Enzymes approved for human therapy: indications, mechanisms and adverse effects

Research and drug developments fostered under orphan drug product development programs have greatly assisted the introduction of efficient and safe enzyme-based therapies for a range of rare disorders. The introduction and regulatory approval of 20 different recombinant enzymes has enabled, often for the first time, effective enzyme-replacement therapy for some lysosomal storage disorders, including Gaucher (imiglucerase, taliglucerase, and velaglucerase), Fabry (agalsidase alfa and beta), and Pompe (alglucosidase alfa) diseases and mucopolysaccharidoses I (laronidase), II (idursulfase), IVA (elosulfase), and VI (galsulfase). Approved recombinant enzymes are also now used as therapy for myocardial infarction (alteplase, reteplase, and tenecteplase), cystic fibrosis (dornase alfa), chronic gout (pegloticase), tumor lysis syndrome (rasburicase), leukemia (L-asparaginase), some collagen-based disorders such as Dupuytren's contracture (collagenase), severe combined immunodeficiency disease (pegademase bovine), detoxification of methotrexate (glucarpidase), and vitreomacular adhesion (ocriplasmin). The development of these efficacious and safe enzyme-based therapies has occurred hand in hand with some remarkable advances in the preparation of the often specifically designed recombinant enzymes; the manufacturing expertise necessary for commercial production; our understanding of underlying mechanisms operative in the different diseases; and the mechanisms of action of the relevant recombinant enzymes. Together with information on these mechanisms, safety findings recorded so far on the various adverse events and problems of immunogenicity of the recombinant enzymes used for therapy are presented.