Enzymes replacement

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). 

Aiuti A, Vai S, MorteUaro A, Casorati G, Ficara F, Andolfi G, Ferrari G, Tabucchi A, Carlucci F, Ochs HD, Notarangelo LD, Roncarolo MG, Bordignon C (2002b) Immune reconstitution in ADA-SCID after PBL gene therapy and discontinuation of enzyme replacement. Nat Med 8 423 25... 

The replacement of His 234 with Lys abolished the enzymatic activity, confirming the biochemical evidence obtained by Cooke et al. [13] and by Rexova-Benkova et aL [14] that a histidine readue is critical for the activity of the enzyme. Replacement of either Ser 237 or Ser 240 with Gly reduced the enzyme activity to 48% and 6% reqrectively, indicating that Ser residues are also inqrortant for the activity. 

Maximizing nutritional status through pancreatic enzyme replacement and vitamin and nutritional supplements is necessary for normal growth and development and for maintaining long-term lung function. 

Pancreatic enzyme replacement is the mainstay of gastrointestinal therapy. Most enzyme products are formulated as capsules containing enteric-coated microspheres or microtablets to avoid inactivation of enzymes in the acidic stomach instead, they dissolve in the more alkaline environment of the duodenum. Capsules may be opened and the microbeads swallowed with food, as long as they are not chewed. A powder form is available for patients unable to swallow the capsules or microbeads, but bioavailability is poor. While products may contain similar enzyme ratios, they are not bioequivalent and cannot be substituted. Generic enzyme products generally display poor dissolution and should not be used.5 Table 13-3 lists commonly used enzyme replacement products. 

TABLE 13-3. Common Pancreatic Enzyme Replacement Products... 

Laboratory testing confirms the diagnosis of CF, and Jessica has been referred to her regional CF center for treatment. Additional stool studies indicate the presence of severe fat maldigestion. The pulmonologist indicates that she would like to start Jessica (weight 8.2 kg) on pancreatic enzyme replacement therapy. 

Evaluate the patient s stool patterns. Steatorrhea indicates suboptimal enzyme replacement or non-compliance. Infants should have two to three well-formed stools daily, while older children and adults may have one or two stools. 

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). 

H3. Hershfield, M. S Chaffee, S., and Sorensen, R. U., Enzyme replacement therapy with polyethylene glycol-adenosine deaminase in adenosine deaminase deficiency Overview and case reports of three patients, including two now receiving gene therapy. Pediatr. Res. 33 (Suppl.), S42-S48 (1993). 

Martiniuk, F., Chen, A., Donnabella, V. et al. (2000) Correction of glycogen storage disease type II by enzyme replacement with a recombinant human acid maltase produced by over-expression in a CHO-DHFR(neg) cell line. Biochemical and Biophysical Research Communications, 276 (3), 917-923. 

Schiffmann, R., Floeter, M. K., Dambrosia, J. M. et al. Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease. Muscle Nerve 28 703-710, 2003. 

Winkel, L. P., Van den Hout, J. M., Kamphoven, J. H. et al. Enzyme replacement therapy in late-onset Pompe s disease a three-year follow-up. Ann Neurol 55 495-502, 2004. 

Oral pancreatic enzyme supplements are available as powders, uncoated or coated tablets, capsules, enteric-coated spheres and microspheres, or enteric-coated microtablets encased in a cellulose or gelatin capsule (Table 28-2). Microencapsulated enteric-coated products are not superior to recommended doses of conventional non-enteric-coated enzyme preparations. The quantity of active lipase delivered to the duodenum appears to be a more important determinant in pancreatic enzyme replacement therapy than the dosage form. GI side effects appear to be dose related but occur less frequently with enteric-coated products. 

Enzyme replacement Gaucher s disease, Fabry disease, and mucopolysaccharidosis Cerezyme, Fabrazyme, Aldurazyme... 

Adenosine deaminase (ADA) deficiency, an autosomal recessive disorder, produces severe combined immunodeficiency (SCID). Lacking both B-cell and T-cell function, children are multiply infected with many organisms Pneumocystis carinii, Candida) and do not survive without treatment. Enzyme replacement therapy and bone marrow transplantation may be used. Experimental gene therapy trials have not yet yielded completely successfiil cures. 

Xylose isomerases with higher thermostability were found in the strains of Streptomyces and relaxed Actinoplanaceae (which includes the generdLAmpullariella and Actinopianes). High thermo-tolerance is desirable for production of HFCS because at equilibrium, as the temperature of the enzyme reaction is increased, the ketose/aldose ratio increases proportionately 30). In addition, reactors running at higher temperatures have less risk of microbial contamination, allowing for less frequent and less costly enzyme replacement. 

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