Enzyme-Replacement Therapy

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). 

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. 

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). 

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. 

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. 

Table 3-1. Examples of enzyme replacement therapy for inherited diseases.

ENZYME REPLACEMENT THERAPY FOR INBORN ERRORS OF METABOLISM... 

Lysosomal enzyme deficiencies, which frequently result in disease due to accumulation of the substrate for the missing enzyme, are suitable targets for enzyme replacement therapy (ERT). 

As with the mucolipidoses and the enzyme-deficiency diseases (see Chapters), strategies using enzyme replacement therapy are being developed fortreatmentof many of the MPS syndromes. 

Kakkis ED, Muenzer J, Tiller GE, Waber L, Belmont J, Passage M et al. Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med 2001 344(3) 182-8. 

Lidove O, Joly D, Barbey F, Bekri S, Alexandra IF, Peigne V et al. Clinical results of enzyme replacement therapy... 

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