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• W2895697618 abstract "Pre-existing neutralizing antibody (NAb) against adeno-associated virus (AAV) commonly found in primates is a major host barrier that can severely compromise in vivo gene transfer by AAV vectors. To achieve proof-of-concept success in clinical development of recombinant AAV (rAAV)-based in vivo gene therapy, it is crucial to consider the potential interference of NAb and to enroll serologically compatible study subjects. In this study, we report a large AAV NAb dataset comprising multiple large animal species and AAV serotypes and compare two NAb assays based on in vitro or in vivo transduction inhibition, respectively. Together with previously published AAV seroepidemiology studies, these data can serve as a reference for selecting suitable serotypes, study subjects of large animal species, and potentially human patients for rAAV treatment. In addition, we modeled the intrathalamus rAAV9 delivery in the presence of circulating anti-AAV9 NAb generated by either pre-immunization or passive transfer of NAb-positive large animal serum to mice. The data showed that circulating NAb may not be the sole determinant to inhibit brain transduction. Other aspects of pre-existing AAV immunity following natural infection or rAAV administration may be further studied to establish a more accurate inclusion criterion for clinical studies employing intraparenchymal rAAV9 injections. Pre-existing neutralizing antibody (NAb) against adeno-associated virus (AAV) commonly found in primates is a major host barrier that can severely compromise in vivo gene transfer by AAV vectors. To achieve proof-of-concept success in clinical development of recombinant AAV (rAAV)-based in vivo gene therapy, it is crucial to consider the potential interference of NAb and to enroll serologically compatible study subjects. In this study, we report a large AAV NAb dataset comprising multiple large animal species and AAV serotypes and compare two NAb assays based on in vitro or in vivo transduction inhibition, respectively. Together with previously published AAV seroepidemiology studies, these data can serve as a reference for selecting suitable serotypes, study subjects of large animal species, and potentially human patients for rAAV treatment. In addition, we modeled the intrathalamus rAAV9 delivery in the presence of circulating anti-AAV9 NAb generated by either pre-immunization or passive transfer of NAb-positive large animal serum to mice. The data showed that circulating NAb may not be the sole determinant to inhibit brain transduction. Other aspects of pre-existing AAV immunity following natural infection or rAAV administration may be further studied to establish a more accurate inclusion criterion for clinical studies employing intraparenchymal rAAV9 injections. Recombinant adeno-associated viruses (rAAVs) have been widely used as in vivo gene transfer vectors and extensively tested in various gene therapy applications. Translational studies revealed that, following in vivo delivery of rAAVs, the complex interactions between rAAV and the primate immune system represent a major hurdle toward efficacious and sustainable in vivo gene transfer.1Manno C.S. Pierce G.F. Arruda V.R. Glader B. Ragni M. Rasko J.J. Ozelo M.C. Hoots K. Blatt P. Konkle B. et al.Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response.Nat. Med. 2006; 12: 342-347Crossref PubMed Scopus (1568) Google Scholar, 2Vandamme C. Adjali O. Mingozzi F. Unraveling the Complex Story of Immune Responses to AAV Vectors Trial After Trial.Hum. Gene Ther. 2017; 28: 1061-1074Crossref PubMed Scopus (136) Google Scholar, 3Mingozzi F. High K.A. Overcoming the Host Immune Response to Adeno-Associated Virus Gene Delivery Vectors: The Race Between Clearance, Tolerance, Neutralization, and Escape.Annu. Rev. Virol. 2017; 4: 511-534Crossref PubMed Scopus (118) Google Scholar In humans, pre-existing neutralizing antibody (NAb) against assembled AAV capsid in the circulation is the first immunological barrier that can potentially compromise or abrogate transduction.4Louis Jeune V. Joergensen J.A. Hajjar R.J. Weber T. Pre-existing anti-adeno-associated virus antibodies as a challenge in AAV gene therapy.Hum. Gene Ther. Methods. 2013; 24: 59-67Crossref PubMed Scopus (181) Google Scholar Unfortunately, NAbs against AAV are widespread in general human populations.5Calcedo R. Vandenberghe L.H. Gao G. Lin J. Wilson J.M. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses.J. Infect. Dis. 2009; 199: 381-390Crossref PubMed Scopus (521) Google Scholar The presence of NAb is believed to stem from mother-to-child transmission and from natural AAV infection during childhood.6Calcedo R. Morizono H. Wang L. McCarter R. He J. Jones D. Batshaw M.L. Wilson J.M. Adeno-associated virus antibody profiles in newborns, children, and adolescents.Clin. Vaccine Immunol. 2011; 18: 1586-1588Crossref PubMed Scopus (222) Google Scholar The influence of NAb on rAAV-mediated in vivo gene delivery depends on several factors, such as route of administration, target tissue, NAb titer, and rAAV dose. Delivery to the bloodstream is most susceptible to NAb;7Scallan C.D. Jiang H. Liu T. Patarroyo-White S. Sommer J.M. Zhou S. Couto L.B. Pierce G.F. Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice.Blood. 2006; 107: 1810-1817Crossref PubMed Scopus (198) Google Scholar, 8Jiang H. Couto L.B. Patarroyo-White S. Liu T. Nagy D. Vargas J.A. Zhou S. Scallan C.D. Sommer J. Vijay S. et al.Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy.Blood. 2006; 108: 3321-3328Crossref PubMed Scopus (247) Google Scholar immune-privileged organs such as the brain and eyes are more resistant to NAb;9Gray S.J. Nagabhushan Kalburgi S. McCown T.J. Jude Samulski R. Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates.Gene Ther. 2013; 20: 450-459Crossref PubMed Scopus (248) Google Scholar NAb of a higher titer has a more profound inhibitory effect on transduction;10Wang L. Calcedo R. Bell P. Lin J. Grant R.L. Siegel D.L. Wilson J.M. Impact of pre-existing immunity on gene transfer to nonhuman primate liver with adeno-associated virus 8 vectors.Hum. Gene Ther. 2011; 22: 1389-1401Crossref PubMed Scopus (136) Google Scholar increasing the rAAV dose can overcome NAb to some extent.11Hurlbut G.D. Ziegler R.J. Nietupski J.B. Foley J.W. Woodworth L.A. Meyers E. Bercury S.D. Pande N.N. Souza D.W. Bree M.P. et al.Preexisting immunity and low expression in primates highlight translational challenges for liver-directed AAV8-mediated gene therapy.Mol. Ther. 2010; 18: 1983-1994Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar In addition to humans, non-human primates (NHPs) are also natural hosts of AAV and therefore commonly possess AAV NAbs that interfere with rAAV-mediated translational gene therapy studies and basic research. To circumvent the inhibitory effect of NAb, many approaches have been developed and demonstrated proof-of-concept efficacy, such as plasmapheresis12Monteilhet V. Saheb S. Boutin S. Leborgne C. Veron P. Montus M.F. Moullier P. Benveniste O. Masurier C. A 10 patient case report on the impact of plasmapheresis upon neutralizing factors against adeno-associated virus (AAV) types 1, 2, 6, and 8.Mol. Ther. 2011; 19: 2084-2091Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, 13Chicoine L.G. Montgomery C.L. Bremer W.G. Shontz K.M. Griffin D.A. Heller K.N. Lewis S. Malik V. Grose W.E. Shilling C.J. et al.Plasmapheresis eliminates the negative impact of AAV antibodies on microdystrophin gene expression following vascular delivery.Mol. Ther. 2014; 22: 338-347Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar and using empty capsid decoys.14Mingozzi F. Anguela X.M. Pavani G. Chen Y. Davidson R.J. Hui D.J. Yazicioglu M. Elkouby L. Hinderer C.J. Faella A. et al.Overcoming preexisting humoral immunity to AAV using capsid decoys.Sci. Transl. Med. 2013; 5: 194ra92Crossref PubMed Scopus (223) Google Scholar However, these methods generally are not effective in tackling high-NAb titers, and their clinical impact on gene therapy is yet to be established. The simplest and most effective workaround is to screen subjects for AAV NAb and recruit suitable ones in a trial. Although it excludes a substantial number of patients from a clinical study, the enrollment criterion based on NAb titer is essential to demonstrate the efficacy of gene therapy for hemophilia B.15Nathwani A.C. Tuddenham E.G. Rangarajan S. Rosales C. McIntosh J. Linch D.C. Chowdary P. Riddell A. Pie A.J. Harrington C. et al.Adenovirus-associated virus vector-mediated gene transfer in hemophilia B.N. Engl. J. Med. 2011; 365: 2357-2365Crossref PubMed Scopus (1354) Google Scholar, 16Nathwani A.C. Reiss U.M. Tuddenham E.G. Rosales C. Chowdary P. McIntosh J. Della Peruta M. Lheriteau E. Patel N. Raj D. et al.Long-term safety and efficacy of factor IX gene therapy in hemophilia B.N. Engl. J. Med. 2014; 371: 1994-2004Crossref PubMed Scopus (879) Google Scholar Currently, screening for NAb against the AAV serotype to be used in a gene-therapy study involving human subjects or large animals remains a common and effective practice. Therefore, accurate determination of the AAV NAb in study subjects is key to many rAAV gene transfer studies. AAV NAb present in body fluid is usually determined by an in vitro transduction inhibition assay.5Calcedo R. Vandenberghe L.H. Gao G. Lin J. Wilson J.M. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses.J. Infect. Dis. 2009; 199: 381-390Crossref PubMed Scopus (521) Google Scholar, 17Meliani A. Leborgne C. Triffault S. Jeanson-Leh L. Veron P. Mingozzi F. Determination of anti-adeno-associated virus vector neutralizing antibody titer with an in vitro reporter system.Hum. Gene Ther. Methods. 2015; 26: 45-53Crossref PubMed Scopus (63) Google Scholar In this assay, a body fluid sample such as serum is serially diluted; each diluted sample is incubated with a certain serotype of rAAV expressing a reporter to allow for NAb-rAAV binding. Then the mixture is used to infect cell culture followed by the measurement of reporter expression as a gauge of transduction efficiency. The presence of NAb will inhibit transduction up to a certain dilution factor compared to proper controls. The titer of NAb can be defined as the lowest dilution factor that inhibits transduction by more than 50% or between this lowest dilution factor and the next one (e.g., this study). Alternatively, the dilution factor that inhibits transduction by 50% can be calculated by logistic regression and defined as the NAb titer. It should be noted that the in vitro AAV NAb assay involves several variables that are not standardized among different laboratories, such as incubation and culture conditions, reporter choice, cell type, and MOI. In addition, the reporter rAAVs are usually produced in-house and therefore subject to variations. Nevertheless, studies have shown that the assay remains robust and is resistant to some variables.18Wang M. Crosby A. Hastie E. Samulski J.J. McPhee S. Joshua G. Samulski R.J. Li C. Prediction of adeno-associated virus neutralizing antibody activity for clinical application.Gene Ther. 2015; 22: 984-992Crossref PubMed Scopus (37) Google Scholar At our facility, we have been using a standard operating procedure to perform in vitro NAb assays since 2008. A recent study showed that the NAb results obtained from our laboratory and another laboratory using a different protocol are highly consistent.19Ellsworth J.L. O’Callaghan M. Rubin H. Seymour A. Low Seroprevalence of Neutralizing Antibodies Targeting Two Clade F AAV in Humans.Hum. Gene Ther. Clin. Dev. 2018; (Published online February 27 2018)https://doi.org/10.1089/hum.2017.239Crossref Google Scholar An intrinsic limitation of the in vitro AAV NAb assay is the low sensitivity, due in part to the generally inefficient cell culture transduction by rAAVs. Therefore, a high MOI of reporter rAAV has to be used in the assay, which may artificially overcome the inhibitory effect of low-titer NAb and make a false-negative call. This caveat is especially important in scenarios that are prone to the inhibition by even low-titer NAb, such as systemic delivery to target the liver. To more closely mimic the neutralizing effect of NAb on in vivo rAAV transduction, an adoptive transfer method to detect NAb was developed.7Scallan C.D. Jiang H. Liu T. Patarroyo-White S. Sommer J.M. Zhou S. Couto L.B. Pierce G.F. Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice.Blood. 2006; 107: 1810-1817Crossref PubMed Scopus (198) Google Scholar, 10Wang L. Calcedo R. Bell P. Lin J. Grant R.L. Siegel D.L. Wilson J.M. Impact of pre-existing immunity on gene transfer to nonhuman primate liver with adeno-associated virus 8 vectors.Hum. Gene Ther. 2011; 22: 1389-1401Crossref PubMed Scopus (136) Google Scholar In this assay, mice are pre-conditioned by receiving IV injection of a test sample, such as intravenous immunoglobulin (IVIg) or serum, followed by a second injection of a certain serotype of rAAV expressing a secretory reporter. The in vivo transduction is measured by quantifying reporter expression in the serum and compared to proper controls. Due to the high in vivo transduction capability of rAAV, a low dose of reporter rAAV is sufficient to yield robust expression and therefore allows for the detection of low-titer NAbs, i.e., at a higher sensitivity. The in vivo NAb assay was employed to screen for AAV8 sero-negative patients of hemophilia B and proved to be essential for the success of the gene therapy trial.15Nathwani A.C. Tuddenham E.G. Rangarajan S. Rosales C. McIntosh J. Linch D.C. Chowdary P. Riddell A. Pie A.J. Harrington C. et al.Adenovirus-associated virus vector-mediated gene transfer in hemophilia B.N. Engl. J. Med. 2011; 365: 2357-2365Crossref PubMed Scopus (1354) Google Scholar, 16Nathwani A.C. Reiss U.M. Tuddenham E.G. Rosales C. Chowdary P. McIntosh J. Della Peruta M. Lheriteau E. Patel N. Raj D. et al.Long-term safety and efficacy of factor IX gene therapy in hemophilia B.N. Engl. J. Med. 2014; 371: 1994-2004Crossref PubMed Scopus (879) Google Scholar However, the in vivo NAb assay is far more cumbersome than the in vitro assay, especially when a large number of samples need to be screened. Circulating AAV NAb may also compromise transduction in the brain and eyes following a direct rAAV injection into these immune-privileged compartments.20Samaranch L. Salegio E.A. San Sebastian W. Kells A.P. Foust K.D. Bringas J.R. Lamarre C. Forsayeth J. Kaspar B.K. Bankiewicz K.S. Adeno-Associated Virus Serotype 9 Transduction in the Central Nervous System of Nonhuman Primates.Hum. Gene Ther. 2012; 23: 382-389Crossref PubMed Scopus (215) Google Scholar, 21Kotterman M.A. Yin L. Strazzeri J.M. Flannery J.G. Merigan W.H. Schaffer D.V. Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates.Gene Ther. 2015; 22: 116-126Crossref PubMed Scopus (116) Google Scholar, 22Janelidze S. Nordström U. Kügler S. Brundin P. Pre-existing immunity to adeno-associated virus (AAV)2 limits transgene expression following intracerebral AAV2-based gene delivery in a 6-hydroxydopamine model of Parkinson’s disease.J. Gene Med. 2014; 16: 300-308Crossref PubMed Scopus (9) Google Scholar Previous studies revealed that such an inhibitory effect depends on several factors, such as the serotype,23Peden C.S. Burger C. Muzyczka N. Mandel R.J. Circulating anti-wild-type adeno-associated virus type 2 (AAV2) antibodies inhibit recombinant AAV2 (rAAV2)-mediated, but not rAAV5-mediated, gene transfer in the brain.J. Virol. 2004; 78: 6344-6359Crossref PubMed Scopus (192) Google Scholar NAb titer,24Sanftner L.M. Suzuki B.M. Doroudchi M.M. Feng L. McClelland A. Forsayeth J.R. Cunningham J. Striatal delivery of rAAV-hAADC to rats with preexisting immunity to AAV.Mol. Ther. 2004; 9: 403-409Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 25Treleaven C.M. Tamsett T.J. Bu J. Fidler J.A. Sardi S.P. Hurlbut G.D. Woodworth L.A. Cheng S.H. Passini M.A. Shihabuddin L.S. Dodge J.C. Gene transfer to the CNS is efficacious in immune-primed mice harboring physiologically relevant titers of anti-AAV antibodies.Mol. Ther. 2012; 20: 1713-1723Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar and route of administration.21Kotterman M.A. Yin L. Strazzeri J.M. Flannery J.G. Merigan W.H. Schaffer D.V. Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates.Gene Ther. 2015; 22: 116-126Crossref PubMed Scopus (116) Google Scholar Early studies mainly focused on AAV2 and AAV5 when evaluating the impact of circulating AAV NAb on brain transduction by a direct intraparenchymal injection. More recently, AAV9 and AAVrh.10 have been shown to more efficiently target CNS cells by a direct brain injection and therefore are suitable for gene therapy development for a range of CNS diseases such as Parkinson’s disease and lysosomal diseases with CNS involvement.26Hocquemiller M. Giersch L. Audrain M. Parker S. Cartier N. Adeno-Associated Virus-Based Gene Therapy for CNS Diseases.Hum. Gene Ther. 2016; 27: 478-496Crossref PubMed Scopus (176) Google Scholar, 27Sondhi D. Johnson L. Purpura K. Monette S. Souweidane M.M. Kaplitt M.G. Kosofsky B. Yohay K. Ballon D. Dyke J. et al.Long-term expression and safety of administration of AAVrh.10hCLN2 to the brain of rats and nonhuman primates for the treatment of late infantile neuronal ceroid lipofuscinosis.Hum. Gene Ther. Methods. 2012; 23: 324-335Crossref PubMed Scopus (74) Google Scholar Here, we report a survey of circulating AAV NAbs in six different species of large animals that are commonly used in pre-clinical gene therapy development. In particular, the high-throughput in vitro NAb assay allowed us to analyze a large number of rhesus macaques (RMs) and cynomolgus macaques (CMs) and to test for multiple AAV serotypes. In addition, we also conducted in vivo NAb assay with a subset of serum samples, which showed higher sensitivity than the in vitro assay with the exceptions of some animal species. Lastly, we found that the circulating anti-AAV9 NAb up to 1:20–1:40 alone may not be sufficient to inhibit Th injection of rAAV9 in mice. Together, these results shed more light on screening and selecting suitable study subjects of large animal species and potentially humans for rAAV-mediated gene therapy. During the past few years, we performed an in vitro AAV NAb assay according to a standard operating procedure with serum samples from various large animal species, including RM, CM, marmoset, chimpanzee, dog, and sheep, generating a total of 2,555 assay data points. These serum samples were collected from naive animals that were screened for NAb titer for various purposes. In most cases, animals were screened to identify the ones with non-detectable or low levels of NAb for pre-clinical rAAV gene-therapy studies. The results are summarized and presented in Figure 1. RM and CM account for the vast majority of donor animals (1,632 and 790 data points, respectively), reflecting their common use in translational gene therapy development. NAbs against a series of clinically relevant AAV serotypes were tested, including AAV1, 2, 3B, 5, 6, 8, 9, DJ, DJ8, rh.8, and rh.10, among which AAV1, 8, 9, rh.10 were most often tested. Anti-AAV1 NAb shows low prevalence in both RM and CM; sero-negative samples account for 55% and 57% in these species, respectively. Similarly, anti-AAV9 NAb shows low prevalence or tends to display low titer of less than 1:10 in these species. In contrast, both RM and CM tend to have high anti-AAV8 NAb titers of more than 1:10. Anti-AAVrh.10 NAb appears more prevalent in CM than in RM, mainly due to more CM samples containing titers of more than 1:20. Notably, RM samples have widespread anti-AAV2 NAb with only 1.3% sero-negative, but low prevalence of anti-AAV3B and AAV5 NAbs with more than 50% sero-negative despite small sample sizes. This NAb profile is similar to that of human populations previously reported.28Boutin S. Monteilhet V. Veron P. Leborgne C. Benveniste O. Montus M.F. Masurier C. Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors.Hum. Gene Ther. 2010; 21: 704-712Crossref PubMed Scopus (626) Google Scholar The sample sizes and serotypes tested for the other species are limited (Figure 1C). However, anti-AAV9 and rh.10 NAbs appear common in marmoset, dog, and sheep, but the titers are generally lower in marmoset than the other two species. Taken together, the survey of anti-AAV NAbs comprises several large-animal species and AAV serotypes with a large sample size in many cases. For RM and CM, two NHP species commonly used in translational gene therapy studies, they tend to have low prevalence and/or low titer of anti-AAV1 and AAV9 NAbs; the opposite is observed for anti-AAV8 NAb. For a subset of serum samples that we tested by the in vitro NAb assay, we also performed an in vivo NAb assay that is based on adoptive transfer of serum sample to wild-type (WT) mice, and quantification of its inhibitory effect on in vivo transduction by rAAV of a certain serotype expressing human alpha 1-antitrypsin (hA1AT) as a secretory reporter. The hA1AT in the recipient mouse serum can be quantitatively measured to gauge transduction efficiency. The experimental workflow is illustrated in Figure 2A and detailed in the Materials and Methods. Most samples tested in the in vivo NAb assay were sero-negative in the in vitro NAb assay (titer < 1:5) (Figure 2B), because the main purpose of performing the in vivo NAb assay was to identify the samples with a low NAb titer that was not detectable in the less-sensitive in vitro NAb assay. As expected, a small fraction of sero-negative samples determined by the in vitro NAb assay were able to significantly inhibit rAAV.hA1AT transduction in mice. In contrast, the majority of samples showing a high titer of more than 1:10 in the in vitro NAb assay were able to significantly inhibit rAAV.hA1AT transduction in mice (Figure 2B). Interestingly, almost all serum samples from marmoset and sheep were not able to inhibit in vivo transduction despite their NAb titers of more than 1:5 in the in vitro NAb assay (Figure 2C). Overall, we found good correlation between the in vitro and in vivo NAb assays; most sero-negative samples determined by the in vitro assay did not significantly inhibit in vivo rAAV transduction, whereas most sero-positive samples determined by the in vitro assay did. The in vivo assay was able to identify the inhibitory sera that presumably contain an anti-AAV NAb titer below the detection limit of the in vitro assay (1:5 in this study). To model the effect of circulating NAb on direct brain gene delivery by rAAV9, we first pre-immunized mice with an AAV9 vector expressing EGFP (scAAV9.EGFP) by either Th injection or intramuscular (IM) injection. Four weeks later, anti-AAV9 NAb in the sera was determined by the in vitro NAb assay (Figures 3A and 3B ). IM injection led to robust NAb formation of more than 1:20 in all mice (n = 6). In contrast, only one mouse receiving Th injection showed detectable NAb (n = 6). As expected, naive mice receiving no rAAV treatment were sero-negative (n = 4). Five weeks after the first injection, all mice received Th injection of an AAV9 vector expressing firefly luciferase (rAAV9.Fluc). For the mice that received the first Th injection, the second Th injection was performed at the contralateral hemisphere. Four weeks later, all mice were sacrificed and analyzed for Fluc expression in the tissue lysate of hippocampus and thalamus of the hemisphere receiving rAAV9.Fluc (Figures 3A and 3C). Compared with the mice receiving only the Th injection of rAAV9.Fluc, pre-treatment with a Th injection of scAAV9.EGFP did not change the transduction capability of the following rAAV9.Fluc in either brain region. In contrast, pre-immunization with scAAV9.EGFP by IM injection significantly reduced the transduction by rAAV9.Fluc in both brain regions, in most mice to several logs lower. These results indicate a correlation between the presence of systemic anti-AAV9 NAb induced by IM pre-immunization and the severely compromised brain transduction by a following direct intraparenchymal delivery of rAAV9. However, the IM pre-immunization regimen could trigger pleiotropic immune responses beyond generating circulating NAb. To further test whether the AAV9 NAb induced by the IM pre-immunization regimen was the sole cause of compromised brain transduction by brain rAAV9 delivery, we performed a passive transfer experiment (Figure 4A). We first pooled three cynomolgus monkey serum samples that were previously determined to be positive for AAV9 NAb, which allowed us to use the same NHP serum sample of sufficient amount to pre-condition multiple mice. In the pilot experiment, we determined that IV delivery of 200 μL of the NHP serum pool to mice generated robust AAV9 NAb in the mouse sera (Figure 4B). Next, we treated another batch of pre-conditioned mice or naive mice with Th delivery of rAAV9.Fluc. Four weeks later, mice were sacrificed, and we analyzed Fluc expression in the tissue lysate of hippocampus, thalamus, and liver. In contrast to the pre-immunization experiment (Figure 3C), passive transfer of AAV9 NAb-containing NHP serum did not compromise the intracranial gene delivery by rAAV9 (Figure 4C). In the naive mice not receiving NHP serum, the intracranial injection also led to liver transduction due to vector leakage out of the CNS compartment (Figure 4C). As expected, the liver transduction in the pre-conditioned mice was diminished (Figure 4C). The inhibitory effect of circulating AAV NAb on gene-therapy efficacy is evident in clinical studies. The lack of effective methods to circumvent neutralization necessitates the exclusion of sero-positive patients from some clinical trials. The same issue exists when performing a pre-clinical toxicology study and/or gene-transfer efficiency study in large-animal species such as NHPs. Previous studies surveyed NAbs against several AAV serotypes in general human populations,5Calcedo R. Vandenberghe L.H. Gao G. Lin J. Wilson J.M. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses.J. Infect. Dis. 2009; 199: 381-390Crossref PubMed Scopus (521) Google Scholar, 28Boutin S. Monteilhet V. Veron P. Leborgne C. Benveniste O. Montus M.F. Masurier C. Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors.Hum. Gene Ther. 2010; 21: 704-712Crossref PubMed Scopus (626) Google Scholar specific patient populations,29Greenberg B. Butler J. Felker G.M. Ponikowski P. Voors A.A. Pogoda J.M. Provost R. Guerrero J. Hajjar R.J. Zsebo K.M. Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure.Gene Ther. 2016; 23: 313-319Crossref PubMed Scopus (67) Google Scholar, 30Harrington E.A. Sloan J.L. Manoli I. Chandler R.J. Schneider M. McGuire P.J. Calcedo R. Wilson J.M. Venditti C.P. Neutralizing Antibodies Against Adeno-Associated Viral Capsids in Patients with mut Methylmalonic Acidemia.Hum. Gene Ther. 2016; 27: 345-353Crossref PubMed Scopus (25) Google Scholar, 31Rincon M.Y. Prada C.E. Lopez M. Castillo V. Echeverria L.E. Serrano N. Determination of Anti-Adeno-Associated Viral Vector Neutralizing Antibodies in Patients With Heart Failure in the Cardiovascular Foundation of Colombia (ANVIAS): Study Protocol.JMIR Res. Protoc. 2016; 5: e102Crossref PubMed Google Scholar, 32Corden A. Handelman B. Yin H. Cotrim A. Alevizos I. Chiorini J.A. Neutralizing antibodies against adeno-associated viruses in Sjögren’s patients: implications for gene therapy.Gene Ther. 2017; 24: 241-244Crossref PubMed Scopus (6) Google Scholar and several animal species.33Calcedo R. Franco J. Qin Q. Richardson D.W. Mason J.B. Boyd S. Wilson J.M. Preexisting Neutralizing Antibodies to Adeno-Associated Virus Capsids in Large Animals Other Than Monkeys May Confound In Vivo Gene Therapy Studies.Hum. Gene Ther. Methods. 2015; 26: 103-105Crossref PubMed Scopus (37) Google Scholar, 34Rapti K. Louis-Jeune V. Kohlbrenner E. Ishikawa K. Ladage D. Zolotukhin S. Hajjar R.J. Weber T. Neutralizing antibodies against AAV serotypes 1, 2, 6, and 9 in sera of commonly used animal models.Mol. Ther. 2012; 20: 73-83Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar Collectively, these studies provide a guidance for selecting AAV serotype vectors to maximize the serologically compatible study subjects. Here, we greatly extend this effort by reporting a large AAV NAb dataset consisting of multiple animal species and AAV serotypes. The vast majority of data points concern RMs and CMs, two species commonly used in rAAV gene therapy development. These data can be informative for the selection of AAV serotypes and animal species for testing a gene-therapy application. For example, similar to humans,28Boutin S. Monteilhet V. Veron P. Leborgne C. Benveniste O. Montus M.F. Masurier C. Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors.Hum." @default.
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