The treatment of hemophilia A: from protein replacement to AAV-mediated gene therapy

Shen, Youjin; Yin, Jun

doi:10.1007/s10529-008-9869-0

Cited by 14 publications

(8 citation statements)

References 58 publications

(91 reference statements)

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“…Aliquots of heparin-purified AAV2-CMV-hFIX and AAV-221-IV-CMV-hFIX were preincubated with each of the following: (1) heparin or (2) pooled plasma from immunocompetent mice that had been injected with AAV1 vector, AAV2 vector, or monoclonal antibody A20, which recognizes intact viral particles (Wobus et al, 2000). After these incubations, vectors were tested for in vitro transduction, using COS cells.…”

Section: Purification and Properties Of Aav-221-iv Particlesmentioning

confidence: 99%

Efficient AAV1–AAV2 Hybrid Vector for Gene Therapy of Hemophilia

Hauck

Xu²,

Xie

et al. 2006

Human Gene Therapy

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Adeno-associated virus (AAV) serotype 1 (AAV1) has been shown to be more effective than the well-studied AAV serotype 2 (AAV2) in muscle gene transfer. Replacement of amino acids 350 to 430 of AAV2 VP1 with the corresponding amino acids from VP1 of AAV1 resulted in a hybrid vector, termed AAV-221-IV, which behaved similarly to AAV1 in vitro and in vivo in muscle. Intramuscular injection of 1 × 10 11 vector particles per mouse of hybrid vector carrying a human FIX transgene in CD4 knockout mice resulted in an average level of human FIX in the plasma of 450 ng/ml, 4-to 10-fold higher than in mice injected with an AAV2 vector carrying the same transgene, and 80% of the transgene levels in animals treated with the same dose of AAV1. DNA analysis of injected muscle showed a 10-fold higher copy number after gene delivery by the hybrid vector compared with AAV2. A comparison of total DNA versus DNA from intact virus particles suggests a higher stability of hybrid virus particles. These results suggest that changes in the AAV capsid have an effect on virus-cell receptor interaction, and also influence trafficking and processing of the virus particle in the cell. This "hybrid vector" retains the heparin-binding sites of AAV2 and, therefore, can be purified by passage through a heparin-Sepharose column with the same efficiency as AAV2. When tested in vivo, either in CD4 knockout mice or in a hemophilic mouse model, the heparin-purified hybrid vector showed >10-fold higher activity than similarly purified AAV2. This demonstrates the utility of this hybrid vector in the performance of large-scale heparin column purification to generate a vector with a high expression profile for muscle-directed gene delivery. Initiation of clinical studies with this hybrid vector may be facilitated because it differs from AAV2 by only nine amino acids.

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Section: Purification and Properties Of Aav-221-iv Particlesmentioning

confidence: 99%

Efficient AAV1–AAV2 Hybrid Vector for Gene Therapy of Hemophilia

Hauck

Xu²,

Xie

et al. 2006

Human Gene Therapy

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“…As of 2009, twelve different serotypes have been isolated from both human and non-human primates (a number which is expected to increase), all of which vary in transduction efficiency and tissue tropism (Youjin and Jun, 2009). Serotype 2 (AAV-2) was the first adeno-associated virus to be sequenced and cloned, and was therefore the first serotype to be used within gene transfer studies (Hermonat and Muzyczka, 1984;Laughlin et al, 1983;Samulski et al, 1982).…”

Section: Gene Transfer Of Fviii With Adeno-associated Viral Vectorsmentioning

confidence: 99%

“…Wild-type AAV-2 was found to encode two large open reading frames, composed of the replication (Rep78, Rep68, Rep52, and Rep40) and capsid genes (VP1, VP2, and VP3). To accommodate transgenes, these genes were removed leaving behind the inverted terminal repeats required for replication and packaging into a viron (Youjin and Jun, 2009). AAV-2 and other AAV serotypes have the ability to efficiently transduce both non-dividing and dividing cells (Hallek et al, 1998).…”

Section: Gene Transfer Of Fviii With Adeno-associated Viral Vectorsmentioning

confidence: 99%

Gene Therapy Strategies Incorporating Large Transgenes

Johnston¹,

Doering²,

Spencer³

2011

Gene Therapy - Developments and Future Perspectives

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“…The main challenge is to develop a method that delivers the transgene to selected cells, where a proper gene expression can be achieved. Several trials have aimed at introducing genes straight into human cells, focusing on diseases caused by single-gene defects, such as cystic fibrosis [1], hemophilia [2], adenosine deaminase deficiency [3], muscular dystrophy [4], and sickle cell anemia [5]. …”

Section: Introductionmentioning

confidence: 99%

Efficient Nonviral Gene Therapy Using Folate-Targeted Chitosan-DNA Nanoparticles In Vitro

et al. 2012

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Nonviral cationic polymers like chitosan can be combined with DNA to protect it from degradation. The chitosan is a biocompatible, biodegradable, nontoxic, and cheap polycationic polymer with low immunogenicity. The objective of this study was to synthesize and then assess different chitosan-DNA nanoparticles and to select the best ones for selectivein vitrotransfection in human epidermoid carcinoma (KB) cell lines. It revealed that different combinations of molecular weight, the presence or absence of folic acid ligand, and different plasmid DNA sizes can lead to nanoparticles with various diameters and diverse transfection efficiencies. The intracellular trafficking, nuclear uptake, and localization are also studied by confocal microscopy, which confirmed that DNA was delivered to cell nuclei to be expressed.

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The treatment of hemophilia A: from protein replacement to AAV-mediated gene therapy

Cited by 14 publications

References 58 publications

Efficient AAV1–AAV2 Hybrid Vector for Gene Therapy of Hemophilia

Efficient AAV1–AAV2 Hybrid Vector for Gene Therapy of Hemophilia

Gene Therapy Strategies Incorporating Large Transgenes

Efficient Nonviral Gene Therapy Using Folate-Targeted Chitosan-DNA Nanoparticles In Vitro

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