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Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis; 2006.

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Fabry Disease: Perspectives from 5 Years of FOS.

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Chapter 10Enzyme replacement therapy – a brief history


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The concept of enzyme replacement therapy for lysosomal storage diseases was enunciated by de Duve in 1964. However, much cell biology had to be learned before lysosomal enzymes could be developed into pharmaceuticals. A model system, consisting of cultured skin fibroblasts from patients with mucopolysaccharidoses (MPS), showed that their defective glycosaminoglycan catabolism could be corrected by factors derived from cells of a different genotype. The corrective factors were identified as lysosomal enzymes with a special feature, or recognition signal, that would permit efficient uptake. As the recognition signal was absent from a number of lysosomal enzymes secreted by fibroblasts from patients with I-cell disease (a monogenic disorder), it was postulated to be a post-translational modification of the lysosomal enzymes. It was subsequently shown to be a carbohydrate and identified as mannose-6-phosphate (M6P), which was recognized by ubiquitous M6P receptors. A second model system was the clearance, in vivo, of lysosomal enzymes from plasma. The recognition signal for this system was identified as mannose, and clearance was shown to be mediated by the mannose receptor of the reticuloendothelial system. This second system was immediately put to use for the treatment of Gaucher disease type I, in which macrophages are the affected cells. Native, and later recombinant, glucocerebrosidase was modified to expose terminal mannose residues; it became the first successful pharmaceutical for a lysosomal storage disease. Recombinant lysosomal enzymes containing the M6P signal have been developed (or are in the advanced stages of development) into pharmaceuticals for the treatment of Fabry disease, MPS I, MPS II, MPS VI and Pompe disease.


The concept of enzyme replacement therapy for lysosomal storage diseases was introduced four decades ago by Christian de Duve, with the following brief explanation: "In our pathogenic speculations and in our therapeutic attempts, it may be well to keep in mind that any substance which is taken up intracellularly in an endocytic process is likely to end up within lysosomes. This obviously opens up many possibilities for interaction, including replacement therapy" [1]. The connection between endocytosis and lysosomes was already well established [2] but the concept of lysosomal storage diseases was new at the time, having just been proposed by Hers and collaborators after the discovery of acid maltase deficiency as the basis of Pompe disease [3]. Experimental support for enzyme replacement came from the effectiveness of administering invertase to hydrolyse sucrose in liver lysosomes in vivo [2] or in lysosomes of cultured macrophages in vitro [4]. However, immediate attempts to apply the concept to the treatment of patients with Pompe disease were not successful [3, 5].

Corrective factors and recognition signals

A model system for enzyme replacement therapy arose from studies of cultured skin fibroblasts derived from patients with mucopolysaccharide storage diseases (MPS). Such fibroblasts showed excessive accumulation of [35S]glycosaminoglycans, which was interpreted as being due to inadequate degradation of these macromolecules [6]. It was discovered serendipitously that a mixture of fibroblasts derived from patients with MPS I (Hurler syndrome) and MPS II (Hunter syndrome) had a normal pattern of [35S]glycosaminoglycan metabolism (Figure 1) [7]. The two diseases were known to be genetically distinct [8], MPS I being inherited in an autosomal recessive fashion and MPS II being an X-linked disorder, leading Fratantoni et al. [7] to hypothesize that the fibroblasts of different genotypes were providing each other with the missing gene product. Further studies showed that it was not necessary to have the genetically distinct cells in contact with each other for such cross-correction, as medium conditioned by one could be corrective to the other [9]. The strategy of cross-correction could be extended to related diseases – cells that corrected each other would have a different genotype, whereas cells that didn't cross-correct would have the same genotype (but see the important exception below).

Figure 1. When Hurler and Hunter cells were mixed in culture, an essentially normal pattern of [35S]mucopolysaccharide accumulation was obtained; that is, cells of the two different genotypes had corrected each other in culture.

Figure 1

When Hurler and Hunter cells were mixed in culture, an essentially normal pattern of [35S]mucopolysaccharide accumulation was obtained; that is, cells of the two different genotypes had corrected each other in culture. Adapted with permission from [7]. (more...)

As Hurler syndrome had been postulated to be a lysosomal storage disease based on observation of the dramatically swollen liver lysosomes in affected patients [10], Fratantoni et al. [9] hypothesized that the 'corrective factors' in conditioned medium might be lysosomal enzymes that were secreted by one cell line and endocytosed by the other. However, the corrective factors did not correspond to any lysosomal enzyme known at the time (this situation changed a couple of years later, when a β-glucuronidase deficiency MPS was discovered [11, 12]). Purification of the Hurler and Hunter corrective factors was undertaken, not from conditioned medium but from urine, a body fluid relatively rich in lysosomal enzymes. Function was assigned to the purified factors by using a variety of biochemical methods, resulting in the Hurler and Hunter corrective factors being named α-l-iduronidase and iduronate sulfatase respectively [13, 14].

Cells that required Hurler corrective factor to normalize their [35S]glycosaminoglycan metabolism (from patients with Hurler syndrome and with Scheie syndrome [15]) were also deficient in α-l-iduronidase activity [13, 14]). Correction of Hurler fibroblasts was accompanied by uptake of α-l-iduronidase. As good portents for enzyme replacement therapy, uptake was remarkably efficient and only a very small amount of α-l-iduronidase had to be internalized in order to provide complete correction.

This might have been the end of the story, except for a small discrepancy in the elution pattern of the enzymatic activity and the corrective activity from a hydroxyapatite column [13], suggesting that the two activities of the Hurler corrective factor were not precisely identical. Following up on this discrepancy, Shapiro et al. [16] separated α-l-iduronidase into corrective and non-corrective fractions on a column of heparin-Sepharose, indicating that the corrective factor had some feature that was not needed for catalytic activity but was needed for uptake. Similarly, multiple forms of β-glucuronidase were found, differing in uptake and corrective activity [17, 18].

The existence of a specific signal for uptake of a lysosomal enzyme had been suggested by the results of a study into a newly discovered disorder resembling the MPS – named inclusion-cell disease (I-cell disease) because of the prominent phase-dense inclusions in cultured fibroblasts [19]. While these fibro-blasts had multiple lysosomal enzyme deficiencies, the medium surrounding them contained a large excess of lysosomal enzymes [20, 21]. However, the enzymes secreted by I-cell disease fibroblasts were not endocytosed by other cells and were not corrective; presumably, they lacked the signal for uptake into lysosomes [22]. Because a number of lysosomal enzymes were affected by this single gene defect (I-cell disease is inherited in an autosomal recessive manner), the signal was postulated to be a post-translational modification of the enzyme proteins. It was further postulated to be carbohydrate in nature, as it could be destroyed by mild periodate treatment [23]. The concept of a recognition system based on carbohydrates was strongly influenced by the discoveries of Ashwell and colleagues regarding the role of carbohydrates in the uptake of circulating glycoproteins by the liver [24, 25].

The presence of a specific recognizable signal implied a saturable, receptor-mediated process, and suggested that uptake of lysosomal enzymes would follow Michaelis–Menten kinetics. It was expected that analogues of the recognition signals would behave as competitive inhibitors of uptake. This expectation was investigated via the uptake of α-l-iduronidase [26] and of β-glucuronidase [27] by the corresponding deficient fibroblasts. The discovery by Kaplan et al. [27] that the best inhibitor of β-glucuronidase uptake was mannose-6-phosphate (M6P), and their suggestion that M6P was (or was part of) the long-sought recognition signal, was startling, as no phosphorylated carbohydrate had previously been reported to exist on mammalian glycoproteins [27]. It was immediately confirmed for the uptake of α-l-iduronidase [26] and other lysosomal enzymes, using a variety of biochemical methods [2830]; the ultimate proof came from structural analysis of the phosphorylated carbohydrate groups [31]. The signal discovered through endocytosis proved also to be the signal for targeting nascent hydrolases to lysosomes [32].

The defect in I-cell disease, which prevents the cells from synthesizing the M6P recognition signal, was shown to be a deficiency of the first of two enzymes involved in the synthesis of the M6P signal [33, 34]. Two receptors for M6P were discovered; the chemistry and biology of the M6P receptors and their role in cell trafficking became a broad and very active field of cell biology [35]. These topics are the subjects of many reviews, including Chapters 3 and 5 of this volume. The significance of the M6P system for enzyme replacement therapy will be discussed below.

Concurrent with these studies in cultured fibroblasts, an in-vivo system led to the finding of another signal for uptake of lysosomal enzymes. Several lysosomal enzymes, injected intravenously into rats, were found to be rapidly cleared from the circulation; however, they persisted much longer if pretreated with periodate or if co-injected with an agalactoglycoprotein [36, 37]. Again, carbohydrates were postulated to provide signals for specific recognition. In this case, the key sugar for recognition was mannose [38], and uptake was into reticuloendothelial cells of the liver [39, 40]. The mannose receptor, which recognizes N-acetylglucosamine and l-fucose as well as mannose, was shown to occur on the surface of macrophages [41, 42]. It is of some historic interest that the invertase uptake experiments, which featured prominently in the original proposal of enzyme replacement therapy (see above [2, 4]), were successful because invertase is a glycoprotein with mannan chains that are recognized by the mannose receptor [43].

Development of enzyme replacement therapy

Realization that uptake of lysosomal enzymes was receptor-mediated had obvious implications for therapy. To be safe and therapeutically useful, not only would a lysosomal enzyme have to be of human origin, highly purified and available in adequate quantity, but it would also have to carry the recognition signal for the target cells. Such an enzyme was first developed by Brady and colleagues for type 1 Gaucher disease. In this disorder, the target cells are macrophages, cells that have surface receptors recognizing mannose residues. Highly purified placental glucocerebrosidase was sequentially treated with exo-glycosidases to remove the sialic acid, galactose and N-acetylglucosamine residues from its complex oligosaccharides; uptake into non-parenchymal cells was highest when all three glycosidases were used [44]. In contrast to native enzyme, which gave limited results when administered to patients, glucocerebrosidase with exposed mannose residues was remarkably successful in reversing clinical manifestations of type I Gaucher disease [45, 46] and was approved by the Food and Drug Administration. It was soon replaced with recombinant glucocerebrosidase secreted by over-expressing Chinese hamster ovary (CHO) cells, which was as effective clinically as the placental enzyme but was preferable because it could be made available in unlimited amounts and was free of pathogens. The recombinant enzyme was also trimmed with the three exo-glycosidases to expose mannose residues [47].

Producing lysosomal enzymes with the M6P signal for targeting to other cells was more difficult because it was not possible to use enzyme purified from tissue. The phosphate group is necessary to target the enzyme to lysosomes, but is not needed for the activity of the enzyme once it resides within the organelle; thus, tissue enzyme is generally dephosphorylated, in whole or in part, by acid phosphatase present in lysosomes. However, CHO cells and other cultured cells over-expressing a soluble recombinant lysosomal enzyme can secrete a highly phosphorylated form, as first demonstrated for α-galactosidase [48]. Such secretion by over-expressing CHO cells has also been demonstrated for a number of other lysosomal enzymes, including α-l-iduronidase [49] and α-glucosidase [50]. The cell biology underlying this secretion is not well understood, but its usefulness is undeniable and forms the basis of commercial production of several therapeutic lysosomal enzymes. Human cells may be used in a similar way, and therapeutic recombinant enzymes made by CHO cells and by human fibroblasts have been produced for Fabry disease. The development of enzyme replacement therapy for Fabry disease is the subject of Chapter 36 in this volume.

The story of enzyme replacement therapy would not be complete without some mention of animal models in the development process. Although therapeutic glucocerebrosidase was developed without pre-testing in an animal model (none would be available for another 8 years [51]), subsequent pre-clinical studies all included trials on animal models of the deficiency. Dogs [52], cats [53], quail [54] and mice [55] have been used to show a therapeutic effect of the lysosomal enzyme prior to initiation of clinical trials.

It took nearly three decades to progress from the concept of enzyme replacement to commercial development of glucocerebrosidase as a pharmaceutical for Gaucher disease, and an additional decade for the commercial development of α-l-iduronidase, α-galactosidase, α-glucosidase, N-acetylgalactosamine 4-sulfatase and iduronate sulfatase as pharmaceuticals for their respective deficiency diseases (MPS I, Fabry disease, Pompe disease, MPS VI and MPS II). Much of that delay was time needed for understanding the basic science underlying receptor-mediated endocytosis and trafficking of these enzymes. Perhaps this holds a lesson for other forms of therapy that are currently under development, such as gene therapy or stem cell therapy.


de Duve C. From cytases to lysosomes. Fed Proc. 1964;23:1045–9. [PubMed: 14209796]
de Duve C, Wattiaux R. Functions of lysosomes. Annu Rev Physiol. 1966;28:435–92. [PubMed: 5322983]
Baudhuin P, Hers HG, Loeb H. An electron microscopic and biochemical study of type II glycogenosis. Lab Invest. 1964;13:1139–52. [PubMed: 14207888]
Cohn ZA, Ehrenreich BA. The uptake, storage, and intracellular hydrolysis of carbohydrates by macrophages. J Exp Med. 1969;129:201–25. [PMC free article: PMC2138593] [PubMed: 5782768]
de Barsy T, Jacquemin P, Van Hoof F, Hers HG. Enzyme replacement in Pompe disease: an attempt with purified human acid α-glucosidase. Birth Defects Orig Artic Ser. 1973;9:184–90. [PubMed: 4611528]
Fratantoni JC, Hall CW, Neufeld EF. The defect in Hurler's and Hunter's syndromes: faulty degradation of mucopolysaccharide. Proc Natl Acad Sci USA. 1968;60:699–706. [PMC free article: PMC225102] [PubMed: 4236091]
Fratantoni JC, Hall CW, Neufeld EF. Hurler and Hunter syndromes: mutual correction of the defect in cultured fibroblasts. Science. 1968;162:570–2. [PubMed: 4236721]
McKusick VA, Kaplan D, Wise D, Hanley WB, Suddarth SB, Sevick ME. et al. The genetic mucopolysaccharidoses. Medicine (Baltimore). 1965;44:445–83. [PubMed: 4221470]
Fratantoni JC, Hall CW, Neufeld EF. The defect in Hurler and Hunter syndromes. II. Deficiency of specific factors involved in mucopolysaccharide degradation. Proc Natl Acad Sci USA. 1969;64:360–6. [PMC free article: PMC286170] [PubMed: 4244031]
Van Hoof F, Hers HG. L'ultrastructure des cellules hepatiques dans la maladie de Hurler (gargoylisme) [Ultrastructure of hepatic cells in Hurler syndrome (gargoylism)] C R Acad Sci. 1964;259:1281–3. [PubMed: 14191205]
Sly WS, Quinton BA, McAlister WH, Rimoin DL. Beta glucuronidase deficiency: report of clinical, radiologic, and biochemical features of a new mucopolysaccharidosis. J Pediatr. 1973;82:249–57. [PubMed: 4265197]
Hall CW, Cantz M, Neufeld EF. A β-glucuronidase deficiency mucopolysaccharidosis: studies in cultured fibroblasts. Arch Biochem Biophys. 1973;155:32–8. [PubMed: 4268215]
Bach G, Friedman R, Weissmann B, Neufeld EF. The defect in the Hurler and Scheie syndromes: deficiency of α-l-iduronidase. Proc Natl Acad Sci USA. 1972;69:2048–51. [PMC free article: PMC426865] [PubMed: 4262258]
Bach G, Eisenberg F Jr,, Cantz M, Neufeld EF. The defect in the Hunter syndrome: deficiency of sulfoiduronate sulfatase. Proc Natl Acad Sci USA. 1973;70:2134–8. [PMC free article: PMC433682] [PubMed: 4269173]
Wiesmann U, Neufeld EF. Scheie and Hurler syndromes: apparent identity of the biochemical defect. Science. 1970;169:72–4. [PubMed: 4246082]
Shapiro LJ, Hall CW, Leder IG, Neufeld EF. The relationship of α- l-iduronidase and Hurler corrective factor. Arch Biochem Biophys. 1976;172:156–61. [PubMed: 3136]
Brot FE, Glaser JH, Roozen KJ, Sly WS, Stahl PD. In vitro correction of deficient human fibroblasts by β-glucuronidase from different human sources. Biochem Biophys Res Commun. 1974;57:1–8. [PubMed: 4857181]
Glaser JH, Roozen KJ, Brot FE, Sly WS. Multiple isoelectric and recognition forms of human β-glucuronidase activity. Arch Biochem Biophys. 1975;166:536–42. [PubMed: 1119807]
Hanai J, Leroy J, O'Brien JS. Ultrastructure of cultured fibroblasts in I-cell disease. Am J Dis Child. 1971;122:34–8. [PubMed: 5567403]
Lightbody J, Wiesmann U, Hadorn B, Herschkowitz N. I-cell disease: multiple lysosomal-enzyme defect. Lancet. 1971;i:451. [PubMed: 4100420]
Wiesmann UN, Lightbody J, Vassella F, Herschkowitz NN. Multiple lysosomal deficiency due to enzyme leakage? N Engl J Med. 1971;284:109–10. [PubMed: 4249768]
Hickman S, Neufeld EF. A hypothesis for I-cell disease: defective hydrolases that do not enter lysosomes. Biochem Biophys Res Commun. 1972;49:992–9. [PubMed: 4345092]
Hickman S, Shapiro LJ, Neufeld EF. A recognition marker required for uptake of a lysosomal enzyme by cultured fibroblasts. Biochem Biophys Res Commun. 1974;57:55–61. [PubMed: 4364008]
Morell AG, Gregoriadis G, Scheinberg IH, Hickman J, Ashwell G. The role of sialic acid in determining the survival of glycoproteins in the circulation. J Biol Chem. 1971;246:1461–7. [PubMed: 5545089]
Ashwell G, Morell AG. The role of surface carbohydrates in the hepatic recognition and transport of circulating glycoproteins. Adv Enzymol Relat Areas Mol Biol. 1974;41:99–128. [PubMed: 4609051]
Sando GN, Neufeld EF. Recognition and receptor-mediated uptake of a lysosomal enzyme, α-l-iduronidase, by cultured human fibroblasts. Cell. 1977;12:619–27. [PubMed: 922886]
Kaplan A, Achord DT, Sly WS. Phosphohexosyl components of a lysosomal enzyme are recognized by pinocytosis receptors on human fibroblasts. Proc Natl Acad Sci USA. 1977;74:2026–30. [PMC free article: PMC431066] [PubMed: 266721]
Kaplan A, Fischer D, Achord D, Sly W. Phosphohexosyl recognition is a general characteristic of pinocytosis of lysosomal glycosidases by human fibroblasts. J Clin Invest. 1977;60:1088–93. [PMC free article: PMC372461] [PubMed: 908752]
Ullrich K, Mersmann G, Weber E, Von Figura K. Evidence for lysosomal enzyme recognition by human fibroblasts via a phosphorylated carbohydrate moiety. Biochem J. 1978;170:643–50. [PMC free article: PMC1183943] [PubMed: 646806]
Hasilik A, Neufeld EF. Biosynthesis of lysosomal enzymes in fibroblasts. Phosphorylation of mannose residues. J Biol Chem. 1980;255:4946–50. [PubMed: 6989822]
Varki A, Kornfeld S. Structural studies of phosphorylated high mannose-type oligosaccharides. J Biol Chem. 1980;255:10847–58. [PubMed: 7430158]
Fischer HD, Gonzalez-Noriega A, Sly WS, Morre DJ. Phosphomannosyl-enzyme receptors in rat liver. Subcellular distribution and role in intracellular transport of lysosomal enzymes. J Biol Chem. 1980;255:9608–15. [PubMed: 6253448]
Reitman ML, Varki A, Kornfeld S. Fibroblasts from patients with I-cell disease and pseudo-Hurler polydystrophy are deficient in uridine 5′-diphosphate-N-acetylglucosamine: glycoprotein N-acetylglucosaminylphosphotransferase activity. J Clin Invest. 1981;67:1574–9. [PMC free article: PMC370727] [PubMed: 6262380]
Hasilik A, Waheed A, von Figura K. Enzymatic phosphorylation of lysosomal enzymes in the presence of UDP-N-acetylglucosamine. Absence of the activity in I-cell fibroblasts. Biochem Biophys Res Commun. 1981;98:761–7. [PubMed: 6452876]
Dahms NM, Lobel P, Kornfeld S. Mannose 6-phosphate receptors and lysosomal enzyme targeting. J Biol Chem. 1989;264:12115–18. [PubMed: 2545698]
Stahl P, Six H, Rodman JS, Schlesinger P, Tulsiani DR, Touster O. Evidence for specific recognition sites mediating clearance of lysosomal enzymes in vivo. Proc Natl Acad Sci USA. 1976;73:4045–9. [PMC free article: PMC431322] [PubMed: 186782]
Stahl P, Schlesinger PH, Rodman JS, Doebber T. Recognition of lysosomal glycosidases in vivo inhibitied by modified glycoproteins. Nature. 1976;264:86–8. [PubMed: 1004542]
Achord DT, Brot FE, Sly WS. Inhibition of the rat clearance system for agalacto-orosomucoid by yeast mannans and by mannose. Biochem Biophys Res Commun. 1977;77:409–15. [PubMed: 329842]
Achord DT, Brot FE, Bell CE, Sly WS. Human β-glucuronidase: in vivo clearance and in vitro uptake by a glycoprotein recognition system on reticulo-endothelial cells. Cell. 1978;15:269–78. [PubMed: 699046]
Schlesinger PH, Doebber TW, Mandell BF, White R, DeSchryver C, Rodman JS. et al. Plasma clearance of glycoproteins with terminal mannose and N-acetylglucosamine by liver non-parenchymal cells. Studies with β-glucuronidase, N-acetyl-β-d-glucosaminidase, ribonuclease B and agalacto-orosomucoid. Biochem J. 1978;176:103–9. [PMC free article: PMC1186209] [PubMed: 728098]
Stahl PD, Rodman JS, Miller MJ, Schlesinger PH. Evidence for receptor-mediated binding of glyco-proteins, glycoconjugates, and lysosomal glycosidases by alveolar macrophages. Proc Natl Acad Sci USA. 1978;75:1399–403. [PMC free article: PMC411479] [PubMed: 274729]
Pontow SE, Kery V, Stahl PD. Mannose receptor. Int Rev Cytol. 1992;137B:221–44. [PubMed: 1478821]
Rodman JS, Schlesinger P, Stahl P. Rat plasma clearance of horseradish peroxidase and yeast invertase is mediated by specific recognition. FEBS Lett. 1978;85:345–8. [PubMed: 202501]
Furbish FS, Steer CJ, Krett NL, Barranger JA. Uptake and distribution of placental glucocerebrosidase in rat hepatic cells and effects of sequential deglycosylation. Biochim Biophys Acta. 1981;673:425–34. [PubMed: 6784774]
Barton NW, Furbish FS, Murray GJ, Garfield M, Brady RO. Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease. Proc Natl Acad Sci USA. 1990;87:1913–16. [PMC free article: PMC53594] [PubMed: 2308952]
Barton NW, Brady RO, Dambrosia JM, Di Bisceglie AM, Doppelt SH, Hill SC. et al. Replacement therapy for inherited enzyme deficiency – macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med. 1991;324:1464–70. [PubMed: 2023606]
Grabowski GA, Barton NW, Pastores G, Dambrosia JM, Banerjee TK, McKee MA. et al. Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources. Ann Intern Med. 1995;122:33–9. [PubMed: 7985893]
Ioannou YA, Bishop DF, Desnick RJ. Overexpression of human α-galactosidase A results in its intracellular aggregation, crystallization in lysosomes, and selective secretion. J Cell Biol. 1992;119:1137–50. [PMC free article: PMC2289730] [PubMed: 1332979]
Kakkis ED, Matynia A, Jonas AJ, Neufeld EF. Overexpression of the human lysosomal enzyme α-l-iduronidase in Chinese hamster ovary cells. Protein Expr Purif. 1994;5:225–32. [PubMed: 7950365]
Van Hove JL, Yang HW, Wu JY, Brady RO, Chen YT. High-level production of recombinant human lysosomal acid α-glucosidase in Chinese hamster ovary cells which targets to heart muscle and corrects glycogen accumulation in fibroblasts from patients with Pompe disease. Proc Natl Acad Sci USA. 1996;93:65–70. [PMC free article: PMC40179] [PubMed: 8552676]
Liu Y, Suzuki K, Reed JD, Grinberg A, Westphal H, Hoffmann A. et al. Mice with type 2 and 3 Gaucher disease point mutations generated by a single insertion mutagenesis procedure. Proc Natl Acad Sci USA. 1998;95:2503–8. [PMC free article: PMC19391] [PubMed: 9482915]
Shull RM, Kakkis ED, McEntee MF, Kania SA, Jonas AJ, Neufeld EF. Enzyme replacement in a canine model of Hurler syndrome. Proc Natl Acad Sci USA. 1994;91:12937–41. [PMC free article: PMC45555] [PubMed: 7809150]
Byers S, Crawley AC, Brumfield LK, Nuttall JD, Hopwood JJ. Enzyme replacement therapy in a feline model of MPS VI: modification of enzyme structure and dose frequency. Pediatr Res. 2000;47:743–9. [PubMed: 10832731]
Kikuchi T, Yang HW, Pennybacker M, Ichihara N, Mizutani M, Van Hove JL. et al. Clinical and metabolic correction of Pompe disease by enzyme therapy in acid maltase-deficient quail. J Clin Invest. 1998;101:827–33. [PMC free article: PMC508631] [PubMed: 9466978]
Ioannou YA, Zeidner KM, Gordon RE, Desnick RJ. Fabry disease: preclinical studies demonstrate the effectiveness of α-galactosidase A replacement in enzyme-deficient mice. Am J Hum Genet. 2001;68:14–25. [PMC free article: PMC1234907] [PubMed: 11115376]
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