Haemophilic factors produced by transgenic livestock: abundance that can enable alternative therapies worldwide

Abstract

SummaryHaemophilia replacement factors, both plasma-derived and recombinant, are in relatively short supply and are high-cost products. This has stymied the study and development of alternative methods of administration of haemophilia therapy even in the most economically advanced countries, owing to the large amounts of material needed because bioabsorption and bioavailability of haemophilic factors can be less than 10% when using non-intravenous routes of delivery. There is therefore a need to increase access to therapy worldwide by decreasing the cost and increasing the abundance so that therapy can be achieved through simplified, alternative delivery methods. Transgenic livestock have been used to produce haemophilic factors in milk. Only the pig mammary gland has been shown to carry out the post-translational processing necessary to enable both the biological activity and long circulation half-life needed for therapeutic glycoproteins. Furthermore, the large amounts of recombinant protein that can be produced from pig milk make feasible the use of alternative delivery methods such as oral, intratracheal, subcutaneous, and intramuscular administration.

Protein Replacement Therapy and Gene Transfer in Canine Models of Hemophilia A, Hemophilia B, von Willebrand Disease, and Factor VII Deficiency

“…But their development has not been without setbacks, and limitations persist. The products are expensive (typically $50,000 to $100,000 per year for an adult) and not readily available in less developed countries (Manco-Johnson et al 2007; Roosendaal and Lafeber 2007; Van Cott et al 2004), so for most patients worldwide, replacement therapy is usually used to treat acute bleeding on demand rather than to provide continuous prophylactic coverage. Furthermore, the products’ half-life in the circulation is relatively short and quite variable among patients (e.g., 8 to 23 hours for F.VIII), mandating repeated venipunctures or port implantation for prophylactic administration (Brinkhous et al 1996; van den Berg et al 2007).…”

Haemophilia B: Christmas disease

“…Transgenic products of antithrombin and α 2 -antitrypsin are already undergoing clinical trials and a transgenic factor IX molecule derived from pigs is in the early stages of development [46]. The advantage of this approach is that it could result in the production of large amounts of coagulation factor concentrate at relatively low cost.…”

Recent Advances in Immune Modulation

“…Another strategy is to induce tolerance before gene transfer, such as recurrent exposure to protein or peptide. In hemophilia B mouse models, oral feeding of frequent high-dose hFIX (formulated in milk) [Van Cott et al, 2004], oral gene transfer [Roy et al, 1999], and repeated nasal administration of protein or peptide [Cao et al, 2006] have been developed. In hemophilia A models, new strategies include high doses of FVIII to inhibit FVIII-specific memory B cells [Hausl et al, 2005], oral feeding of FVIII-C2 domain [Rawle et al, 2004], nasal administration of peptide(s) [Rawle et al, 2006], infusion of lipopolysaccharide (LPS)-activated B-cell blasts transduced with a fusion IgG containing the C2 or A2 domains of FVIII [Lei et al, 2005], and ex vivo transduction of hematopoietic stem cells [Moayeri et al, 2005].…”