Enzyme Replacement Therapy

2018 ◽  
pp. 1-22
Author(s):  
Abderrezak Khelfi
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Lysosomal Storage ◽  
Enzyme Preparations ◽  
Enzyme Replacement ◽  
Therapeutic Uses ◽  
Enzyme Defects ◽  
Biological Sources ◽  
Therapeutic Enzymes ◽  
Deficiency Diseases

Enzyme replacement therapy is a therapeutic approach in which the specific enzyme that is absent or inactive in affected individuals is replaced with a functional enzyme molecule derived from biological sources or produced by biotechnology. A large number and variety of enzyme defects have been identified in humans. Over 40 hereditary deficiency diseases were reported. The common feature is that enzyme deficiency leads to the accumulation of undegraded molecules and lysosomal storage, resulting in organ dysfunction. Crude enzyme preparations are often unsuitable for therapeutic uses because of their potential contamination and antigenicity. Advances in gene identification and cloning led to the subsequent production and demonstration of equal efficacy of recombinant human enzyme. The adverse events recorded range from boxed warnings for severe allergic reactions. This chapter summarizes therapeutic enzymes used in clinical practice, with particular reference to those obtained from biological sources and biotechnology processes.

Enzyme Replacement Therapy for Genetic Disorders Associated with Enzyme Deficiency

2021 ◽  
Vol 28 ◽  
Author(s):  
Marialaura Marchetti ◽  
Serena Faggiano ◽  
Andrea Mozzarelli
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Rare Diseases ◽  
Mammalian Cells ◽  
Metabolic Diseases ◽  
Genetic Disorders ◽  
Life Quality ◽  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
Enzyme Replacement

: Mutations in human genes might lead to loss of functional proteins, causing diseases. Among these genetic disorders, a large class is associated with the deficiency in metabolic enzymes, resulting in both an increase in the concentration of substrates and a loss in the metabolites produced by the catalyzed reactions. The identification of therapeutic actions based on small molecules represents a challenge to medicinal chemists because the target is missing. Alternative approaches are biology-based, ranging from gene and stem cell therapy, CRISPR/Cas9 technology, distinct types of RNAs, and enzyme replacement therapy (ERT). This review will focus on the latter approach that since the 1990s has been successfully applied to cure many rare diseases, most of them being lysosomal storage diseases or metabolic diseases. So far, a dozen enzymes have been approved by FDA/EMA for lysosome storage disorders and only a few for metabolic diseases. Enzymes for replacement therapy are mainly produced in mammalian cells and some in plant cells and yeasts and are further processed to obtain active, highly bioavailable, less degradable products. Issues still under investigation for the increase in ERT efficacy are the optimization of enzymes interaction with cell membrane and internalization, the reduction in immunogenicity, and the overcoming of blood-brain barrier limitations when neuronal cells need to be targeted. Overall, ERT has demonstrated its efficacy and safety in the treatment of many genetic rare diseases, both saving newborn lives and improving patients’ life quality, and represents a very successful example of targeted biologics.

Management of hypersensitivity reactions to enzyme replacement therapy in children with lysosomal storage diseases

2020 ◽  
Vol 125 (4) ◽  
pp. 460-467
Author(s):  
Irem Turgay Yagmur ◽  
Ozlem Unal Uzun ◽  
Aynur Kucukcongar Yavas ◽  
Ilknur Kulhas Celik ◽  
Muge Toyran ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Lysosomal Storage Diseases ◽  
Hypersensitivity Reactions ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Enzyme Replacement

scholarly journals Toward Engineering the Mannose 6-Phosphate Elaboration Pathway in Plants for Enzyme Replacement Therapy of Lysosomal Storage Disorders

2019 ◽  
Vol 8 (12) ◽  
pp. 2190
Author(s):  
Ying Zeng ◽  
Xu He ◽  
Tatyana Danyukova ◽  
Sandra Pohl ◽  
Allison R. Kermode
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Substantial Reduction ◽  
Cost Effective ◽  
Biologically Active ◽  
Lysosomal Storage ◽  
In Planta ◽  
Enzyme Replacement ◽  
Mannose 6 Phosphate ◽  
Mps I

Mucopolysaccharidosis (MPS) I is a severe lysosomal storage disease caused by α-L-iduronidase (IDUA) deficiency, which results in accumulation of non-degraded glycosaminoglycans in lysosomes. Costly enzyme replacement therapy (ERT) is the conventional treatment for MPS I. Toward producing a more cost-effective and safe alternative to the commercial mammalian cell-based production systems, we have produced recombinant human IDUA in seeds of an Arabidopsis mutant to generate the enzyme in a biologically active and non-immunogenic form containing predominantly high mannose N-linked glycans. Recombinant enzyme in ERT is generally thought to require a mannose 6-phosphate (M6P) targeting signal for endocytosis into patient cells and for intracellular delivery to the lysosome. Toward effecting in planta phosphorylation, the human M6P elaboration machinery was successfully co-expressed along with the recombinant human IDUA using a single multi-gene construct. Uptake studies using purified putative M6P-IDUA generated in planta on cultured MPS I primary fibroblasts indicated that the endocytosed recombinant lysosomal enzyme led to substantial reduction of glycosaminoglycans. However, the efficiency of the putative M6P-IDUA in reducing glycosaminoglycan storage was comparable with the efficiency of the purified plant mannose-terminated IDUA, suggesting a poor in planta M6P-elaboration by the expressed machinery. Although the in planta M6P-tagging process efficiency would need to be improved, an exciting outcome of our work was that the plant-derived mannose-terminated IDUA yielded results comparable to those obtained with the commercial IDUA (Aldurazyme® (Sanofi, Paris, France)), and a significant amount of the plant-IDUA is trafficked by a M6P receptor-independent pathway. Thus, a plant-based platform for generating lysosomal hydrolases may represent an alternative and cost-effective strategy to the conventional ERT, without the requirement for additional processing to create the M6P motif.

Sign in / Sign up

Export Citation Format

Share Document