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

Boutin, Sylvie; Monteilhet, Virginie; Véron, Philippe; Leborgne, Christian; Benveniste, Olivier; Montus, M.; Masurier, Carole

doi:10.1089/hum.2009.182

Cited by 778 publications

(803 citation statements)

References 56 publications

(61 reference statements)

Supporting

Mentioning

769

Contrasting

Unclassified

Order By: Relevance

“…15 These and other similar results strongly support the model that individuals originally infected by AAV2 develop NAbs that cross-react with other AAV serotypes. 10,19 Of the 277 samples assayed, only 2 samples were negative for NAbs against AAV2 but positive for another serotype. (Figure 6) In each of these samples (both from the same patient), low titer antibodies against both AAV5 and AAV8 were found.…”

Section: Discussionmentioning

confidence: 99%

“…In approximately 20-60% of this subpopulation, an adaptive humoral response results in the development and maintenance of antibodies capable of neutralizing subsequent infection by AAV2 (neutralizing antibodies (NAbs)). [8][9][10][11][12][13][14][15][16][17][18][19] The existence of NAbs can limit rAAV therapeutic applications that rely on systemic vector administration, for example, by interfering with cell surface binding or promoting reticuloendothelial clearance and destruction of AAV vectors. [20][21][22] Additionally, previous human studies have observed that NAbs against AAV2 cross-neutralize other serotypes of AAV.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia

Li¹,

Narkbunnam

Samulski³

et al. 2011

Gene Ther

186

190

View full text Add to dashboard Cite

The Joint Outcome Study Investigators 7Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia

Li¹,

Narkbunnam

Samulski³

et al. 2011

Gene Ther

186

190

View full text Add to dashboard Cite

show abstract

“…Recently, Manno et al (44) performed a phase I study of AAV-mediated FIX transgene delivery in patients with hemophilia B, in which one patient with a higher preexisting NAb titer demonstrated lower levels of FIX in the serum than another patient with lower preexisting NAbs against AAV2. These results suggest that preexisting NAbs in the human population can attenuate vector transduction efficiency and inhibit transgene expression upon systemic application (44).In the general human population, over 95% of individuals have been infected by AAV2, with 50% of them having NAbs (3,4,6,10,18,21,24,27,35,48,62,65). The prevalence of NAb in children is lower, ranging from 13 to 25% (9, 35).…”

mentioning

confidence: 99%

“…Although 11 additional types of AAV have been isolated for gene therapy purposes, little to no cross-reactivity of NAbs is demonstrated among these types in animals (27,30,38,60,65). In humans, recent studies have shown that different degrees of NAb cross-reactivity exist between AAV2 and other types (6,10,27,45). There is a lower prevalence of NAbs against AAV1,10).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Single Amino Acid Modification of Adeno-Associated Virus Capsid Changes Transduction and Humoral Immune Profiles

DiPrimio

Bowles

et al. 2012

J Virol

View full text Add to dashboard Cite

Adeno-associated virus (AAV) vectors have the potential to promote long-term gene expression. Unfortunately, humoral immunity restricts patient treatment and in addition provides an obstacle to the potential option of vector readministration. In this study, we describe a comprehensive characterization of the neutralizing antibody (NAb) response to AAV type 1 (AAV1) through AAV5 both in vitro and in vivo. These results demonstrated that NAbs generated from one AAV type are unable to neutralize the transduction of other types. We extended this observation by demonstrating that a rationally engineered, muscle-tropic AAV2 mutant containing 5 amino acid substitutions from AAV1 displayed a NAb profile different from those of parental AAV2 and AAV1. Here we found that a single insertion of Thr from AAV1 into AAV2 capsid at residue 265 preserved high muscle transduction, while also changing the immune profile. To better understand the role of Thr insertion at position 265, we replaced all 20 amino acids and evaluated both muscle transduction and the NAb response. Of these variants, 8 mutants induced higher muscle transduction than AAV2. Additionally, three classes of capsid NAb immune profile were defined based on the ability to inhibit transduction from AAV2 or mutants. While no relationship was found between transduction, amino acid properties, and NAb titer or its cross-reactivity, these studies map a critical capsid motif involved in all steps of AAV infectivity. Our results suggest that AAV types can be utilized not only as templates to generate mutants with enhanced transduction efficiency but also as substrates for repeat administration.A deno-associated virus (AAV) vectors have been safely and successfully used in phase I clinical trials (39,40,54). In particular, therapeutic effects have been achieved in patients with Leber's congenital amaurosis and hemophilia B. Among 30 patients with Leber's congenital amaurosis, 28 demonstrated remarkably improved eyesight after AAV type 2 (AAV2) delivery of the rpe65 gene to the retina. Regarding the recent hemophilia B trial, all six patients had therapeutic factor IX (FIX) expression within a beneficial 1% to 8% of normal levels as long as 18 months after intravenous delivery of an AAV vector encoding an optimized FIX cassette (54).AAV is a nonenveloped, single-stranded DNA virus that requires a helper virus, such as adenovirus (Ad) or herpes simplex virus, for efficient replication. Despite the lack of inflammation or other AAV-associated complications following administration of AAV2 vectors in several organs, neutralizing antibody (NAb) titers against the AAV2 capsid were found to be significantly increased following vector administration, particularly in the lung, muscle, and liver (7, 8, 43-45, 49, 54, 63). NAbs in circulation are able to block AAV transduction after systemic administration. Recently, Manno et al. (44) performed a phase I study of AAV-mediated FIX transgene delivery in patients with hemophilia B, in which one patient with a higher preexisting NAb ti...

show abstract

Immune Response and Intraocular Inflammation in Patients With Leber Hereditary Optic Neuropathy Treated With Intravitreal Injection of Recombinant Adeno-Associated Virus 2 Carrying the ND4 Gene

et al. 2019

View full text Add to dashboard Cite

IMPORTANCE Intravitreal gene therapy is regarded as generally safe with limited mild adverse events, but its systemic effects remain to be investigated. OBJECTIVE To examine the association between immune response and intraocular inflammation after ocular gene therapy with recombinant adeno-associated virus 2 carrying the ND4 gene (rAAV2/2-ND4). DESIGN, SETTING, AND PARTICIPANTS This secondary analysis of an open-label, dose-escalation phase 1/2 randomized clinical trial of rAAV2/2-ND4 included data from February 13, 2014 (first patient visit), to March 30, 2017 (last patient visit at week 96), the first 2 years after injection. Patients older than 15 years with diagnosed ND4 Leber hereditary optic neuropathy (LHON) and visual acuity of at least counting fingers were enrolled in 1 of 5 cohorts. Four dose cohorts of 3 patients each were treated sequentially. An extension cohort of 3 patients received the dose of 9 × 10 10 viral genomes per eye. INTERVENTIONS Patients received increasing doses of rAAV2/2-ND4 (9 × 10 9 , 3 × 10 10 , 9 × 10 10 , and 1.8 × 10 11 viral genomes per eye) as a single unilateral intravitreal injection. Patients were monitored for 96 weeks after injection; ocular examinations were performed regularly, and blood samples were collected for immunologic testing. MAIN OUTCOMES AND MEASURES A composite ocular inflammation score (OIS) was calculated based on grades of anterior chamber cells and flare, vitreous cells, and haze according to the Standardization of Uveitis Nomenclature. The systemic immune response was quantified by enzyme-linked immunospot (cellular immune response), enzyme-linked immunosorbent assay (IgG titers), and luciferase assay (neutralizing antibody [NAb] titers). RESULTS The present analysis included 15 patients (mean [SD] age, 47.9 [17.2] years; 13 men and 2 women) enrolled in the 5 cohorts of the clinical trial. Thirteen patients experienced intraocular inflammation after rAAV2/2-ND4 administration. Mild anterior chamber inflammation and vitritis were reported at all doses, and all cases were responsive to treatment. A maximum OIS of 9.5 was observed in a patient with history of idiopathic uveitis. Overall, OIS was not associated with the viral dose administered. No NAbs against AAV2 were detected in aqueous humor before treatment. Two patients tested positive for cellular immune response against AAV2 at baseline and after treatment. Humoral immune response was not apparently associated with the dose administered or with the immune status of patients at baseline. No association was found between OISs and serum NAb titers. CONCLUSIONS AND RELEVANCE In this study, intravitreal administration of rAAV2/2-ND4 in patients with LHON was safe and well tolerated. Further investigations may shed light into the local immune response to rAAV2/2-ND4 as a potential explanation for the observed intraocular inflammation.

show abstract

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

Cited by 778 publications

References 56 publications

Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia

Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia

Single Amino Acid Modification of Adeno-Associated Virus Capsid Changes Transduction and Humoral Immune Profiles

Immune Response and Intraocular Inflammation in Patients With Leber Hereditary Optic Neuropathy Treated With Intravitreal Injection of Recombinant Adeno-Associated Virus 2 Carrying the ND4 Gene

Contact Info

Product

Resources

About