Safety and liver transduction efficacy of rAAV5-cohPBGD in nonhuman primates: a potential therapy for acute intermittent porphyria.
Acute intermittent porphyria (AIP) results from haplo-insufficient activity of porphobilinogen deaminase (PBGD) and is characterized clinically by life-threatening, acute neurovisceral attacks. To date, liver transplantation is the only curative option for AIP. The aim of the present preclinical nonhuman primate study was to determine the safety and transduction efficacy of an adeno-associated viral vector encoding PBGD (recombinant AAV serotype 5-codon-optimized human porphobilinogen deaminase, rAAV5-cohPBGD) administered intravenously as part of a safety program to start a clinical study in patients with AIP. Macaques injected with either 1 × 10(13) or 5 × 10(13) vector genomes/kg of clinical-grade rAAV5-cohPBGD were monitored by standardized clinical parameters, and vector shedding was analyzed. Liver transduction efficacy, biodistribution, vector integration, and histopathology at day 30 postvector administration were determined. There was no evidence of acute toxicity, and no adverse effects were observed. The vector achieved efficient and homogenous hepatocellular transduction, reaching transgenic PBGD expression levels equivalent to 50% of the naturally expressed PBGD mRNA. No cellular immune response was detected against the human PBGD or AAV capsid proteins. Integration site analysis in transduced liver cells revealed an almost random integration pattern supporting the good safety profile of rAAV5-cohPBGD. Together, data obtained in nonhuman primates indicate that rAAV5-cohPBGD represents a safe therapy to correct the metabolic defect present in AIP patients.
1 Division of Hepatology and Gene Therapy, Center for Applied Medical Research , 31008 Pamplona, Spain .
Astrid
A
Pañeda
Esperanza
E
Lopez-Franco
Christine
C
Kaeppel
Carmen
C
Unzu
Ana Gloria
AG
Gil-Royo
Delia
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D'Avola
Stuart G
SG
Beattie
Cristina
C
Olagüe
Roberto
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Ferrero
Ana
A
Sampedro
Itsaso
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Mauleon
Stephan
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Hermening
Florence
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Salmon
Alberto
A
Benito
Juan Jose
JJ
Gavira
María Eugenia
ME
Cornet
María
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del Mar Municio
Christof
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von Kalle
Harald
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Petry
Jesus
J
Prieto
Manfred
M
Schmidt
Antonio
A
Fontanellas
Gloria
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González-Aseguinolaza
D000818:Animals; D000229:Dependovirus; D015316:Genetic Therapy; D005822:Genetic Vectors; D057895:Haploinsufficiency / Q000235:genetics*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics* / Q000627:therapeutic use; D008251:Macaca; D017118:Porphyria, Acute Intermittent / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D014018:Tissue Distribution / Q000235:genetics; D014161:Transduction, Genetic
D011163:Hydroxymethylbilane Synthase