Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria

作者：Delia D’Avola, Esperanza López‐Franco, Bruno Sangro, Astrid Pañeda, Nadina Grossios, Irene Gil-Fariña, Alberto Benito, Jaap Twisk, María de la Paz, Juan Ruiz, Manfred Schmidt, Harald Petry, Pauline Harper, Rafael Enrı́quez de Salamanca, Antonio Fontanellas, Jesús Prìeto, Gloria González‐Aseguinolaza · 发表于：Journal of Hepatology · 年份：2016 · DOI：10.1016/j.jhep.2016.05.012 · 被引用次数：144 · 研究领域：Porphyrin Metabolism and Disorders、Neurological diseases and metabolism、Virus-based gene therapy research

BACKGROUND & AIMS: Acute intermittent porphyria (AIP) results from porphobilinogen deaminase (PBGD) haploinsufficiency, which leads to hepatic over-production of the neurotoxic heme precursors porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) and the occurrence of neurovisceral attacks. Severe AIP is a devastating disease that can only be corrected by liver transplantation. Gene therapy represents a promising curative option. The objective of this study was to investigate the safety of a recombinant adeno-associated vector expressing PBGD (rAAV2/5-PBGD) administered for the first time in humans for the treatment of AIP. METHODS: In this phase I, open label, dose-escalation, multicenter clinical trial, four cohorts of 2 patients each received a single intravenous injection of the vector ranging from 5×10(11) to 1.8×10(13) genome copies/kg. Adverse events and changes in urinary PBG and ALA and in the clinical course of the disease were periodically evaluated prior and after treatment. Viral shedding, immune response against the vector and vector persistence in the liver were investigated. RESULTS: Treatment was safe in all cases. All patients developed anti-AAV5 neutralizing antibodies but no cellular responses against AAV5 or PBGD were observed. There was a trend towards a reduction of hospitalizations and heme treatments, although ALA and PBG levels remained unchanged. Vector genomes and transgene expression could be detected in the liver one year after therapy. CONCL...