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

Abstract

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.

Enhanced liver gene transfer and evasion of preexisting humoral immunity with exosome-enveloped AAV vectors

“…Aside from the treatment of hemophilia, this is a potentially attractive feature of exo-AAV, which may be useful for applications like promoterless AAV, 33 or any application of gene transfer in which high levels of hepatocyte targeting are needed. 34 Of note, one advantage of combining exosomes with AAV vectors, as opposed to using exosomes to carry naked plasmid DNA, resides in the long-lived transgene expression that can be obtained with AAV vectors in liver. 2,35 Additionally, we have previously demonstrated that producing exo-AAV in the absence of capsid does not lead to detectable transduction, at least in cultured cells.…”

Prospect and progress of gene therapy in acute intermittent porphyria

“…Also, because the frequency of acute attacks in AIP patients is highly variable and can change in the absence of identifiable factors, the clinical data from this trial should be taken as an additional aspect of the safety of the treatment. This study provided important data regarding the safety of AAV5 vectors for human gene therapy and has major implications for the design of future intervention studies [39]. In contrast to what has been observed with AAV-2 and -8 vectors used for the treatment of hemophilia [40,41], AAV-5 vector did not elicit cellular immune responses.…”

“…While two patients, both receiving low doses of vector, experienced a significant clinical improvement, the beneficial effect on the rest of the patients was not so clear. However, most of the participants in the study scored better in psychometric tests following therapy [39]. It could be speculated that the different genetic backgrounds among patients result in different endogenous PBGD activity and may be the reason of this heterogeneity.…”

“…Eight patients with severe AIP and recurrent attacks received a single intravenous injection of the vector and four different doses were tested. The main end point of the study, assessing the safety of the treatment, was satisfied as all vector doses were excellently tolerated [39]. In contrast to previous liver-directed AAV gene therapy trials [40,41], no liver damage was observed.…”

“…The orphan drug status was granted to an AAV5 vector expressing the PBGD protein under the control of a liver-specific promoter ( Figure 2). The clinical development of this orphan drug started in 2009, first with demonstration of the safety of the therapeutic vector in rodents and nonhuman primates [38] and subsequently in a phase I clinical trial [39]. The AIP gene therapy phase I clinical trial was carried out in Spain.…”