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Review
. 2017 Sep 1:118:109-134.
doi: 10.1016/j.addr.2017.05.004. Epub 2017 May 11.

Lysosomal enzyme replacement therapies: Historical development, clinical outcomes, and future perspectives

Melani Solomon  1 , Silvia Muro  2
Affiliations
Review

Lysosomal enzyme replacement therapies: Historical development, clinical outcomes, and future perspectives

Melani Solomon et al. Adv Drug Deliv Rev. .

Abstract

Lysosomes and lysosomal enzymes play a central role in numerous cellular processes, including cellular nutrition, recycling, signaling, defense, and cell death. Genetic deficiencies of lysosomal components, most commonly enzymes, are known as "lysosomal storage disorders" or "lysosomal diseases" (LDs) and lead to lysosomal dysfunction. LDs broadly affect peripheral organs and the central nervous system (CNS), debilitating patients and frequently causing fatality. Among other approaches, enzyme replacement therapy (ERT) has advanced to the clinic and represents a beneficial strategy for 8 out of the 50-60 known LDs. However, despite its value, current ERT suffers from several shortcomings, including various side effects, development of "resistance", and suboptimal delivery throughout the body, particularly to the CNS, lowering the therapeutic outcome and precluding the use of this strategy for a majority of LDs. This review offers an overview of the biomedical causes of LDs, their socio-medical relevance, treatment modalities and caveats, experimental alternatives, and future treatment perspectives.

Keywords: Blood-brain barrier delivery; Enzyme carriers; Enzyme replacement therapy; Enzyme _targeting and delivery; ICAM-1 mediated enzyme delivery; Lysosomal diseases; Lysosomal enzyme deficiency; Lysosomal storage disorders; Multi-organ dysfunction; Neurodegeneration; Side effects.

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Figures

Figure 1
Figure 1. Lysosome function and dysfunction
(A) Lysosomal components, including structural membrane proteins, H+-ATPase pump, membrane enzymes, channels and transporters, as well as luminal lysosomal enzymes. (B) Biosynthesis route for lysosomal enzymes, encompassing nuclear transcription, endoplasmic reticulum glycosylation (B1), Golgi apparatus maturation (B2 and B3), and transport to endosomes (B4) and lysosomes (B5) via intracellular mannose-6-phosphate receptors. (C) Secretory route for lysosomal enzymes (C1), also including endocytic uptake by cell surface mannose or mannose-6-phosphate receptors (C2 and C3), for delivery to lysosomes (C4). (D) Some cellular functions in which lysosomes are involved.
Figure 2
Figure 2. Cross-correction effect of lysosomal enzymes
In a wild-type (Wt) cell, the nascent enzyme undergoes sequential post-translational modifications in the endoplasmic reticulum (A) and the Golgi apparatus (B), where the enzyme acquires mannose residues or mannose-6-phosphate (M6P) residues. A fraction of this enzyme is secreted extracellularly (C) and can bind to M6P receptor of a neighboring LD cell (D). The neighboring LD cell internalizes the functional lysosomal enzyme secreted by the healthy cell via M6P receptor endocytosis (E). Resulting endosomes containing the enzyme will eventually fuse with lysosomes (F), delivering the Wt enzyme in the LD cell and correcting the storage defect. This phenomenon is called cross-correction and forms the basis for lysosomal enzyme replacement therapy.
Figure 3
Figure 3. Examples of novel lysosomal enzyme replacement therapy approaches
(A) Enhanced enzyme activity in the heart and kidneys of the mouse model of Fabry disease, after intravenous injection with the same dose of α-galactosidase A recombinantly produced in tobacco cells (PRX-102; currently in Phase III clinical trial) versus CHO cell (clinically approved). Adapted from [210], with permission. (B) A fusion protein formed by recombinantly tagging the enzyme arylsulfatase A with a monoclonal antibody against the insulin receptor (HIRMAb-ASA; green), shows good fluorescence microscopy colocalization with lysosomes (red) when examined in metachromatic leukodystrophy (MLD) patients fibroblasts (top panel; 24 h). Radiotracing of this fusion protein also showed brain uptake 2 h after intravenous injection in Rhesus monkey (bottom panel). Adapted from [355], with permission. (C) PLGA nanoparticles _targeted by g7 glycopeptide accumulate in the brain of Iduronidase knockout mice 2 h after intravenous injection, carrying albumin as a model cargo protein. Adapted from [407], with permission. (D) Enhanced brain and peripheral biodistribution of radiolabeled, recombinant acid sphingomyelinase (the enzyme deficient in Types A–B Niemann-Pick disease), 30 min after intravenous injection of ICAM-1-_targeted polymer nanoparticles versus the “naked” enzyme currently in Phase III clinical trial (Localization Ratio (tissue-to-blood ratio) = percent of injected dose per gram of organ divided by the percent of the injected dose per gram of blood). Adapted from [426, 447], with permission.
Figure 4
Figure 4. Immunogenicity of enzymes administered for lysosomal enzyme replacement therapy
A lysosomal enzyme containing a catalytic site and a _targeting moiety (mannose or M6P) can evoke an immune response after infusion in the patient, wherein either neutralizing antibodies (A) or non-neutralizing antibodies (B) are raised against the enzyme. Neutralizing antibodies can block the enzyme _targeting site, preventing the enzyme from binding to mannose or M6P receptors on _target cells and, hence, preventing their lysosomal delivery (A1). Instead, neutralizing antibodies that bind to the enzyme catalytic site will permit its uptake by endocytosis and lysosomal trafficking into the _target cell, but will block its catalytic function, preventing substrate reduction and disease attenuation (A2). Instead, non-neutralizing antibodies do not affect these functions, but instead bind to the enzyme and tag it for removal by macrophages via Fc receptors (B).
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References

    1. Luzio JP, Pryor PR, Bright NA. Lysosomes: fusion and function. Nature reviews Molecular cell biology. 2007;8:622–632. - PubMed
    1. Nixon RA, Yang DS. Autophagy failure in Alzheimer’s disease--locating the primary defect. Neurobiology of disease. 2011;43:38–45. - PMC - PubMed
    1. Abeliovich A, Gitler AD. Defects in trafficking bridge Parkinson’s disease pathology and genetics. Nature. 2016;539:207–216. - PubMed
    1. Qi L, Zhang XD, Wu JC, Lin F, Wang J, DiFiglia M, Qin ZH. The role of chaperone-mediated autophagy in huntingtin degradation. PLoS One. 2012;7:e46834. - PMC - PubMed
    1. Futerman AH, van Meer G. The cell biology of lysosomal storage disorders. Nature reviews Molecular cell biology. 2004;5:554–565. - PubMed

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