Correction of factor VIII deficiency in a murine model for hemophilia a through targeting factor VIII transgene expression to epidermis

Fakharzadeh, Steven; Sarkart, R.; Zhang, Y.; Kazazian, Haig H.

doi:10.1016/s0923-1811(98)83183-6

Cited by 3 publications

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“…Within the limits and assumptions of these calculations, we felt that this was an excellent beginning. Recently, Fakharzadeh et al have reported the rescue of factor VIII‐deficient mice by epidermal release of the coagulation factor (27). Female factor VIII‐deficient mice (−/−) were mated with male mice transgenic for an involucrin promoter–factor VIII transgene.…”

Section: Route Of An Epidermis‐secreted Protein To the Circulationmentioning

confidence: 99%

Systemic Replacement Therapy from Genetically Modified Epidermal Keratinocytes

Taichman

1999

Proc Assoc American Phys

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Section: Route Of An Epidermis‐secreted Protein To the Circulationmentioning

confidence: 99%

Systemic Replacement Therapy from Genetically Modified Epidermal Keratinocytes

Taichman

1999

Proc Assoc American Phys

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“…Current applications of genetic pharmacology being studied are the production of various clotting factors in hematologic disorders or the use of erythropoietin‐encoding DNA for enhanced red blood cell reproduction in patients with chronic anemias. 50–78 Similarly, expression of various hormones, growth factors, etc., can modify pathologic conditions. Methods of administration of such genes include, for example, IM injections, introduction of the genes to the skin by gene gun delivery, or grafting of genetically modified keratinocytes into the skin.…”

Section: Current Applications Of the Gene Gunmentioning

confidence: 99%

The gene gun: current applications in cutaneous gene therapy

et al. 2000

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“…Recent studies showed that skin transplants from doubly transgenic mice that expressed factor VIII only under the dermis-specific involucrin promoter were able to reconstitute clotting in factor VIII/RAG double knockout mice. 48…”

Section: Use Of Retroviral Vectors As Ex Vivo Transduction Agentsmentioning

confidence: 99%

Animal Testing of Retroviral-Mediated Gene Therapy for Factor VIII Deficiency

Greengard

Jolly²

1999

Thromb Haemost

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IntroductionHemophilia A results from the plasma deficiency of factor VIII, a gene carried on the X chromosome. Bleeding results from a lack of coagulation factor VIII, a large and complex protein that circulates in complex with its carrier, von Willebrand factor (vWF).1 Severe hemophilia A (<1% of normal circulating levels) is associated with a high degree of mortality, due to spontaneous and trauma-induced, life-threatening and crippling bleeding episodes.2 Current treatment in the United States consists of infusion of plasma-derived or recombinant factor VIII in response to bleeding episodes.3 Such treatment fails to prevent cumulative joint damage, a major cause of hemophilia-associated morbidity.4 Availability of prophylactic treatment, which would reduce the number and severity of bleeding episodes and, consequently, would limit such joint damage, is limited by cost and the problems associated with repeated venous access. Other problems are associated with frequent replacement treatment, including the dangers of transmission of blood-borne infections derived from plasma used as a source of factor VIII or tissue culture or formulation components. These dangers are reduced, but not eliminated, by current manufacturing techniques. Furthermore, approximately 1 in 5 patients with severe hemophilia treated with recombinant or plasma-derived factor VIII develop inhibitory humoral immune responses. In some cases, new inhibitors have developed, apparently in response to unnatural modifications introduced during manufacture or purification.5 Gene therapy could circumvent most of these difficulties. In theory, a single injection of a vector encoding the factor VIII gene could provide constant plasma levels of factor in the long term. However, long-term expression after gene transfer of a systemically expressed protein in higher mammals has seldom been described. In some cases, a vector that appeared promising in a rodent model has not worked well in larger animals, for example, due to a massive immune response not seen in the rodent.6 An excellent review of early efforts at factor VIII gene therapy appeared in an earlier volume of this series.7 A summary of results from various in vivo experiments is shown in Table 1. This chapter will focus on results pertaining to studies using vectors based on murine retroviruses, including our own work.

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Correction of factor VIII deficiency in a murine model for hemophilia a through targeting factor VIII transgene expression to epidermis

Cited by 3 publications

References 0 publications

Systemic Replacement Therapy from Genetically Modified Epidermal Keratinocytes

Systemic Replacement Therapy from Genetically Modified Epidermal Keratinocytes

The gene gun: current applications in cutaneous gene therapy

Animal Testing of Retroviral-Mediated Gene Therapy for Factor VIII Deficiency

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