Enzyme reconstitution/replacement therapy for lysosomal storage diseases.

Division of Human Genetics, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, USA.
Current Opinion in Pediatrics (Impact Factor: 2.74). 01/2008; 19(6):628-35. DOI: 10.1097/MOP.0b013e3282f161f2
Source: PubMed

ABSTRACT Over the past 15 years, the lysosomal storage diseases have become paradigms for the specific treatment of monogenic disorders, particularly those affecting children. This review summarizes the phenotypes and recent literature regarding enzyme reconstitution (replacement) therapy and outcomes for such treatable lysosomal storage diseases: Gaucher disease, Fabry disease, Pompe disease and the mucopolysaccharidoses.
Recent clinical trials have shown that enzyme reconstitution therapy effectively treats many of the manifestations of the lysosomal storage diseases. When initiated early in the disease course, enzyme reconstitution therapy can reverse some disease manifestations, but may not completely alleviate the disease progression. Enzyme reconstitution therapy is generally well tolerated. Many adverse events are antibody-related, but can be managed without requiring cessation of enzyme reconstitution therapy. Documented IgE reactions, i.e. anaphylactoid, are quite rare (fewer than 1%).
Enzyme reconstitution therapy is a safe and effective treatment modality available for several of the lysosomal storage diseases. Owing to the short history of enzyme reconstitution therapy, the long-term outcomes of enzyme reconstitution therapy-treated individuals are unknown and require further investigation. Medical professionals must learn to identify patients likely to benefit from these life-changing therapies so as to prevent many of the devastating, irreversible complications of the lysosomal storage diseases.

  • [Show abstract] [Hide abstract]
    ABSTRACT: La Enfermedad de Fabry (EF) constituye una alteración hereditaria del metabolismo de los glicoesfingolípidos, debida a la deficiencia parcial o completa de la enzima alfa-galactosidasa A. Es una enfermedad de transmisión genética ligada a X, que afecta universalmente a todas las etnias humanas con una incidencia comunicada de 1 cada 100.000 nacimientos, aunque es probable que esta cifra subestime la real prevalencia de la enfermedad, especialmente por el gran número de casos no diagnosticados. La EF se manifiesta en su forma más florida, en varones homocigotas que carecen completamente de actividad alfa-galactosidasa A, provocando una miríada de alteraciones, incluyendo anomalías renales (proteinuria progresiva e insuficiencia renal), cardiovasculares (cardiopatías, arritmias, accidentes cerebrovasculares), neurológicas (dolor acral y abdominal), y cocleo-vestibulares, entre las más importantes. Sin embargo, la afectación cutánea constituye la alteración más específica de la enfermedad y es en general, la que conduce a la sospecha diagnóstica. La EF no tratada reduce francamente la expectativa de vida de acuerdo a la severidad de la afectación renal y cardiovascular, si bien la terapia con reemplazo enzimático puede modificar e incluso detener el curso de la enfermedad. En 2010, una paciente de 28 años oriunda de la Provincia de Santa Fe, consultó porangioqueratomas, que condujeron al diagnóstico de enfermedad de Fabry. Desde entonces hemos estudiado y tratado a toda la familia, con ocho casos confirmados a la fecha y otros tantos en evaluación.
    Revista argentina de dermatología. 12/2011; 92(4):18-45.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypophosphatasia (HPP) is an inborn error of metabolism caused by deficiency of the tissue-nonspecific alkaline phosphatase (TNSALP), resulting in a defect of bone mineralization. Natural substrates for this ectoenzyme accumulate extracellulary including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5-phosphate (PLP), a co-factor form of vitamin B6. Enzyme replacement therapy (ERT) for HPP by functional TNSALP is one of the therapeutic options. The C-terminal-anchorless human recombinant TNSALP derived from Chinese hamster ovary cell lines was purified. TNSALP-null mice (Akp2 (-/-) ), an infantile model of HPP, were treated from birth using TNSALP and vitamin B6 diet. Long-term efficacy studies of ERT consisted of every 3 days subcutaneous or intravenous injections till 28 days old (dose 20 U/g) and subsequently every 3 days intravenous injections for 6 months (dose 10 U/g). We assessed therapeutic effect by growth and survival rates, fertility, skeletal manifestations, and radiographic and pathological finding. Treated Akp2 (-/-) mice grew normally till 4 weeks and appeared well with a minimum skeletal abnormality as well as absence of epilepsy, compared with untreated mice which died by 3 weeks old. The prognosis of TNSALP-treated Akp2 (-/-) mice was improved substantially: 1) prolonged life span over 6 months, 2) improvement of the growth, and 3) normal fertility. After 6 months of treatment, we found moderate hypomineralization with abnormal proliferative chondrocytes in growth plate and articular cartilage. In conclusion, ERT with human native TNSALP improves substantial clinical manifestations in Akp2 (-/-) mice, suggesting that ERT with anchorless TNSALP is also a potential therapy for HPP.
    Journal of Inherited Metabolic Disease 08/2013; 37(2). · 4.14 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked, recessive, lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase. Early bone involvement leads to decreased growth velocity and short stature in nearly all patients. Our analysis aimed to investigate the effects of enzyme replacement therapy (ERT) with idursulfase (Elaprase) on growth in young patients with mucopolysaccharidosis type II. Analysis of longitudinal anthropometric data of MPS II patients (group 1, n = 13) who started ERT before 6 years of age (range from 3 months to 6 years, mean 3.6 years, median 4 years) was performed and then compared with retrospective analysis of data for MPS II patients naïve to ERT (group 2, n = 50). Patients in group 1 received intravenous idursulfase at a standard dose of 0.58 mg/kg weekly for 52-288 weeks. The course of average growth curve for group 1 was very similar to growth pattern in group 2. The average value of body height in subsequent years in group 1 was a little greater than in group 2, however, the difference was not statistically significant. In studied patients with MPS II, idursulfase did not appear to alter the growth patterns.
    PLoS ONE 01/2014; 9(1):e85074. · 3.53 Impact Factor