Phenotypic correction of a mouse model of hemophilia A using AAV2 vectors encoding the heavy and light chains of FVIII

Scallan, Ciaran D.; Liu, Tongyao; Parker, Amy; Patarroyo-White, Susannah; Chen, Haifeng; Jiang, Haiyan; Vargas, Joseph A.; Nagy, Dea; Powell, Stephen Joseph; Wright, J. Fraser; Sarkar, Rita; Kazazian, Haig H.; McClelland, Alan; Couto, Linda B.

doi:10.1182/blood-2003-01-0222

Cited by 68 publications

(80 citation statements)

References 38 publications

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“…Although FVIII activity initially peaked to 8% of normal, expression was not sustained, declining to 2% nine months after injection . These findings, although confirmed independently by Jiang et al (2003), are contradictory to similar preclinical and clinical studies for hemophilia B in which therapeutically effective levels of FIX are sustained over time (Manno et al, 2005 andSchuettrumpt et al, 2005). This is because FIX is a significantly smaller transgene than FVIII with a cDNA of 2.8 kb.…”

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

confidence: 48%

“…Complicating the issue, a chain imbalance was noted with a 25 to 100 fold excess of light chain. This was found to be due to inefficient translational or posttranslational processing that could not be circumvented by changing the administration ratio of heavy to light chain vectors (Scallan et al, 2003). When extended to the hemophilia A dog model, only partial phenotypic correction was achieved, irrespective of adeno-associated serotype used.…”

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

confidence: 88%

“…This smaller sequence allows for the inclusion of larger regulatory elements (such as liver specific promoters and enhancers) within the adeno-associated viral vector that are not able to be incorporated after the inclusion of the FVIII cDNA sequence. Within the Jiang (2003) and reports, a minipromoter was all that could be incorporated into the AAV-2 vector to promote FVIII expression. Therefore, it was concluded that regulatory elements, that were unable to be included in the AAV-2 vector (due to insert size restraints associated with adeno-associated viral vectors), were required to enhance FVIII expression.…”

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

confidence: 99%

See 2 more Smart Citations

Gene Therapy Strategies Incorporating Large Transgenes

Johnston¹,

Doering²,

Spencer³

2011

Gene Therapy - Developments and Future Perspectives

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

confidence: 48%

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

confidence: 88%

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

confidence: 99%

See 1 more Smart Citation

Gene Therapy Strategies Incorporating Large Transgenes

Johnston¹,

Doering²,

Spencer³

2011

Gene Therapy - Developments and Future Perspectives

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“…Stable and therapeutic levels of FVIII have been achieved in HA mice (reviewed in refs. [5][6][7][8][9] by transduction of liver with gamma retroviral vectors (RVs) [Ͼ20% of normal FVIII (10)], adenoviral vectors [Ͼ50% of normal (11)(12)(13)(14)(15)], lentiviral vectors [Ͼ5% of normal (16,17)], hydrodynamic injection of plasmid DNA [Ͼ300% of normal (18)], and adeno-associated virus vectors [2-100% of normal (19)(20)(21)(22)(23)]. Ex vivo gene therapy of endothelial cells (24) or hematopoietic stem cells (25) has also resulted in Ͼ50% of normal FVIII activity.…”

mentioning

confidence: 99%

Absence of a desmopressin response after therapeutic expression of factor VIII in hemophilia A dogs with liver-directed neonatal gene therapy

Nichols

Sarkar

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Hemophilia A (HA) is a bleeding disorder caused by factor VIII (FVIII) deficiency. FVIII replacement therapy can reduce bleeding but is expensive, inconvenient, and complicated by development of antibodies that inhibit FVIII activity in 30% of patients. Neonatal hepatic gene therapy could result in continuous secretion of FVIII into blood and might reduce immunological responses. Newborn HA mice and dogs that were injected i.v. with a retroviral vector (RV) expressing canine B domain-deleted FVIII (cFVIII) achieved plasma cFVIII activity that was 139 ؎ 22% and 116 ؎ 5% of values found in normal dogs, respectively, which was stable for 1.5 yr. Coagulation tests were normalized, no bleeding had occurred, and no inhibitors were detected. This is a demonstration of long-term fully therapeutic gene therapy for HA in a large animal model. Desmopressin (DDAVP; 1-deamino-[D-Arg 8 ]vasopressin) is a drug that increases FVIII activity by inducing release of FVIII complexed with von Willebrand factor from endothelial cells. It has been unclear, however, if the FVIII is synthesized by endothelial cells or is taken up from blood. Because the plasma cFVIII in these RVtreated dogs derives primarily from transduced hepatocytes, they provided a unique opportunity to study the biology of the DDAVP response. Here we show that DDAVP did not increase plasma cFVIII levels in the RV-treated dogs, although von Willebrand factor was increased appropriately. This result suggests that the increase in FVIII in normal dogs after DDAVP is due to release of FVIII synthesized by endothelial cells.H emophilia A (HA) is an X-linked bleeding disorder with an incidence of 1 in 5,000 males (1). Severe HA patients have Յ1% of normal factor VIII (FVIII) activity (normal levels are 200 ng͞ml) and frequently bleed spontaneously. Patients with 1-5% of normal activity have moderately severe bleeding, and patients with 5-25% of normal activity usually bleed only with surgery or trauma. HA is generally treated with FVIII protein injections, which are expensive and inconvenient. An alternative treatment for mild HA is desmopressin (DDAVP; 1-deamino-[D-Arg 8 ]vasopressin), which releases FVIII complexed with von Willebrand factor (VWF) from endothelial cells (2). It has been unclear, however, as to whether this stored FVIII is synthesized de novo in endothelial cells or taken up from blood, because both endothelial cells and hepatocytes express FVIII mRNA (3).HA is a candidate for gene therapy, which involves transfer of a FVIII gene into cells that secrete functional protein into blood. The 7-kb FVIII cDNA encodes a 2,332-aa protein that is cleaved intracellularly to an N-terminal heavy chain (A1, A2, and B domains) and a C-terminal light chain (A3, C1, and C2 domains) (4). Because the B domain released after FVIII activation is not necessary for function, B domain-deleted (BDD) constructs of only 4.5 kb have been used in most gene therapy approaches. (25) has also resulted in Ͼ50% of normal FVIII activity.Gene therapy for HA has been less effective in lar...

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“…For instance, the specific activity of canine Factor VIII has been reported to be sevenfold greater than human Factor VIII [15]. Thus, expression of a canine variant gene may allow for overall higher activity compared with a human version for equivalent levels of Factor VIII protein.…”

mentioning

confidence: 99%

Cutaneous gene therapy for haemophilia

Fakharzadeh

2004

Expert Opinion on Biological Therapy

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Phenotypic correction of a mouse model of hemophilia A using AAV2 vectors encoding the heavy and light chains of FVIII

Cited by 68 publications

References 38 publications

Gene Therapy Strategies Incorporating Large Transgenes

Gene Therapy Strategies Incorporating Large Transgenes

Absence of a desmopressin response after therapeutic expression of factor VIII in hemophilia A dogs with liver-directed neonatal gene therapy

Cutaneous gene therapy for haemophilia

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