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J Hepatol. 2016 Oct;65(4):776-783. doi: 10.1016/j.jhep.2016.05.012. Epub 2016 May 17.

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

Author information

1
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.
2
Gene therapy and regulation of Gene Expression Program, Centro de Investigación Médica Aplicada, Universidad de Navarra, Avda. Pio XII 55, Pamplona 31008, Spain.
3
DIGNA BIOTECH S.L. C/Boix y Morer 6-8°, Madrid 28003, Spain.
4
UniQure biopharma B.V., Meibegdreef 61, 1105 BA Amsterdam, The Netherlands.
5
National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
6
Radiology, Clínica Universidad de Navarra, Avda. Pio XII 36, Pamplona 31008, Spain.
7
Porphyria Centre Sweden, Karolinska University Hospital, Stockholm, Sweden.
8
Centro de Investigación del Hospital Universitario 12 de Octubre, Avda. de Cordoba Km 54, Madrid 28041, Spain.
9
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.
10
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.
11
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.

Abstract

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.

CONCLUSIONS:

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.

LAY SUMMARY:

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.

CLINICAL TRIAL NUMBER:

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.

KEYWORDS:

AAV/PBGD; Acute intermittent porphyria; Adeno-associated virus; Gene therapy

PMID:
27212246
DOI:
10.1016/j.jhep.2016.05.012
[Indexed for MEDLINE]
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