Protein replacement therapy

Since the mid 1960s, with the discovery of cryoprecipitate by Judith Graham Pool, there has been a growing understanding of the biology associated with protein replacement therapies (Pool and Shannon, 1965). A serious recurring obstacle to protein replacement therapies is the development of inhibitory antibodies in some... 

There are two protein replacement products available for A1AD, both pooled human plasma donor-derived products. Approval of these products was based upon replacement of serum AAT to the above-mentioned levels. Neither has been proven to prevent lung disease in a prospective, double-blinded placebo-controlled fashion, but retrospective registry data suggest a beneficial effect. However, protein replacement therapy has been very safe. Particularly remarkable has been the lack of an adaptive immune response by patients on therapy, which may relate to the genetic homogeneity of this A1AD population, in which approximately 95% have one particular missense mutant allele (PI Z). 

Other Targets and Protein Replacement Therapy for Anti-angiogenesis... 

Boyer, S. H., Siggers, D. C., and Krueger, L. J., 1973, Caveat to protein replacement therapy for genetic disease. Immunological implications of accurate molecular diagnosis, Lancet 2 654. 

Antihemophilic factor [9001-28-9] (AHF) is a protein found in normal plasma that is necessary for clot formation. It is needed for transformation of prothrombin to thrombin. Administration of AHF by injection or infusion can temporarily correct the coagulation defect present in patients with hemophilia. Antihemophilic factor VIII (Alpha Therapeutic) has been approved by the FDA as replacement therapy in patients with hemophilia B to prevent bleeding episodes, and also during surgery to correct defective hemostasis (178). 

One limitation of enzyme replacement therapy is the targeting of enzyme proteins to appropriate sites of substrate accumulation. Administration of a cholesterol esterase conjugated to albumin results in the degradation of pathologic cholesterol ester accumulations within the lysosomes of fibroblasts from a patient with cholesterol ester storage disease (246). 

HMG CoA-Reductase HMG-CoA-Reductase Inhibitors Homologous Desensitization Homologous Proteins Homologous Recombination Homology Modeling Hormonal Contraceptives Hormone Replacement Therapy (HRT)... 

Observational studies have suggested possible favourable effects of estrogen replacement therapy (ERT) on the risk of coronary heart disease in postmenopausal women. Since elevated plasma cholesterol has been identified as the primary risk factor for cardiovascular disease, investigations have focused on the inverse association between plasma cholesterol concentration and soy protein consumption. The cholesterol-lowering properties of soy have been demonstrated, and a good correlation has been found in... 

WAGNER J D, CEFALU W T, ANTHONY M S, LITWAK K N, ZHANG L and CLARKSON T B (1997) Dietary soy protein and estrogen replacement therapy improve cardiovascular risk factors and decrease aortic cholesteryl ester content in ovariectomized cynomolgus monkeys. ... 

ADA deficiency is most commonly associated with these mutations of the ADA structural gene that result in either unstable or inactive enzyme protein. Immune reconstitution would be achieved by enzyme replacement therapy with polyethylene glycol-modified bovine ADA (PEG-AD A), alone or in combination with gene therapy (H3). 

Uint L, Gebara OC, Pinto LB, Wajngarten M, Boschcov P, da Luz PL, Gidlund M (2003) Hormone replacement therapy increases levels of antibodies againstheatshock protein 65 and certain species of oxidized low density lipoprotein. Braz J Med Biol Res 36 491-494... 

Walsh BW, Paul S, Wild RA, Dean RA, Tracy RP, Cox DA, Anderson PW (2000) The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women a randomized, controlled trial. J Clin Endocrinol Metab 85 214-218... 

To date, most approved protein-based drugs are for therapeutic or replacement therapies. They are recombinant versions of natural proteins such as insulin and erythropoietin. Their characteristics and functions are relatively well defined and known. The next phase of biopharmaceuticals, such as antibodies and vaccines, is more complex and requires more tests and characterizations. Controls for the reliability, contamination, and fidelity of expression systems will be high on the agenda in the coming decade. 

Isolated soy protein, rich in phytoestrogen, enhances vascular reactivity in female monkeys with atherosclerosis, an effect similar to that observed with estrogen replacement therapy. The effect appears dependent on the phytoestrogen content of soy and is not observed when animals are fed soy protein devoid of its phytoestrogen content (Honore et al., 1997). One in vitro study... 

Therapy is relatively simple and requires only intravenous infusion of gammaglobulin. Unfortunately, the cost is high although it is essential to appreciate that such replacement therapy does not necessarily need to raise the amounts of protein in the plasma to be life-saving. The important clinical requirement is the decrease and preferable abolition of acute bacterial infections. 

The availability of endogenous enzymes and their variants has allowed the use of enzymes as replacement therapy and as therapeutic agents. With continued refinement in recombinant protein technology, the cost of human recombinant proteins may become more affordable. As more novel human recombinant enzymes are developed, a wide variety of medical disorders will be amenable to enzyme therapies. Additional molecular engineering such as pegylation or creation and modification of... 

Adenosine deaminase (ADA) was the first therapeutic enzyme coupled to PEG with the aim of reducing clearance and thereby overcoming the short half-life of ADA. Patients deficient in ADA are unable to regulate purine metabolism. As a result purine metabolites (e.g., adenosine monophosphate) accumulate to cytotoxic levels in B-lymphocytes and lead to severe B-cell depletion that presents clinically as severe combined immunodeficiency syndrome (SCIDS). While intramuscular injection of unmodified ADA provides some relief, antibodies develop rapidly against the protein and prevent it from being useful as replacement therapy. Even in the absence of antibodies, unmodified ADA s plasma half-life is only a few minutes. 

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