Therapeutic hFIX Activity Achieved after Single AAV5-hFIX Treatment in Hemophilia B Patients and NHPs with Pre-existing Anti-AAV5 NABs

Majowicz, Anna; Nijmeijer, Bart; Lampen, Margit H.; Spronck, Lisa; Haan, Martin de; Petry, Harald; Deventer, Sander J. van; Meyer, Christian; Tangelder, Marco J.D.; Ferreira, Valérie

doi:10.1016/j.omtm.2019.05.009

Cited by 96 publications

(118 citation statements)

References 25 publications

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“…50 We have previously shown that no impact of anti-AAV5 NABs on liver transduction was observed for NABs titers up to 1031 in NHPs and 340 in humans. 51 In the present study, therapeutic levels of hFIX expression were achieved in presence of anti-AAV5 NABs remaining after IA at titers ranging from 2261 to 8249. However, the impact of individual complement factors as well as of IgM antibodies on the neutralization activity has been reported for viruses such as hepatitis C, vesicular stomatitis and adenovirus type 5.…”

Section: Discussionmentioning

confidence: 50%

Immunoadsorption enables successful rAAV5-mediated repeated hepatic gene delivery in nonhuman primates

et al. 2019

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Key Points• IA procedure decrease anti-AAV5 NABs to levels compatible with a successful AAV5 vector readministration.• Patients positive for anti-AAV antibodies could benefit from AAVbased gene therapy after IA treatment.Adeno-associated virus (AAV)-based liver gene therapy has been shown to be clinically successful. However, the presence of circulating neutralizing antibodies (NABs) against AAV vector capsids remains a major challenge as it may prevent successful transduction of the target cells. Therefore, there is a need to develop strategies that would enable AAV-mediated gene delivery to patients with preexisting anti-AAV NABs. In the current study, the feasibility of using an immunoadsorption (IA) procedure for repeated, liver-targeted gene delivery in nonhuman primates was explored. The animals were administered IV with recombinant AAV5 (rAAV5) carrying the reporter gene human secreted embryonic alkaline phosphatase (hSEAP). Seven weeks after the first rAAV treatment, all of the animals were readministered with rAAV5 carrying the therapeutic hemophilia B gene human factor IX (hFIX). Half of the animals administered with rAAV5-hSEAP underwent IA prior to the second rAAV5 exposure.The transduction efficacies of rAAV5-hSEAP and rAAV5-hFIX were assessed by measuring the levels of hSEAP and hFIX proteins. Although no hFIX was detected after rAAV5-hFIX readministration without prior IA, all animals submitted to IA showed therapeutic levels of hFIX expression, and a threshold of anti-AAV5 NAB levels compatible with successful readministration was demonstrated. In summary, our data demonstrate that the use of a clinically applicable IA procedure enables successful readministration of an rAAV5-based gene transfer in a clinically relevant animal model. Finally, the analysis of anti-AAV NAB levels in human subjects submitted to IA confirmed the safety and efficacy of the procedure to reduce anti-AAV NABs. Furthermore, clinical translation was assessed using an immunoglobulin G assay as surrogate.

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Section: Discussionmentioning

confidence: 50%

Immunoadsorption enables successful rAAV5-mediated repeated hepatic gene delivery in nonhuman primates

et al. 2019

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“…It is not clear to what extent ELISA and the NAb titer correlate. One study reported little correlation in AAV2 and AAV8 [38], while in another paper, a correlation was suggested in AAV5 with a broad range of NAb titers [39]. As only low NAb titer animals were involved in our study, it may have been difficult to observe the correlation between these parameters.…”

Section: Discussionmentioning

confidence: 69%

Utility of microminipigs for evaluating liver-mediated gene expression in the presence of neutralizing antibody against vector capsid

et al. 2020

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Adeno-associated virus (AAV) vectors can transduce hepatocytes efficiently in vivo in various animal species, including humans. Few reports, however, have examined the utility of pigs in gene therapy. Pigs are potentially useful in preclinical studies because of their anatomical and physiological similarity to humans. Here, we evaluated the utility of microminipigs for liver-targeted gene therapy. These pigs were intravenously inoculated with an AAV8 vector encoding the luciferase gene, and gene expression was assessed by an in vivo imaging system. Robust transgene expression was observed almost exclusively in the liver, even though the pig showed a low-titer of neutralizing antibody (NAb) against the AAV8 capsid. We assessed the action of NAbs against AAV, which interfere with AAV vector-mediated gene transfer by intravascular delivery. When a standard dose of vector was administered intravenously, transgene expression was observed in both NAbnegative and low-titer (14×)-positive subjects, whereas gene expression was not observed in animals with higher titers (56×). These results are compatible with our previous observations using nonhuman primates, indicating that pigs are useful in gene therapy experiments, and that the role of low-titer NAb in intravenous administration of the AAV vector shows similarities across species.

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“…37 To date, all trials have also excluded patients with pre-existing antibodies to the AAV serotype specific to each of the investigational products; however, at least one phase 3 trial for haemophilia B [NCT03569891] has lifted that exclusion criterion due to lack of evidence for associated reduced efficacy or immune responses due to pre-existing low-titre neutralising antibodies to AAV5. 45 Exclusion of key populations such children and adolescents, women with haemophilia, 46 and those with a history of inhibitors to factor replacement is consistent across Phase 1-3 haemophilia GT trials, but a GT trial in people with haemophilia A and inhibitors has been announced. 47 If GT does become available in children and adolescents, there may be ethical questions in terms of gaining informed consent.…”

Section: Questions Regarding Trial Participationmentioning

confidence: 99%

How to discuss gene therapy for haemophilia? A patient and physician perspective

et al. 2019

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Gene therapy has the potential to revolutionise treatment for patients with haemophilia and is close to entering clinical practice. While factor concentrates have improved outcomes, individuals still face a lifetime of injections, pain, progressive joint damage, the potential for inhibitor development and impaired quality of life. Recently published studies in adeno‐associated viral (AAV) vector‐mediated gene therapy have demonstrated improvement in endogenous factor levels over sustained periods, significant reduction in annualised bleed rates, lower exogenous factor usage and thus far a positive safety profile. In making the shared decision to proceed with gene therapy for haemophilia, physicians should make it clear that research is ongoing and that there are remaining evidence gaps, such as long‐term safety profiles and duration of treatment effect. The eligibility criteria for gene therapy trials mean that key patient groups may be excluded, eg children/adolescents, those with liver or kidney dysfunction and those with a prior history of factor inhibitors or pre‐existing neutralising AAV antibodies. Gene therapy offers a life‐changing opportunity for patients to reduce their bleeding risk while also reducing or abrogating the need for exogenous factor administration. Given the expanding evidence base, both physicians and patients will need sources of clear and reliable information to be able to discuss and judge the risks and benefits of treatment.

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Therapeutic hFIX Activity Achieved after Single AAV5-hFIX Treatment in Hemophilia B Patients and NHPs with Pre-existing Anti-AAV5 NABs

Cited by 96 publications

References 25 publications

Immunoadsorption enables successful rAAV5-mediated repeated hepatic gene delivery in nonhuman primates

Immunoadsorption enables successful rAAV5-mediated repeated hepatic gene delivery in nonhuman primates

Utility of microminipigs for evaluating liver-mediated gene expression in the presence of neutralizing antibody against vector capsid

How to discuss gene therapy for haemophilia? A patient and physician perspective

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