therapy have been shown to generate thromboembolic disease and increased serum ferritin levels, suggesting iron overload in the liver15. Thus, lifelong exposure to hemin replacement therapy for the control of AIP symptoms may cause adverse events.

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