title: Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  rAAV2/5-PBGD administration is safe but AIP metabolic correction was not achieved at the doses tested in this trial. Notwithstanding, the treatment had a positive impact in clinical outcomes in most patients.
  
  
  
  Studies in an acute intermittent porphyria (AIP) animal model have shown that gene delivery of PBGD to hepatocytes using an adeno-associated virus vector (rAAV2/5-PBG) prevent mice from suffering porphyria acute attacks. In this phase I, open label, dose-escalation, multicenter clinical trial we show that the administration of rAAV2/5-PBGD to patients with severe AIP is safe but metabolic correction was not achieved at the doses tested; the treatment, however, had a positive but heterogeneous impact on clinical outcomes among treated patients and 2 out of 8 patients have stopped hematin treatment.
  
  
  
  The observational phase was registered at Clinicaltrial.gov as NCT 02076763. The interventional phase study was registered at EudraCT as n° 2011-005590-23 and at Clinicaltrial.gov as NCT02082860.
authors.affiliation: Liver Unit, Clínica Universidad de Navarra, Avda. Pio XII 36, Pamplona 31008, Spain; Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (Ciberehd), Liver Unit, Clínica Universidad de Navarra, Avda. Pio XII 36, Pamplona 31008, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain.
authors.forename: Delia
authors.initials: D
authors.lastname: D'Avola
authors.affiliation: Gene therapy and regulation of Gene Expression Program, Centro de Investigación Médica Aplicada, Universidad de Navarra, Avda. Pio XII 55, Pamplona 31008, Spain.
authors.forename: Esperanza
authors.initials: E
authors.lastname: López-Franco
authors.affiliation: Liver Unit, Clínica Universidad de Navarra, Avda. Pio XII 36, Pamplona 31008, Spain; Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (Ciberehd), Liver Unit, Clínica Universidad de Navarra, Avda. Pio XII 36, Pamplona 31008, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain.
authors.forename: Bruno
authors.initials: B
authors.lastname: Sangro
authors.affiliation: DIGNA BIOTECH S.L. C/Boix y Morer 6-8°, Madrid 28003, Spain.
authors.forename: Astrid
authors.initials: A
authors.lastname: Pañeda
authors.affiliation: UniQure biopharma B.V., Meibegdreef 61, 1105 BA Amsterdam, The Netherlands.
authors.forename: Nadina
authors.initials: N
authors.lastname: Grossios
authors.affiliation: National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Gil-Farina
authors.affiliation: Radiology, Clínica Universidad de Navarra, Avda. Pio XII 36, Pamplona 31008, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Benito
authors.affiliation: UniQure biopharma B.V., Meibegdreef 61, 1105 BA Amsterdam, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Twisk
authors.affiliation: DIGNA BIOTECH S.L. C/Boix y Morer 6-8°, Madrid 28003, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Paz
authors.affiliation: DIGNA BIOTECH S.L. C/Boix y Morer 6-8°, Madrid 28003, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Ruiz
authors.affiliation: National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: UniQure biopharma B.V., Meibegdreef 61, 1105 BA Amsterdam, The Netherlands.
authors.forename: Harald
authors.initials: H
authors.lastname: Petry
authors.affiliation: Porphyria Centre Sweden, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Pauline
authors.initials: P
authors.lastname: Harper
authors.affiliation: Centro de Investigación del Hospital Universitario 12 de Octubre, Avda. de Cordoba Km 54, Madrid 28041, Spain.
authors.forename: Rafael Enríquez
authors.initials: RE
authors.lastname: de Salamanca
authors.affiliation: Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (Ciberehd), Liver Unit, Clínica Universidad de Navarra, Avda. Pio XII 36, Pamplona 31008, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain; Hepatology Program, Centro de Investigación Médica Aplicada, Universidad de Navarra, Avda. Pio XII 55, Pamplona 31008, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Fontanellas
authors.affiliation: Liver Unit, Clínica Universidad de Navarra, Avda. Pio XII 36, Pamplona 31008, Spain; Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (Ciberehd), Liver Unit, Clínica Universidad de Navarra, Avda. Pio XII 36, Pamplona 31008, Spain; Gene therapy and regulation of Gene Expression Program, Centro de Investigación Médica Aplicada, Universidad de Navarra, Avda. Pio XII 55, Pamplona 31008, Spain. Electronic address: jprieto@unav.es.
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain; Gene therapy and regulation of Gene Expression Program, Centro de Investigación Médica Aplicada, Universidad de Navarra, Avda. Pio XII 55, Pamplona 31008, Spain. Electronic address: ggasegui@unav.es.
authors.forename: Gloria
authors.initials: G
authors.lastname: González-Aseguinolaza
mesh_terms: D000622:Aminolevulinic Acid; D000818:Animals; D015316:Genetic Therapy; D006801:Humans; D011163:Hydroxymethylbilane Synthase; D051379:Mice; D017118:Porphyria, Acute Intermittent
chemical_list: D000622:Aminolevulinic Acid; D011163:Hydroxymethylbilane Synthase
keywords: AAV/PBGD; Acute intermittent porphyria; Adeno-associated virus; Gene therapy