Abstract
Therapeutic enzymes are administered for the treatment of a wide variety of diseases. They exert their effects through binding with a high affinity and specificity to disease-causing substrates to catalyze their conversion to a non-noxious product, to induce an advantageous physiological change. However, the metabolic and clinical efficacies of parenterally or intramuscularly administered therapeutic enzymes are very often limited by short circulatory half-lives and hypersensitive and immunogenic reactions. Over the past five decades, the erythrocyte carrier has been extensively studied as a strategy for overcoming these limitations and increasing therapeutic efficacy. This review examines the rationale for the different therapeutic strategies that have been applied to erythrocyte-mediated enzyme therapy. These strategies include their application as circulating bioreactors, targeting the monocyte–macrophage system, the coupling of enzymes to the surface of the erythrocyte and the engineering of CD34+ hematopoietic precursor cells for the expression of therapeutic enzymes. An overview of the diverse biomedical applications for which they have been investigated is also provided, including the detoxification of exogenous chemicals, thrombolytic therapy, enzyme replacement therapy for metabolic diseases and antitumor therapy.
Highlights
Therapeutic enzymes are biocatalyst drugs that bind to target substrates with a high affinity and specificity, catalyzing their conversion into their relevant products
The application of the erythrocyte carrier as an alcohol detoxifier was first proposed by Magnani et al They demonstrated that mice administered acetaldehyde dehydrogenase-loaded erythrocytes intraperitoneally had 35% less blood acetaldehyde compared to controls, one hour after receiving an acute dose of ethanol [19]
More recent studies examining the clinical efficacy of erythrocyte-loaded recombinant Anabaena variabilis phenylalanine ammonia lyase (rAvPAL) in the early treatment of the BTBR Pahenu2 mouse demonstrated a normalized of blood and brain phenylalanine concentrations and prevented cognitive developmental failure, depletion of brain serotonin, dendritic spine abnormalities and myelin basic protein reduction [90]
Summary
Therapeutic enzymes are biocatalyst drugs that bind to target substrates with a high affinity and specificity, catalyzing their conversion into their relevant products. Erythrocyte encapsulated paraoxonase, in combination with the classic antidotal combination, provided the highest antidotal efficacy ever reported against any chemical toxicant [18] Another category of detoxifying enzymes that have been investigated are those associated with the metabolism of ethanol and methanol. In vivo studies in mice receiving acute doses of ethanol and treated with co-encapsulated enzymes showed blood ethanol to be eliminated at rates of 1.7 mmol/L to 4 mmol/L loaded erythrocytes/hour [21,22]. The in vitro and in vivo mouse studies of Bustos et al showed that it was possible to correct the defective δ-aminolevulinic acid dehydratase activity in erythrocytes by encapsulating exogenous human enzyme, providing a rationale for this approach for treating lead intoxication [28,29]. The co-encapsulation of FAD with hydrogenase was shown to overcome this [31]
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