Enzymes Approved for Human Therapy: Indications, Mechanisms and Adverse Effects

Abstract

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.

Biochemical, cell biological, pathological, and therapeutic aspects ofKrabbe's disease

“…Proinflammatory cytokines and chemokines produced by inflammatory cells (astrocytes, microglia, and macrophages) are also known to influence OL differentiation and myelin formation (for review see Schmitz and Chew, 2008), so PSY-associated inflammatory responses in KD may also influence OL differentiation and myelin formation. Direct impact of PSY load on neuronal survival and axonal functions and structural integrities has also been described recently Cantuti-Castelvetri et al, 2012, 2015; however, the role of PSY-induced neuronal and axonal defects in OL differentiation and myelin formation is not currently understood. Moreover, the participation of other brain-resident cells (e.g., astrocytes and microglia) and infiltrating immune GalCer is degraded to ceramide by degalactosylation by both GM1 bgal and GalCer b-gal (GALC).…”

Two-step polymer- and liposome-enzyme prodrug therapies for cancer: PDEPT and PELT concepts and future perspectives

“…At the moment, there are 20 therapies based on recombinant enzymes approved mainly for the treatment of rare diseases [22]. The problems in enzyme administration, such as immunogenicity, difficulty in targeting and unsatisfactory pharmacokinetics [23], have led to the development of delivery systems to enable their in vivo biological therapeutic activity.…”

Nonsense Suppression as an Approach to Treat Lysosomal Storage Diseases

“…For example, significant success has been achieved with developing enzyme replacement therapies (ERT) for LSDs [165]. These treatments have led to significant improvements in the disease phenotypes and have increased the lifespan of patients.…”

“…It is likely that this combination approach may also be required to treat LSDs, particularly in tissues such as the brain and the bone, which are resistant to current therapies. In order to restore a therapeutic level of protein function among recalcitrant tissues, nonsense suppression therapy and/or NMD inhibition may be viable options to complement other LSD treatment options, including: enzyme replacement therapy, the exogenous administration of purified recombinant enzyme [165]; substrate reduction therapy, which utilizes molecules that reduce the synthesis of the accumulation substrate [169]; and chaperone therapy, which uses compounds to stabilize misfolded, but functional, proteins [170]. With the continued development of more effective drugs, nonsense suppression therapy, alone or in combination with other therapeutic approaches, is likely to be a future treatment option for LSDs, as well as other genetic disorders, in patients who harbor nonsense mutations.…”