Striatal Delivery of rAAV-hAADC to Rats with Preexisting Immunity to AAV

Sanftner, Laura; Suzuki, Brian M.; Doroudchi, Mohammad M.; Feng, Lan; McClelland, Alan; Forsayeth, John; Cunningham, Janet

doi:10.1016/j.ymthe.2003.12.005

Cited by 87 publications

(70 citation statements)

References 27 publications

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“…[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. 15 This problem is particularly relevant for patients with hemophilia because the most promising treatment relies on vector delivery to the liver through blood circulation.…”

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

188

191

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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.

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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

188

191

View full text Add to dashboard Cite

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“…Dramatic inhibition of AAV vector gene delivery by NAb's has been demonstrated in numerous animal studies (Halbert et al, , 2000Hildinger et al, 2001;Manning et al, 1998). For example, Mandel et al (Peden et al, 2004) and Sanftner et al (2004) recently reported that pre-existing humoral immunity results in a moderate to significant loss in transduction efficiency even in the brain, considered an immune privileged tissue.…”

Section: Introductionmentioning

confidence: 99%

PEG conjugation moderately protects adeno-associated viral vectors against antibody neutralization

Lee

Maheshri

Kaspar³

et al. 2005

Biotechnol. Bioeng.

132

114

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AAV gene therapy vectors have significant clinical promise, but serum neutralization poses a challenge that must be overcome. We have examined the potential of conjugating the AAV surface with activated polyethylene glycol chains to protect the vector from neutralizing antibodies. Two key parameters were investigated: the polymer chain size and the PEG:lysine conjugation ratio. Transduction data revealed that the vector is fully infectious until a critical PEG conjugation reaction ratio was exceeded, and this critical level was found to vary with polymer chain size. At this key conjugation ratio, however, particles were moderately protected from serum neutralization, 2.3-fold over unmodified vector, demonstrating that there is a small window of PEGylation for which particles are still fully infective and benefit from antibody protection. TEM results and structural analysis indicate that the drop of infectivity as the PEG concentration is increased beyond the critical conjugation ratio may be due to a combination of steric interference with viral regions necessary for infection as well as reaction at important lysine residues. However, this first study analyzing the potential of PEG to protect AAV from serum neutralization shows that the approach has promise, which can be further enhanced if the locations of PEG attachment can be more finely controlled. ß

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“…The potential utility of AAV-2 vectors for treating serious human diseases including hemophilia A and B (8), Parkinson's disease (1,19,31), heart failure (9, 21), and cystic fibrosis (14), among others, has been established in animal models. However, the presence of human preexisting antibodies reactive with primate AAV serotypes may reduce the clinical usefulness of vectors made from these serotypes (17).…”

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confidence: 99%

Novel Caprine Adeno-Associated Virus (AAV) Capsid (AAV-Go.1) Is Closely Related to the Primate AAV-5 and Has Unique Tropism and Neutralization Properties

Arbetman

Lochrie

Zhou

et al. 2005

J Virol

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Preexisting humoral immunity to adeno-associated virus (AAV) vectors may limit their clinical utility in gene delivery. We describe a novel caprine AAV (AAV-Go.1) capsid with unique biological properties. AAV-Go.1 capsid was cloned from goat-derived adenovirus preparations. Surprisingly, AAV-Go.1 capsid was 94% identical to the human AAV-5, with differences predicted to be largely on the surface and on or under the spike-like protrusions. In an in vitro neutralization assay using human immunoglobulin G (IgG) (intravenous immune globulin [IVIG]), AAV-Go.1 had higher resistance than AAV-5 (100-fold) and resistance similar to that of AAV-4 or AAV-8. In an in vivo model, SCID mice were pretreated with IVIG to generate normal human IgG plasma levels prior to the administration of AAV human factor IX vectors. Protein expression after intramuscular administration of AAV-Go.1 was unaffected in IVIG-pretreated mice, while it was reduced 5-and 10-fold after administration of AAV-1 and AAV-8, respectively. In contrast, protein expression after intravenous administration of AAV-Go.1 was reduced 7.1-fold, similar to the 3.8-fold reduction observed after AAV-8 administration in IVIG-pretreated mice, and protein expression was essentially extinguished after AAV-2 administration in mice pretreated with much less IVIG (15-fold). AAV-Go.1 vectors also demonstrated a marked tropism for lung when administered intravenously in SCID mice. The pulmonary tropism and high neutralization resistance to human preexisting antibodies suggest novel therapeutic uses for AAV-Go

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Striatal Delivery of rAAV-hAADC to Rats with Preexisting Immunity to AAV

Cited by 87 publications

References 27 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

PEG conjugation moderately protects adeno-associated viral vectors against antibody neutralization

Novel Caprine Adeno-Associated Virus (AAV) Capsid (AAV-Go.1) Is Closely Related to the Primate AAV-5 and Has Unique Tropism and Neutralization Properties

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