Testing preexisting antibodies prior to AAV gene transfer therapy: rationale, lessons and future considerations

Mendell, Jerry R.; Connolly, Anne M.; Lehman, Kelly; Griffin, Deborah; Khan, Sohrab; Dharia, Sachi D.; Quintana-Gallardo, Lucía; Rodino‐Klapac, Louise R.

doi:10.1016/j.omtm.2022.02.011

Cited by 54 publications

(50 citation statements)

References 64 publications

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“…Regarding current data, population-based studies conducted at a global level have reported important differences in the prevalence of NAb according to the serotype evaluated, the population studied, and the NAb detection method used, the latter being a critical factor when comparing the results of the different studies [ 9 , 10 , 21 , 22 ]. This is due to the fact that AAV antibody assays are not currently standardized globally, so the cutoff points for defining positivity in each study are assay-specific [ 10 , 23 ]. Among the types of assays currently available are neutralizing antibody assays and total antibody assays, the latter being mainly ELISA-based assays with the ability to detect both neutralizing and non-neutralizing antibodies.…”

Section: Discussionmentioning

confidence: 99%

“…Among the types of assays currently available are neutralizing antibody assays and total antibody assays, the latter being mainly ELISA-based assays with the ability to detect both neutralizing and non-neutralizing antibodies. Despite their convenience, reproducibility, and sensitivity, their positivity in the presence of non-neutralizing antibodies excludes a large proportion of potential candidates for gene therapy [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

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Prevalence of Neutralizing Antibodies against Adeno-Associated Virus Serotypes 1, 2, and 9 in Non-Injected Latin American Patients with Heart Failure—ANVIAS Study

Sierra-Delgado

Likhite

Bautista-Niño

et al. 2023

IJMS

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Neutralizing antibody (NAb) activity against the viral capsid of adeno-associated viral (AAV) vectors decreases transduction efficiency, thus limiting transgene expression. Several reports have mentioned a variation in NAb prevalence according to age, AAV serotype, and, most importantly, geographic location. There are currently no reports specifically describing the anti-AAV NAb prevalence in Latin America. Here, we describe the prevalence of NAb against different serotypes of AAV vectors (AAV1, AAV2, and AAV9) in Colombian patients with heart failure (HF) (referred to as cases) and healthy individuals (referred to as controls). The levels of NAb were evaluated in serum samples of 60 subjects from each group using an in vitro inhibitory assay. The neutralizing titer was reported as the first dilution inhibiting ≥50% of the transgene signal, and the samples with neutralizing titers at ≥1:50 dilution were considered positive. The prevalence of NAb in the case and control groups were similar (AAV2: 43% and 45%, respectively; AAV1 33.3% in each group; AAV9: 20% and 23.2%, respectively). The presence of NAb for two or more of the serotypes analyzed was observed in 25% of the studied samples, with the largest amount in the positive samples for AAV1 (55–75%) and AAV9 (93%), suggesting serial exposures, cross-reactivity, or coinfection. Moreover, patients in the HF group exhibited more common combined seropositivity for NAb against AAV1 d AAV9 than those in the control group (91.6% vs. 35.7%, respectively; p = 0.003). Finally, exposure to toxins was significantly associated with the presence of NAb in all regression models. These results constitute the first report of the prevalence of NAb against AAV in Latin America, being the first step to implementing therapeutic strategies based on AAV vectors in this population in our region.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prevalence of Neutralizing Antibodies against Adeno-Associated Virus Serotypes 1, 2, and 9 in Non-Injected Latin American Patients with Heart Failure—ANVIAS Study

Sierra-Delgado

Likhite

Bautista-Niño

et al. 2023

IJMS

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“…59,60 Clues for the distinct cardiac and off-target expression characteristics of each serotype may first come from the different abundance of common (e.g., the wild type (wt)AAV receptor KIAAA0319L) 61 and serotype-specific wtAAV receptor constellations (e.g., wtAAV9: laminin receptor and N-linked glycans; wtAAV6: N-linked sialic acid and EGF receptor; wtAAV5: N-linked sialic acid and PDGF receptor) on the various organs that convey cellular AAV binding and internalization. 62,63 As additional factors such as pre-existing neutralizing antibodies or interacting serum factors 64,65 can influence the in vivo transduction properties of AAVs, a systematic assessment across different mammalian model systems would be needed to provide a conclusive understanding of this complex mechanistic process. We nevertheless conclude up to this point that rAAV5 provides a suitable cardiac transduction pattern with negligible off-target effects when delivered to a human-sized heart by a clinically applicable ROA in combination with cardiac-biased expression control.…”

Section: Discussionmentioning

confidence: 99%

Cardiac-targeted rAAV5-S100A1 gene therapy protects against adverse remodeling and contractile dysfunction in post-ischemic hearts

Kehr

Salatzki

Krautz

et al. 2023

Preprint

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SummaryToxicity by recombinant adeno-associated viruses (rAAV) in clinical gene therapy trials (e.g., by rAAV9-mediated fatal liver failure) significantly impairs translation of preclinical rAAV-based cardiac gene therapies employing these vectors. For rAAV5 - a capsid that has shown long-term safety in clinical trials - our translational study demonstrates effective transduction of the left ventricle (LV) of healthy pigs via catheter-based retrograde intravenous delivery (CRID) by means of luciferase reporter gene biodistribution analyses. Combination of rAAV5 with the cardioprotective human geneS100A1(hS100A1) prevents LV myocardial infarct (MI) enlargement and improves LV systolic contractile performance in a porcine model of post-MI chronic cardiac dysfunction. Use of a cardiac-biased promoter ensured the cardiac-directed expression of the therapeutic human transgene without signs of clinical toxicity. The beneficial effects of rAAV5-hS100A1were linked to an attenuated activity of post-MI inflammatory gene networks and this was further validated in a murine model. These novel data together with proven scalable producibility and low pre-existing immunity against rAAV5 in humans may collectively advance clinical translation of rAAV5-hS100A1as a gene therapy medicinal product (GTMP) for a common cardiovascular disease, such as chronic heart failure (CHF).HighlightsRecent fatal adverse events in recombinant adeno-associated virus (AAV)-based clinical gene therapy trials advise the use of rAAV serotypes with proven long-term clinical safety, such as rAAV5, for the pre-clinical development and clinical translation of rAAV-based cardiac gene therapy medicinal products.In a biodistribution and therapeutic proof-of-concept study in farm pigs, rAAV5 was identified as an effective viral vector for cardiac gene transfer and gene therapy for post-ischemic cardiac dysfunction when applied by a standardized cardiac-targeted catheter-based route of administration with the luciferase reporter and cardioprotective human gene S100A1 (hS100A1), respectively.A systems biology analysis linked the novel finding of mitigated inflammatory and activated cardioprotective gene network activities in rAAV5-hS100A1treated postischemic myocardium with improved study left ventricular ejection fraction and prevention of myocardial infarct extension, respectively, which warrants further mechanistic molecular studies.Since rAAV5 has been recently approved for clinical use in a non-cardiac indication and cardiac-targeted S100A1 gene therapy has been effective in numerous pre-clinical animal models of acute and chronic cardiac dysfunction, our translational data support an expedited developmental path for rAAV5-hS100A1throughout investigational new drug-enabling studies towards a first-in-human clinical trial for post-myocardial infarction heart failure.

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“…NAb assays are either cell-based or mouse-based, and are hence expensive, time-consuming, and have a higher risk of underestimating TAb titer. Since TAb assays screen out all antibodies against AAV capsid, neutralizing and non-neutralizing, the resulting titer is more conservative and safer [ 78 ]. Moreover, different capsid serotypes have been approved by the FDA and EMA and each product requires developing a different anti-AAV antibody assay.…”

Section: Immune Responses To Adeno-associated Viruses (Aavs)mentioning

confidence: 99%

Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer

et al. 2023

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Recombinant adeno-associated viruses (AAVs) have emerged as promising gene delivery vehicles resulting in three US Food and Drug Administration (FDA) and one European Medicines Agency (EMA)-approved AAV-based gene therapies. Despite being a leading platform for therapeutic gene transfer in several clinical trials, host immune responses against the AAV vector and transgene have hampered their widespread application. Multiple factors, including vector design, dose, and route of administration, contribute to the overall immunogenicity of AAVs. The immune responses against the AAV capsid and transgene involve an initial innate sensing. The innate immune response subsequently triggers an adaptive immune response to elicit a robust and specific response against the AAV vector. AAV gene therapy clinical trials and preclinical studies provide important information about the immune-mediated toxicities associated with AAV, yet studies suggest preclinical models fail to precisely predict the outcome of gene delivery in humans. This review discusses the contribution of the innate and adaptive immune response against AAVs, highlighting the challenges and potential strategies to mitigate these responses, thereby enhancing the therapeutic potential of AAV gene therapy.

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Testing preexisting antibodies prior to AAV gene transfer therapy: rationale, lessons and future considerations

Cited by 54 publications

References 64 publications

Prevalence of Neutralizing Antibodies against Adeno-Associated Virus Serotypes 1, 2, and 9 in Non-Injected Latin American Patients with Heart Failure—ANVIAS Study

Prevalence of Neutralizing Antibodies against Adeno-Associated Virus Serotypes 1, 2, and 9 in Non-Injected Latin American Patients with Heart Failure—ANVIAS Study

Cardiac-targeted rAAV5-S100A1 gene therapy protects against adverse remodeling and contractile dysfunction in post-ischemic hearts

Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer

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