Persistent expression of canine factor IX in hemophilia B canines

Chao, Hengjun; Samulski, R. Jude; Bellinger, Dwight A.; Monahan, Paul E.; Nichols, Timothy C.; Walsh, Christopher E.

doi:10.1038/sj.gt.3301024

Cited by 99 publications

(72 citation statements)

References 46 publications

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“…The stable expression of human FIX protein in mice and canine FIX protein in hemophilic B dogs has been demonstrated following gene transfer with rAAV vectors derived from serotype 2 [1][2][3][4][5][6] and more recently with vectors derived from alternative serotypes. 7 Hepatic portal vein (HPV) delivery of rAAV FIX vectors in mice, non-human primates and hemophilic B dogs is well tolerated without significant increases in markers of toxicity, no induction of anti-FIX inhibitors or nonneutralizing antibodies.…”

Section: Introductionmentioning

confidence: 99%

Intravenous administration of an AAV-2 vector for the expression of factor IX in mice and a dog model of hemophilia B

Harding

Koprivnikar

et al. 2004

Gene Ther

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Previous experiments have demonstrated the stable expression of factor IX (FIX) protein in mice and canine models of hemophilia B following portal vein gene transfer with a recombinant adeno-associated virus (rAAV) vector encoding FIX. Here, we present the results of studies that further optimized the rAAV vector transgene cassette used to express FIX and explored the use of the less-invasive intravenous (i.v.) route of vector administration for the treatment of hemophilia B. First, a liver-specific promoter was evaluated in conjunction with cis-acting regulatory elements in mice. Constructs that included both the b-globin intron and the woodchuck hepatitis virus post-transcriptional regulatory element resulted in the highest level of FIX expression in vivo. Using this optimized vector, we demonstrate that i.v. injection was feasible for hepatic gene transfer in mice, achieving 70-80% of portal vein expression levels of FIX. In further studies using the Chapel Hill strain of hemophilia B dogs, we demonstrate for the first time FIX expression and partial correction of the bleeding disorder following i.v. administration of an AAV vector.

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Section: Introductionmentioning

confidence: 99%

Intravenous administration of an AAV-2 vector for the expression of factor IX in mice and a dog model of hemophilia B

Harding

Koprivnikar

et al. 2004

Gene Ther

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“…11,12 Currently, AAV vectors are the most promising gene delivery system in muscle tissues due to its efficient, widespread and persistent gene transfer. Although extensive studies have been carried out using AAV vectors in skeletal muscles for both muscular dystrophies [13][14][15][16][17][18] and for metabolic diseases, [19][20][21][22] few studies involved cardiac muscles.…”

Section: Introductionmentioning

confidence: 99%

Efficient and long-term intracardiac gene transfer in δ-sarcoglycan-deficiency hamster by adeno-associated virus-2 vectors

Wang

Shen

et al. 2003

Gene Ther

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“…Transgene expression was then measured 6 weeks after administration of AAV vectors. Canine FIX levels and human ␣1-antitrypsin levels in mouse sera were detected by ELISA as previously described (14,57).…”

Section: Plasmids and Virusesmentioning

confidence: 99%

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

DiPrimio

Bowles

et al. 2012

J Virol

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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...

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Persistent expression of canine factor IX in hemophilia B canines

Cited by 99 publications

References 46 publications

Intravenous administration of an AAV-2 vector for the expression of factor IX in mice and a dog model of hemophilia B

Intravenous administration of an AAV-2 vector for the expression of factor IX in mice and a dog model of hemophilia B

Efficient and long-term intracardiac gene transfer in δ-sarcoglycan-deficiency hamster by adeno-associated virus-2 vectors

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

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